Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Here, we report biodegradable temperature-triggered covalent gelation systems exhibiting a longer and controllable duration time of the gel state by a "mixing strategy" utilizing a thiol-ene reaction. We synthesized a tri-block copolymer of poly(caprolactone-co-glycolic acid) and PEG (tri-PCG) as a temperature-responsive injectable polymer (IP) and attached acryloyl groups on both termini (tri-PCG-Acryl). A tri-PCG micelle solution containing hydrophobic hexa-functional polythiol (Solution-A) and a tri-PCG-Acryl micelle solution (Solution-B) were mixed together. After mixing, the solution was still in the sol state at r.t., but exhibited an irreversible sol-to-gel transition in response to temperature. The duration time of the gel state while soaking in PBS could be altered from 1 day to 93 days by changing the mixing ratio of Solution-A/B. The physical strengths of the hydrogels were also controllable by changing the mixing ratio. The IP system showed good biocompatibility and a long duration time of the gel state after subcutaneous implantation.

DOI： 10.1039/c7bm00357a

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Biodegradable injectable polymer (IP) systems exhibiting temperature-responsive sol-to-gel transitions between room temperature and body temperature have the potential for use in biomedical applications. However, gelation of such IP systems is a reversible process through physical cross-linking, and the hydrogels thus formed are likely to revert to the sol state under highly wet conditions after injection. In this study, a biodegradable IP system exhibiting temperature responsive irreversible sol-to-gel transition by covalent bond formation was developed by simple mixing of polymers. A triblock copolymer of poly(caprolactone-co-glycolic acid) and poly(ethylene glycol) (tri-PCG) and tri-PCG with attached succinimide ester groups at both termini (tri-PCG-SA-OSu) were prepared and mixed together with a water-soluble polyamine (typically poly-L-lysine). The obtained IP formulation was in the sol state after mixing, but exhibited a rapid sol-to-gel transition within 30 s upon increasing the temperature to 37 degrees C. Once formed, the hydrogel did not revert to the sol state, even after cooling to 4 degrees C, because of the formation of covalent bonds upon transition. The obtained hydrogel soaked in phosphate buffered saline (PBS) exhibited a significantly longer duration time of the gel state. This IP system exhibiting a rapid and irreversible sol-to-gel transition is convenient for medical professionals and possesses great potential for use in biomedical devices for clinical applications such as drug delivery systems and antiadhesive materials.

DOI： 10.1021/acsbiomaterials.6b00581

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：AMER CHEMICAL SOC  

Poly(ethylene glycol) (PEG) is widely used as a biomedical material because it possesses the highest level of biocompatibility among synthetic polymers. However, PEG is water-soluble and non-biodegradable. To provide biodegradable water-insoluble bulk materials possessing the biocompatibility of PEG, water-insoluble poly(ether-ester)s were synthesized by thiol-ene polyaddition of poly(ethylene glycol) diacrylates (PEGDA) and alkyl dithiols (ADTs). Among them, P(PEG-DDT) prepared from PEGDA and decanedithiol (DDT) film cast on a glass substrate possessed temperature-responsive changes only when immersed in water. The P(PEG-DDT) film was transparent in a water bath at 0 degrees C, but become opaque after subsequent soaking in a hot water bath at 40-70 degrees C. The mechanism was examined by measuring transmittance changes in response to temperature, differential colorimetry, and air contact angle of the film in water. Water-insoluble poly(ether-ester)s exhibiting temperature-responsiveness have potential, not only as new bulk-state biomaterials with PEG-like biocompatibility but also as new environmentally friendly temperature-responsive materials.

DOI： 10.1021/bk-2017-1253.ch005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Aqueous solutions of biodegradable polymers exhibiting sol-to-gel transitions in response to external stimuli such as temperature and pH are expected to be used as injectable polymers (IPs) for biomedical applications. In this study, we prepared novel biodegradable temperature-responsive IP systems providing variable gel-forming pH regions. We synthesized PCGA-b-PEG-b-PCGA (tri-PCG) and attached carboxylic acid or primary amine groups on both termini, tri-PCG-COOH and tri-PCG-NH 2, and investigated the temperature-responsive sol-to-gel transition behavior of the mixtures of these two copolymers at various pHs. We found that the gel-forming pH region of the mixed system could be easily controlled by simply changing the mixing ratios of these polymers.

DOI： 10.1080/09205063.2017.1304170

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

On clinical application of biodegradable injectable polymer (IP) systems, quick extemporaneous preparation of IP formulations and longer duration time gel state after injection into the body are the important targets to be developed. Previously, we had reported temperature-responsive covalent gelation systems via bio-orthogonal thiol-ene reaction by mixing strategy' of amphiphilic biodegradable tri-block copolymer (tri-PCG) attaching acryloyl groups on both termini (tri-PCG-Acryl) with reactive polythiol. In other previous works, we found freeze-dry with PEG/dispersion' method as quick extemporaneous preparation method of biodegradable IP formulations. In this study, we applied this quick preparative method to the temperature-triggered covalent gelation system. The instant formulation (D-sample) could be prepared by freeze-dry with PEG/dispersion' just mixing of tri-PCG-Acryl micelle dispersion and tri-PCG/DPMP micelle dispersion with PEG, that can be prepared in 30s from the dried samples. The obtained D-sample showed irreversible gelation and long duration time of gel state, which was basically the same as the formulations prepared by the usual heating dissolution method (S-sample). Interestingly, the D-sample could maintain its sol state for a longer time (24h) after preparing the formulation at r.t. compared with the S-sample, which became a gel in 3h after preparing. The IP system showed good biocompatibility and long duration time of the gel state after subcutaneous implantation. These characteristics of D-samples, quick extemporaneous preparation and high stability in the sol state before injection, would be very convenient in a clinical setting.

DOI： 10.1080/09205063.2017.1330114

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

A box-shaped' three-dimensional (3D) DNA origami of similar to 40-nm dimensions was selectively formed by closing a symmetric open motif with three orthogonal faces. This 3D DNA origami was used as an intelligent nano-container to encapsulate exactly one 10-nm gold nanoparticle (AuNP). AuNPs were functionalized with thiol-modified DNA strands and attached to one of the faces of the open motif, which was designed to be an interior surface of the box and decorated with three complementary strands. The open motif was then closed into the box shape as triggered by the addition of DNA strands joining the remaining edges. An examination of the suitable folding path of an M13 scaffold using fluorescently labeled staple strands revealed that the flexibility at the hinge was essential for the efficient closing of the DNA origami container. Atomic force microscope and transmission electron microscope imaging of agarose-gel-purified complexes clearly showed the successful encapsulation of one AuNP inside the shell.

DOI： 10.1038/pj.2014.128

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

We propose a macromolecular prodrug strategy of an injectable polymer (IP) system for continuous and sustained release of water-soluble low-molecular-weight drugs. A biodegradable graft copolymer-type IP covalently immobilizing model drugs via hydrolyzable ester bonds was synthesized through the coupling reaction of poly(depsipeptide-co-dl-lactide), P(DG-dl-LA), having reactive carboxylic acid side-chain groups with the amino derivative of a model drug (levofloxacin [LEV]) and monomethoxy-poly(ethylene glycol) (PEG). The solution of the obtained graft copolymer-type IP/model drug conjugate exhibited a temperature-responsive sol-to-gel transition between room temperature and body temperature in phosphate buffer solution, similar to P(GD-dl-LA)-g-PEG without LEV. The immobilization of the LEV molecule onto P(DG-dl-LA)-g-PEG did not have a significant influence on the sol-to-gel transition behavior, physical properties, or in vitro degradation rates of the hydrogels. The in vitro release of LEV derivatives from the P(DG-dl-LA)-g-PEG/LEV hydrogel in phosphate buffer solution was continuous for 11weeks, which corresponded to the degradation period of the hydrogel, and slower than that from the control hydrogels prepared from P(DG-dl-LA)-g-PEG and PLGA-b-PEG-b-PLGA that physically entrapped LEV molecules. These results suggest that the covalent attachment strategy is effective in achieving sustained release of low-molecular-weight drugs in IP systems and can be applied to drug delivery devices for highly bioactive drugs. Copyright (c) 2014 John Wiley & Sons, Ltd.

DOI： 10.1002/pat.3265

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/pj.2014.30

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Biodegradable films and sponges of poly(depsipeptide-co-lactide)s with two reactive side-chain groups, poly[(Glc-Asp)-co-LA] and poly[(Glc-Lys)-co-LA], were prepared with entrapped growth factors (bFGF, EGF, and NGF) or models for these growth factors (lysozyme, insulin and lactoferrin) based on their physicochemical similarities. These films and sponges were prepared to evaluate the potential utility of these copolymers as biodegradable scaffolds for tissue engineering. Sustained release of the model proteins from the biodegradable matrices was observed. The cell growth rates on the growth factor-loaded matrices were higher than on those without growth factors and were at the same level as with the addition of native growth factors. The effective differentiation of PC12 cells into nerve-like cells were observed on NGF-loaded copolymer film. These results indicate that the released growth factors maintained their activity and that these copolymers would be good candidates for scaffolds for tissue engineering. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.reactfunctpolym.2014.04.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI PUBLISHING CORPORATION  

We synthesized series of amphiphilic AB-type block copolymers having systematic variation in the core-forming segments using poly(lactide-co-depsipeptide)s as a hydrophobic segment and prepared polymeric micelles using the block copolymers, PEG-b-poly(lactide-co-depsipeptide). We then discussed the relationship between the core-forming segment structure and drug loading efficiency for the polymeric micelles. PEG-b-poly(lactide-co-depsipeptide) s, PEG-b-PLGL containing L-leucine (Leu), and PEG-b-PLGF containing L-phenylalanine (Phe), with similar molecular weights and various mole fractions of depsipeptide units, were synthesized. Polymeric micelles entrapping model drug (fluorescein, FL) were prepared using these copolymers. As a result, PEG-b-poly(lactide-co-depsipeptide) micelles showed higher drug loading compared with PEG-b-PLLA and PEG-b-PDLLA as controls. The drug loading increased with increase in the mole fraction of depsipeptide unit in the hydrophobic segments. The introduction of aliphatic and aromatic depsipeptide units was effective to achieve higher FL loading into the micelles. PEG-b-PLGL micelle showed higher drug loading than PEG-b-PLGF micelle when the amount of FL in feed was high. These results obtained in this study should be useful for strategic design of polymeric micelle-type drug delivery carrier with high drug loading efficiency.

DOI： 10.1155/2014/579212

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Injectable biodegradable copolymer hydrogels, which exhibit temperature-responsive sol-to-gel transition, have recently drawn much attention as promising biomedical materials such as drug delivery, cell implantation, and tissue engineering. These injectable hydrogels can be implanted in the human body with minimal surgical invasion. Temperature-responsive gelling copolymers usually possess block- and/or branched architectures and amphiphilicity with a delicate hydrophobic/hydrophilic balance. Poly(ethylene glycol) (PEG) has typically been used as hydrophilic segments due to its biocompatibility and temperature-dependent dehydration nature. Aliphatic polyesters such as polylactide, poly(lactide-co-glycolide), poly(epsilon-caprolactone), and their modified copolymers have been used as hydrophobic segments based on their biodegradability and biocompatibility. Copolymers of PEG with other hydrophobic polymers such as polypeptides, polydepsipeptides have also been recently reported as injectable hydrogels. In this review, brief history and recent advances in injectable biodegradable polymer hydrogels are summarized especially focusing on the relationship between polymer architecture and their gelation properties. Moreover, the applications of these injectable polymer gels for biomedical use such as drug delivery and tissue engineering are also described. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.reactfunctpolym.2012.11.003

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：AMER CHEMICAL SOC  

Polymeric micelle is one of the most fascinating nanoparticles formed by self-assemblies of block copolymers as vehicles for drug delivery system. The therapeutic effects of polymeric micelles carrying antitumor agents in cancer chemotherapy are derived from the results of their localization at tumor sites by EPR (enhanced permeability and retention) effect. To achieve efficient drug delivery to tumor site, stealth character and stability of the polymeric micelles in blood stream are very important. Cross-linking in core or shell of polymeric micelles with covalent bonds has been carried out to achieve stabilization of polymeric micelles. However, covalent cross-linking has some drawbacks, such as toxicity, loss of biodegradability etc. Although electrostatic interactions (including ionic bonds and coordination bonds with metal ion) are weaker than covalent bonds, there may be some advantages such as reversibility, degradability and low toxicity. In this review, recent studies on the stabilization of polymeric micelles by electrostatic interactions including coordination bonds are introduced.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

We report (i) synthesis of novel graft copolymers of a alpha-CD/PEG polyrotaxane (PRX) backbone and enantiomeric PLA side chains, PRX-g-PLLA and PRX-g-PDLA, (ii) selective stereocomplex formation on a movable PRX in the bulk state, and (iii) preparation of soft materials with continuous anisotropic phases by blending of the L- and D-isomers.

DOI： 10.1039/c3py21055c

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

DOI： 10.1002/smll.201200092

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Water-swellable biodegradable materials exhibiting mechanically tenacious and tough characters in the wet state were prepared by a simple blend of two enantiomeric polylactide-grafted dextran copolymers (Dex-g-PLLA and Dex-g-PDLA). DSC and WAXD analyses demonstrated the formation of SC crystals in the copolymer blend films. SC blend films showed lamellar-type microphase-separated structures. When swollen with water, these blend films showed the same level of tensile strengths and Young's modulus as the films in the dry state. SC blend films degraded gradually over a month under physiological conditions with a degradation rate faster than the corresponding Dex-g-PLLA films. The SC-forming enantiomeric mixture of polylactide-grafted polysaccharides should be a good candidate for an implantable biocompatible material exhibiting favorable mechanical properties and degradation behavior. (C) 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 50: 2669-2676, 2012

DOI： 10.1002/pola.26044

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Language：English   Publishing type：Part of collection (book)   Publisher：SPRINGER-VERLAG BERLIN  

Recently, self-assembled systems using biodegradable polymers at the nanometer scale, such as microspheres, nanospheres, polymer micelles, nanogels, and polymersomes, have attracted much attention especially in biomedical fields. To construct such self-assembled systems, it is extremely important to have precise control of intermolecular noncovalent interactions, such as hydrophobic interactions based on their amphiphilic molecular structures. Biodegradable polymers, especially aliphatic polyesters such as polylactide, polyglycolide, poly(epsilon-caplolactone) and their copolymers, have been used as biomedical materials for a long time. This chapter is mainly focused on aliphatic polyesters and related polymers, and reviews the synthetic methods for amphiphilic biodegradable polymers containing aliphatic polyesters as components. Moreover, the application of various types of self-assembly systems using amphiphilic biodegradable copolymers such as micro- or nanosized particles (microspheres, nanospheres, polymer micelles, nanogels, polymersomes), supramolecular physically interlocked systems, and stimuli-responsive systems for biomedical use such as drug delivery systems are also reviewed.

DOI： 10.1007/12_2011_160

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Polymeric micelles, as drug delivery vehicles, must achieve specific targeting and high stability in the body for efficient drug delivery. We recently reported the preparation of polyanion-coated biodegradable polymeric micelles by coating positively charged polymeric micelles consisting of poly(L-lysine)-block-poly(L-lactide) (PLys-b-PLLA) AB diblock copolymers with anionic hyaluronic acid (HA) by polyion complex (PIC) formation. The obtained HA-coated micelles showed significantly higher stability in aqueous solution. In this study, to evaluate the HA-coated polymeric micelles as a drug carrier, model drug release from the micelles and cytotoxicity of the micelles were investigated. The HA-coated micelles showed sustained release of model drugs and low cytotoxicity. It is known that there are receptors for HA on liver sinusoidal endothelial cells (LSEC). Specific interactions of HA-coated micelles with LSECs and Kupffer cells were investigated and compared with polymeric micelles coated with other polyanionic polysaccharides, i.e., heparin (Hep) and carboxymethyl-dextran (CMDex). Although Hep-coated micelles and CMDex-coated micelles were incorporated into both Kupffer cells and LSECs, HA-coated micelles were taken up only into LSECs. These results suggest HA-coated micelles have potential utility as drug delivery vehicles exhibiting specific accumulation into LSECs. (C) 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jconrel.2010.11.008

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ijpharm.2024.123801

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DOI： 10.3390/gels10020139

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Topological gels possess structures that are cross‐linked only via physical constraints; ideally, no attractive intermolecular interactions act between their components, which yields interesting physical properties. However, most reported previous topological gels were synthesized based on supramolecular interlocked structures such as polyrotaxane, for which attractive intermolecular interactions are essential. Here, we synthesize a water‐soluble “molecular net” (MN) with a large molecular weight and three‐dimensional network structure using poly(ethylene glycol). When a water‐soluble monomer (N‐isopropylacrylamide) is polymerized in the presence of the MNs, the extending polymer chains penetrates the MNs to form an ideal topological MN gel with no specific attractive interactions between its components. The MN gels show unique physical properties as well a significantly high degree of swelling and high extensibility due to slipping of the physical cross‐linking. We postulate this method to yield a new paradigm in gel science with unprecedented physical properties.

DOI： 10.1002/anie.202317045

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Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acsbiomaterials.3c00327

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

An aqueous polymer solution exhibiting a temperature-responsive sol-to-gel transition shows great potential as an injectable polymer (IP) system for biomedical materials. Block copolymers composed of biodegradable aliphatic polyesters and poly(ethylene glycol) (PEG) are known for their applications in medical devices. Their neat morphology and temperature responsiveness depend on their molecular structures, such as their main-chain architectures (linear or branched), block sequences, molecular weights, lengths of hydrophobic and hydrophilic segments, randomness of the hydrophobic copolymer segment, and terminal structures. However, systematic studies on the effects of these parameters have not yet been conducted. In this study, we synthesized ABA triblock, BAB triblock, and 4-arm branched block copolymers consisting of PEG as the hydrophilic segment and poly(epsilon-caprolactone-co-glycolic acid) as the hydrophobic segment with varying segment lengths, amounts of monomer (epsilon-caprolactone/glycolic acid) in the copolymer, and degrees of terminal modification. Their neat morphology and temperature-responsive transition behavior were analyzed. The obtained results provide molecular design guidelines for preparing biodegradable IPs that exhibit a powdery solid morphology and target-temperature gelation properties and offer the possibility of functionalization by terminal modification.

DOI： 10.1039/d2py01574a

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Adipose-derived stem cells (AdSCs), a type of mesenchymal stem cell, are expected to be applicable to regenerative medicine and cellular delivery systems. The maintenance of cell multipotency and control of the differentiation direction are important for these applications. However, the differentiation direction of these cells is widely believed to depend on the physical properties of their scaffold. In this study, we explored whether the multipotency of AdSCs, that is, their ability to differentiate into multiple cells, is maintained when they are removed from injectable polymer (IP) hydrogels with various degrees of cross-linking and induced to differentiate into osteoblasts and adipocytes. We confirmed that AdSCs cultured in IP hydrogels maintained an undifferentiated state. However, their differentiation into osteoblasts and adipocytes cannot be ensured; specifically, the multipotency of AdSCs may decrease when they are cultured in IP hydrogels. When cultured in an IP hydrogel with extreme softness and poor cell adhesion properties, the AdSCs remained in an undifferentiated state, but their multipotency was reduced. These results provide important insights into stem cell delivery systems using IP hydrogels.

DOI： 10.1038/s41428-022-00739-4

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Other Link： https://www.nature.com/articles/s41428-022-00739-4

Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

Hyaluronic acid (HA)-coated biodegradable polymeric micelles were developed as nanoparticulate vaccine delivery systems to establish an effective nasal vaccine.

DOI： 10.1039/d1bm01985f

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

Biodegradable double network (DN) gels with remarkably high mechanical strength and toughness were synthesised. The biodegradable DN gels can be potentially applied in biomedical applications such as cartilage regeneration.

DOI： 10.1039/d2py00360k

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.actbio.2021.08.033

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A promising approach for the regeneration of tissues or organs with three-dimensional hierarchical structures is the preparation of scaffold-cell complexes that mimic these hierarchical structures. This requires an effective technique for immobilizing cell-specific ligands at arbitrarily chosen positions on matrices. Here, we report a versatile system for arranging cell-specific ligands onto desired compartments of biodegradable matrices for site-selective cell arrangement. We utilized the specific binding abilities of specific DNAs, immobilizing them as tags to arrange cell-recognition ligands at desired areas of the matrices by specific binding with cell-recognition ligand-DNA conjugates. We synthesized poly(L-lactide) (PLLA), a biodegradable polymer, with an oligo-DNA (trimer of deoxyguanosine: dG(3)) attached via a poly(ethylene glycol) (PEG) spacer to generate dG(3)-PEG-b-PLLA. The peptides Arg-Gly-Asp-Ser (RGDS) and Arg-Glu-Asp-Val (REDV) were chosen as cell-recognition ligands and were attached to an adapter DNA (aDNA), which can specifically bind to the dG(3) moiety through G-quadruplex formation. The obtained dG(3)-PEG-b-PLLA was deposited on a small spot of the PLLA film, and the aDNA RGDS or aDNA REDV conjugate was added on the film to immobilize these ligands at the spot. We confirmed the specific adhesion of L929 cells (a mouse fibroblast cell line) and human umbilical vein endothelial cells (HUVECs) on the small areas coated with dG(3)-PEG-b-PLLA in the presence of aDNA-RGDS and aDNA-REDV, respectively, even after applying shear stress by flowing medium across the spot. Cell-specific attachment of the target cells was effectively achieved in a spatially controlled manner. This technique has the potential for the construction of cell-scaffold complexes that mimic the hierarchical structures of natural organs and may represent a breakthrough in realizing regenerative medicine and tissue engineering of complex organs.

DOI： 10.1021/acs.biomac.0c00814

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Language：English   Publishing type：Research paper (scientific journal)  

Early-stage hemocompatibility is indispensable for manufacturing tissue-engineered vascular grafts used in regenerative medicine. In this study, we report the in vivo blood response and patency of small-diameter synthetic vascular grafts modified with the Arg-Glu-Asp-Val (REDV) peptide. Vascular grafts were prepared by casting REDV-conjugated poly(depsipeptide-co-caprolactone) on a stainless-steel mandril (diameter: 1.8 mm). After implanting the grafts into the abdominal aorta of rats for 24 h, all three control grafts without the peptide and three out of the four REDV (control sequence) peptide-modified grafts showed occlusion. The luminal surfaces of these grafts were covered with thick thrombi. In contrast, all the grafts containing the REDV peptide were patent, and their luminal surfaces were covered with a thin layer of fibrin. These results indicated that the REDV peptide on the luminal surface effectively reduced early-stage fibrin clot deposition and formed the pseudo-endothelium layer in a peptide sequence-specific manner, resulting in graft patency.

DOI： 10.1021/acs.biomac.0c00457

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/pcr2.10094

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/pcr2.10094

Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

© 2019 Elsevier Ltd Thermal properties and degradation of enantiomeric random copolyesteramides poly(L-lactic acid-co-L-alanine) [P(LLA-LAL)] and poly(D-lactic acid-co-D-alanine) [P(DLA-DAL)] copolymers with wide alanine unit content ranges from 0 to 21 and 22 mol% were investigated by differential scanning calorimetry and themogravimetry. The total enthalpy of cold crystallization enthalpy and melting enthalpy as an indicator of crystallinity decreased with a decrease in lactic acid unit content or an increase in alanine unit content. Equilibrium melting temperature values of α-form homo-crystallites for the unblended samples decreased with an increase in alanine unit content (157.3–179.6 °C) and those of δ-form homo-crystallites for the unblended L100 and D100 (190.7 and 185.1 °C) were much higher than the reported values (both 172.8 °C, Polymer 2017, 9, 625). Thermal stability was enhanced by enantiomeric polymer blending, although thermal degradation was accelerated by incorporated alanine units. The activation energy for thermal degradation (ΔEtd) of the blend samples decreased with an increase in alanine unit content, whereas that of the unblended samples showed complicated dependence on alanine unit content and became maximum at alanine unit contents of 21 and 22 mol%. The blend samples had higher ΔEtd values comparted to those of the unblended samples, except for the alanine unit contents of 21 and 22 mol%. The reason for the high ΔEtd values of the unblended samples compared with that of the blend sample at the alanine unit contents of 21 and 22 mol% is discussed.

DOI： 10.1016/j.polymdegradstab.2019.109047

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© 2020 Wiley Periodicals, Inc. Because acellular vascular xenografts induce an immunological reaction through macrophage infiltration, they are conventionally crosslinked with glutaraldehyde (GA). However, the GA crosslinking reaction inhibits not only the host immune reaction around the graft but also the graft's enzymatic degradability, which is one of the key characteristics of acellular grafts that allow them to be replaced by host tissue. In this study, we used an 8-arm polyethylene glycol (PEG) to successfully suppress macrophage infiltration, without eliminating graft degradation. Decellularized ostrich carotid arteries were modified with GA or N-hydroxysuccinimide-activated 8-arm PEG (8-arm PEG-NHS), which has a molecular weight of 17 kDa. To evaluate the enzymatic degradation in vitro, the graft was immersed in a collagenase solution for 12 hr. The 8-arm PEG-modified graft was degraded to the same extent as the unmodified graft, but the GA-modified graft was not degraded. The graft was transplanted into rat subcutaneous tissue for up to 8 weeks. Although CD68-positive cells accumulated in the unmodified graft, they did not infiltrate into either modified graft. However, the GA-modified grafts calcified, but the 8-arm PEG-modified graft did not calcify after transplantation. These data suggested that 8-arm PEG-NHS is a promising modification agent for biodegradable vascular xenografts, to suppress acute macrophage infiltration only.

DOI： 10.1002/jbm.a.36960

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DOI： 10.3390/polym11101607

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DOI： 10.3390/polym11101607

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

DNA has been well-known for its applications in programmable self-assembly of materials. Nonetheless, utility of DNA origami, which offers more opportunity to realize complicated operations, has been very limited. Here we report self-assembly of a biomolecular motor system, microtubule-kinesin mediated by DNA origami nanostructures. We demonstrate that a rodlike DNA origami motif facilitates self-assembly of microtubules into asters. A smooth-muscle like molecular contraction system has also been realized using the DNA origami in which self-assembled microtubules exhibited fast and dynamic contraction in the presence of kinesins through an energy dissipative process. This work provides potential nanotechnological applications of DNA and biomolecular motor proteins.

DOI： 10.1021/acs.nanolett.9b01201

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DOI： 10.1149/2.0441909jes

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Publishing type：Research paper (scientific journal)   Publisher：The Electrochemical Society  

DOI： 10.1149/MA2018-03/1/89

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Publishing type：Research paper (scientific journal)   Publisher：The Electrochemical Society  

DOI： 10.1149/MA2018-03/1/94

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society  

A new pH-responsive hydrogel biomaterial, that is composed of solely two popular biocompatible materials, oligodeoxynucleotides (ODN) and polyethylene glycol (PEG) have been prepared. Merely five deoxycytidine residues were elongated to the ends of linear or 4-arm PEG in ×1000 larger scale than conventional systems by using liquid-phase DNA synthesis technique, and applied them as a macromonomer for the preparation of hydrogels. The syntheses of the conjugates are simply elongating ODN onto the ends of PEG as a semisolid phase substrate using standard phosphoramidite chemistry. The resulting dC5-PEG conjugates gave quite stable and stiff hydrogels triggered by the formation of a unique DNA quadruplex, i-motif. Introduction of only one chemical linkage between two linear conjugates resulted in unexpectedly high thermal stabilities for the melting temperatures of i-motifs themselves. Nonlinearly improved rheological properties compared to the original linear conjugates were also observed, probably because of topological entanglement between macromonomers of fused circles.

DOI： 10.1021/acsmacrolett.8b00063

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

A new class of hydrogels utilizing DNA (DNA quadruplex gel) has been constructed by directly and symmetrically coupling deoxynucleotide phosphoramidite monomers to the ends of polyethylene glycols (PEGs) in liquid phase, and using the resulting DNA-PEG-DNA triblock copolymers as macromonomers. Elongation of merely four deoxyguanosine residues on PEG, which produces typically approximate to 10grams of desired DNA-PEG conjugates in one synthesis, resulted in intelligent and biodegradable hydrogels utilizing DNA quadruplex formation, which are responsive to various input signals such as Na+, K+, and complementary DNA strand. Gelation of DNA quadruplex gels takes place within a few seconds upon the addition of a trigger, enabling free formation just like Ca+-alginate hydrogels or possible application as an injectable polymer (IP) gel. The obtained hydrogels show good thermal stability and rheological properties, and even display self-healing ability.

DOI： 10.1002/asia.201701066

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry  

Significant enhancement of single-molecular binding to a miRNA target and bidentate and asymmetric conjugation of two distinct thiolated DNA strands to single gold nanoparticles (AuNPs) were visibly demonstrated, by introducing two groups of ligands into our nanomechanical DNA origami devices (DNA pliers) to construct allosterically controllable systems.

DOI： 10.1039/c7cc03991c

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PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Ethylene glycol (EG) and succinic anhydride (SA)-based 2-armed PLLA and PDLA correspondingly with tail-to-tail (T-T) and head-to-head (H-H) architectures, together with SA-based linear 2-armed stereo diblock copolymer, were synthesized and the SC crystallization and homo-crystallization behavior of blends of 2-armed PLLA and PDLA with various combinations of molecular architectures, together with that of neat polymers, were investigated. The crystallizability was higher for SC crystalline samples than for homo-crystalline samples during solvent evaporation and slow cooling from the melt. The hydrogen bonds of hydroxyl terminals and/or low molecular weight of EG-based polymer rather than specific chain directional architecture or its combination disturbed and delayed the crystallization, lowering the crystallization temperature (T-c), crystalline], the reciprocal of experimental crystallization half time [1/t(c)(1/2) (exp)], spherulite growth rate (G), enthalpy of crystallization (Delta(Hc)) for 1st cooling, and total enthalpy of cold crystallization and melting [Delta H(tot)] for 2nd heating of both SC crystalline and homocrystalline samples, the melting temperature (T-m) for 1st and 2nd heating, nucleus density and the degree of lamella orientation of spherulites of SC crystalline samples. The opposite chain directional architectures of polymers in blends should have increased Delta H(tot) for 1st heating, Delta H-c for 1st cooling, Delta H(tot) for 2nd heating, and G of SC crystalline samples. The effects of hydrogen bonds of hydroxyl terminal groups, M-n (or M-n per one arm or block), and chain directional combination were determined by the crystallization temperature range and the presence or absence of a solvent. The Tm values of SC crystalline samples were determined by M-n (or M-n per one arm or block), whereas those of homocrystalline samples did not show clear dependence on M-n (or M-n per one arm or block) values per one arm, hydroxyl terminal groups (hydrogen bonding), or chain direction. The intermolecular SC crystallization in the enantiomeric polymer blends was favored compared with intramolecular SC crystallization in the stereo diblock copolymer. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.polymer.2016.04.049

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media {SA}  

DOI： 10.3389/conf.fbioe.2016.01.01123

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media {SA}  

DOI： 10.3389/conf.fbioe.2016.01.01115

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Bottom-up fabrication techniques are expected to alleviate the limitations of top-down fabrication. Bottom-up fabrication requires self-assembling facilities to construct complex structures including DNA nanostructures, DNA robots, further molecular robots, and so on. DNA origami is one of buttom-up fabrication techniques. In this paper, we focus on the automatic recognition of flexible DNA origami named "DNA pliers" in AFM (atomic force microscopy) image. Auto recognition of DNA pliers is challenging and necessary since DNA pliers can have several forms: parallel, cross, and anti-parallel forms, depending on hinge angles. Our method uses the information of the curvature scale space method and convexity-concavity detection extracted from DNA pliers. The experiments show that the combination of the curvature scale space method and convexity-concavity detection can work well for DNA pliers recognition if appropriate contour information for the DNA pliers is available from an AFM image.

DOI： 10.1007/s00354-015-0305-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Single-molecule pH sensors have been developed by utilizing molecular imaging of pH-responsive shape transition of nanomechanical DNA origami devices with atomic force microscopy (AFM). Short DNA fragments that can form i-motifs were introduced to nanomechanical DNA origami devices with pliers-like shape (DNA Origami Pliers), which consist of two levers of 170-nm long and 20-nm wide connected at a Holliday-junction fulcrum. DNA Origami Pliers can be observed as in three distinct forms; cross, antiparallel and parallel forms, and cross form is the dominant species when no additional interaction is introduced to DNA Origami Pliers. Introduction of nine pairs of 12-mer sequence (5'-AACCCCAACCCC-3'), which dimerize into i-motif quadruplexes upon protonation of cytosine, drives transition of DNA Origami Pliers from open cross form into closed parallel form under acidic conditions. Such pH-dependent transition was clearly imaged on mica in molecular resolution by AFM, showing potential application of the system to single-molecular pH sensors.

DOI： 10.3390/s141019329

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Precise structure switching between all of the three forms of three-state nanomechanical DNA origami devices has been accomplished. A nanomechanical DNA origami device called DNA origami pliers, which consists of two levers of 170-nm long, 20-nm wide, and 2-nm thick connected at a Holliday-junction fulcrum, takes three conformations: closed parallel, closed antiparallel, and open cross forms. They were previously applied to construct detection systems for biomolecules in single-molecular resolution by observing the structure switching between cross form and one of the other two forms under atomic force microscope (AFM). We redesigned DNA origami pliers in this study to let them freely switch between all of the three states including parallel-antiparallel direct switching without taking cross form. By the addition of appropriate switcher strands to the solution, hybridization and dehybridization of particular binder strands that fix the levers into predetermined state were selectively triggered as programmed in their sequence. Circuit structure switching through all of the three states in both of the two opposite direction was even successful with the new design. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ymeth.2013.11.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MYU, SCIENTIFIC PUBLISHING DIVISION  

According to our previous research, it was found that the assemblies of poly(vinyl alcohol) (PVA) and DNA, such as nanoparticles, microparticles and hydrogels, were formed through a high hydrostatic pressure process (10000 atm, 10 min) and could be applicable for gene delivery. In the present study, the PVA-DNA assembly was characterized by various methods, such as agarose gel electrophoresis, melting point and circular dichroism measurements, atomic force microscopy (AFM) observation and nuclease digestion assay. From agarose gel electrophoresis and melting point measurement of the PVA-DNA assembly, it was clarified that the interaction between them was hydrogen bonding. The B-type form of DNA of the PVA-DNA assembly was shown by circular dichroism measurement. The increase in width of DNA in the PVA-DNA assembly was observed by AFM. The increase in nuclease resistance of the PVA-DNA assembly was shown. From these results, it was suggested that the PVA was entwined with the DNA duplex via hydrogen bonds under high hydrostatic pressure.

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Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：TRANS TECH PUBLICATIONS LTD  

Starburst triblock copolymers consisting of 8-arm poly(ethylene glycol) (8-arm PEG), poly(L-lactide) (PLLA) or its enantiomer poly(D-lactide) (PDLA) and terminal PEG, 8-arm PEG-b-PLLA-b-PEG (Stri-L) and 8-arm PEG-b- PDLA-b-PEG (Stri-D), were synthesized. An aqueous solution of a 1:1 mixture (Stri-Mix) of Stri-L and Stri-D assumed a sol state at room temperature, but instantaneously formed a physically cross-linked hydrogel in response to increasing temperature. The resulting hydrogel exhibited a high storage modulus at 37 degrees C. The rapid temperature-triggered hydrogel formation, high mechanical strength, and degradation behavior render this polymer system suitable for use in injectable drug delivery system or a biodegradable scaffold for tissue engineering.

DOI： 10.4028/www.scientific.net/AST.86.9

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/smll.201290085

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Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

J-GLOBAL

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Invasive binding event of PNA into DNA duplex was clearly observed both by atomic force microscope (AFM) imaging and electrophoretic mobility shift assay (EMSA) with the aid of nanomechanical DNA origami devices as 'single-molecule' visual probes, showing their potential as universal platform for the analysis of PNA invasion.

DOI： 10.1039/c2cc36358e

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Language：English   Publishing type：Research paper (international conference proceedings)  

We propose versatile sensing systems for a variety of chemical and biological targets at molecular resolution. We have designed functional nanomechanical DNA origami devices that can be used as "single-molecule beacons", which consist of two levers approximately 170 nm long connected at a fulcrum. Various single-molecule inorganic/organic targets ranging from metal ions to proteins as well as a unique binding event of a nucleic acid analogue can be visually detected on AFM by a shape transition of the origami devices. © 2012 IEEE.

DOI： 10.1109/NEMS.2012.6196783

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Language：Japanese  

CiNii Books

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：VSP BV  

A series of amphiphilic 8-arm PEG-b-PLLA co-polymers with star-shaped structure was synthesized through ring-opening polymerization of L-lactide (L-LA) in the presence of 8-arm PEG as a macroinitiator by varying feeding molar rations of L-LA to 8-arm PEG. 8-arm PEG-b-PLLA co-polymers having certain PEG content and PEG length were found to self-assemble into nano-aggregates in aqueous solutions. The size and the morphology of the nano-aggregates were investigated by dynamic light scattering and (1)H-NMR in CDCl(3) and D(2)O. The results indicate that the average diameter was ca. 150 nm, the surface of the nano-aggregates was covered by PEG chains and the PLLA cores formed by hydrophobic interaction are located inside of the nano-aggregates. FITC-dextran molecules, as model for water-soluble macromolecular drugs, were successfully encapsulated into 8-arm PEG-b-PLLA nano-aggregates by simple addition of FITC-dextran to the aqueous phase during the self-assembly process. This result suggests that the nano-aggregates have a vesicle-like morphology. The nano-aggregates dissociated gradually in the order of weeks in PBS (pH 7.4, ionic strength 140 mM) at 37 degrees C. Thus, the novel nano-aggregates of 8-arm PEG-b-PLLA can be expected to have advantages, such as long circulation times, as drug carriers which show sustained release of loaded macromolecular drugs such as antibodies and DNA vaccines in the blood stream. (c) Koninklijke Brill NV, Leiden, 2011

DOI： 10.1163/092050610X521586

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

A simple and conventional method to isolate gold nanoparticle (GNP)/oligo-DNA conjugates having defined number of oligo-DNAs by gel electrophoresis was developed using extension oligo-DNAs Formation of self-organized assemblies of GNPs in two different sizes using the conjugates having one or two complementary oligo-DNAs was demonstrated. This method to prepare GNP/oligo-DNA conjugates with controlled number of DNA strands should be useful to build up functional nanoarrays of GNPs on DNA scaffolds

DOI： 10.1246/cl.2010.1084

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Positively charged core/shell type polymer micelles were prepared from a biodegradable amphiphilic block copolymer, poly(L-lysine)-block-poly(L-lactide). Polyanion-coated biodegradable polymer micelles were then prepared via polyion complex (PIC) formation with poly-anionic hyaluronic acid (HA) on the positively charged micelles. Characterization of the acquired HA-coated micelles was carried out via dynamic light scattering, atomic force microscopic observation and zeta-potential measurements. The HA-coated micelles exhibited extremely high stability against dilution and colloidal stability. The PIC-coated micelle system with high stability would be a useful drug delivery vehicle able to survive long-term circulation in the bloodstream.

DOI： 10.1002/macp.201000167

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

An amphiphilic polyrotaxane (PRX) composed of biodegradable triblock copolymer of poly(ethylene glycol) (PEG) and poly(L-lactide) (PLLA), PLLA PEG PLLA, and many alpha-cyclodextrins (alpha-CD) threaded on the triblock copolymer was successfully synthesized. The PRX was found to be self-assembled into vesicle-like water-soluble nanoaggregates in an aqueous solution.

DOI： 10.1246/cl.2010.250

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

A biodegradable graft copolymer (CD-g-PLLA) composed of alpha-cyclodextrin (alpha-CD) and poly(L-lactide) (PLLA) was synthesized by the ring-opening polymerization of L-LA using mostly trimethylsilylated (alpha-CD (TMS-alpha-CD) as an initiator. TEM measurements of the CD-g-PLLA film showed a nanoscale lamellar-type microphase-separated structure in the most of the film. In contrast, an irregular phase-separated structure was observed in the TMS-CD-g-PLLA film, suggesting that the hydroxyl groups in CD-g-PLLA governed the formation of the lamellar structure, likely because of their important roles in intra- and/or intermolecular hydrogen bonding. The CD-g-PLLA film was mechanically tenacious but soft, and it showed reduced PLLA crystallinity, high transparency, and accelerated hydrolytic degradation. The CD-g-PLLA film served as a host for various dye compounds based on specific host-guest interactions of the alpha-CDs. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.reactfunctpolym.2009.09.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Biodegradable copolymers consisting of a hydrophilic poly[L-aspartic acid-alt-poly(ethylene glycol)] (poly(L-Asp-alt-PEG)) backbone and hydrophobic capryl units as side chains were synthesized. The amphiphilic copolymer wits found to form nanosized hydrogel particles (nanogels) of approximately 15 nm in size by self-assembly at 20 degrees C in aqueous media, and the nanogel solutions displayed phase-transition in response to temperature. The transition of the nanogel solution wits reversible and tunable in the range from 19 to 55 degrees C by variation of the amounts of capryl units introduced and the solution concentration. The nanogels were gradually degraded within days in a phosphate buffer solution (PBS) at 37 degrees C. Temperature-responsive biodegradable nanogel systems consisting of biocompatible PEG may have potential utility for high biocompatibility temperature-responsive nanodevices such as microreactor systems, molecular-chaperones, and drug delivery vehicles.

DOI： 10.1021/la901092x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Biodegradable polyrotaxanes (PRXs) were synthesized from bis-amitio-terminated poly(L-lactide) (PLLA) and alpha-cyclodextrin (alpha-CD), combined with capping by bulky end groups at the amino-termini of PLLA through enzymatically cleavable peptide linkages. The crystalline structure of the PRXs in the solid state was investigated by wide-angle X-ray diffraction (WAXRD), and the results suggested that PRX forms a column-type crystalline structure. Hydrolysis of ester bonds of the PLLA in PRX was prevented due to the supramolecular structure. However, in the presence of a protease (papain), the hydrolysis of PLLA in PRX was induced. The removal of the bulky end groups by the protease acted as a trigger for the release of alpha-CD and allowed hydrolysis of the PLLA ester bonds. Such unique hydrolysis behavior, that is, proteinase-triggered degradation of a polyester, was achieved by the combination of the supramolecular architecture, biodegradable PLLA, and enzymatically cleavable end groups.

DOI： 10.1021/bm900440v

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

To develop new types of biodegradable polymers possessing predictable responses to changes in temperature, ABA-type and BAB-type triblock copolymers composed of various polydepsipeptides (PDP) and poly(ethylene glycol) (PEG) (PDP-PEG-PDP and PEG-PDP-PEG) were synthesized. The specific focus of this study was on the effect of the different side-chain groups of various amino acids on the temperature-responsive behavior of the triblock copolymers. An ABA-type triblock copolymer containing the less hydrophobic glycine (PGG-PEG-PGG) did not exhibit any temperature-responsive behavior; however, ABA-type triblock copolymers containing the hydrophobic alpha-amino acids, L-leucine and L-phenylalanine (PGL-PEG-PGL or PGF-PEG-PGF), did exhibit temperature-responsive behavior. The cloud point of PGF-PEG-PGF was 10 degrees C lower than that of PGL-PEG-PGL. It can be possible to control temperature-sensitivity by changing not only PDP segment length but also kind of alpha-amino acid in PDP segment. Moreover, BAB-type triblock copolymer containing L-leucine (PEG-PGL-PEG) showed temperature-responsive sol-gel transition. Because polydepsipeptides are biodegradable polymers, the information obtained in this study is useful to design biodegradable injectable polymers having controllable temperature-sensitivity for biomedical use. (C) 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3892-3903, 2009

DOI： 10.1002/pola.23456

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

A series of biodegradable graft copolymers composed of poly(ethylene glycol) side-chains and a poly(depsipeptide-co-DL-lactide) backbone (PDG-DL-LA-g-PEG) were prepared as a novel thermo-gelling system. An aqueous solution of PDG-DL-LA-g-PEG (20 wt%) with a certain PEG length and composition showed instantaneous temperature-sensitive gelation at 33 degrees C. The sol-gel transition temperature (T(gel)) Could be controlled from 33 to 51 degrees C by varying the PEG length and compositions without a decrease in mechanical strength of the hydrogels. The 20 wt% hydrogel was eroded gradually in PBS at 37 degrees C for 60 days. This research provides a molecular design approach to create biodegradable thermo-gelling polymers with controllable T(gel) and mechanical toughness. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.polymer.2009.05.045

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Biodegradable shape-memory polymer networks prepared by cross-linking star shape branched oligo(epsilon-caprolactone) (bOCL) with hexamethylene diisocyanate are introduced. The thermal and mechanical properties of these networks were investigated using differential scanning calorimetry and tensile testing, respectively, and the morphology of the phase structure was characterized by polarized optical microscopy. The shape-memory properties of the networks were quantified using thermomechanical tensile experiments and showed strain fixity rates R(f) higher than 97% and strain recovery rates R(r) as high as 100%. Of note, networks of OCL segments with a lower degree of polymerization (DP; 10) exhibited significantly improved temperature-sensitive shape recovery: 90% of the permanent shape was recovered upon heating to within a 2 degrees C range (37-39 degrees C). The networks exhibited complete shape recovery to the permanent shape within 10 s at 42 degrees C. Theophylline-loaded (10 and 20 wt %) shape-memory materials, prepared by cross-linking bOCL with hexamethylene diisocyanate in the presence of theophylline, are also described as a model for a controlled drug release device. The 10 wt % loaded material was sufficiently soft and flexible for complex shape transformation and also showed high R(f) (98%) and R(r) (99%). Sustained release of loaded theophylline was achieved over 1 month without initial burst-release in a phosphate buffer solution (PBS; pH 7.4) at 37 degrees C.

DOI： 10.1021/bm9002078

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SCIENTIFIC PUBLISHERS  

Oligonucleotides, especially oligo-DNAs, are useful building blocks for construction nanometer scale ordered architectures. Many researchers have been carried out to construct nano-architectures using complementary hydrogen bonding of DNAs. However, in order to achieve rational and robust design of various functional nano-architectures using DNAs, it is extremely important to establish basic principles of assembly patterns Of oligo-DNAs based on their complementarity. In this study, to obtain basic information of polyassembly for simple oligo-DNA systems, formation of multiple assemblies of complementary half-sliding oligo-DNAs (cHSOs) was investigated with varying the length and sequence (GC content). A pairs of cHSOs were mixed in combination of complementary each other, and then the formation of high-molecular-weight polyassembly was evaluated by polyacrylamide gel electrophoresis (PAGE) and size exclusion chromatography (SEC). Moreover, the morphology and shape of the polyassembly was investigated by atomic force microscope (AFM) observation on mica. The obtained polyassembly displayed linear and networked morphology, and the continuous length and patterns of the assembly was depend on the length, GC contents and the concentration of the cHSOs.

DOI： 10.1166/jnn.2009.J028

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SCIENTIFIC PUBLISHERS  

Oligonucleotides, especially oligo-DNAs, are useful building blocks for construction nanometer scale ordered architectures. Many researchers have been carried out to construct nano-architectures using complementary hydrogen bonding of DNAs. However, in order to achieve rational and robust design of various functional nano-architectures using DNAs, it is extremely important to establish basic principles of assembly patterns Of oligo-DNAs based on their complementarity. In this study, to obtain basic information of polyassembly for simple oligo-DNA systems, formation of multiple assemblies of complementary half-sliding oligo-DNAs (cHSOs) was investigated with varying the length and sequence (GC content). A pairs of cHSOs were mixed in combination of complementary each other, and then the formation of high-molecular-weight polyassembly was evaluated by polyacrylamide gel electrophoresis (PAGE) and size exclusion chromatography (SEC). Moreover, the morphology and shape of the polyassembly was investigated by atomic force microscope (AFM) observation on mica. The obtained polyassembly displayed linear and networked morphology, and the continuous length and patterns of the assembly was depend on the length, GC contents and the concentration of the cHSOs.

DOI： 10.1166/jnn.2009.J028

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Language：English   Publishing type：Research paper (international conference proceedings)  

Thermo-gelling biodegradable polymers with a sol-gel transition point (Tgel) between room temperature and body temperature are expected to be useful for injectable polymer systems in biomedical applications such as drug delivery depot and scaffold for tissue engineering. In this study, a series of biodegradable graft-copolymers composed of PEG side-chains and a poly(depsipeptide-co-DL-lactide) backbone (PDG-DL-LA-g-PEG) were prepared as a novel thermo-gelling system. An aqueous solution of the copolymer showed instantaneous temperature-sensitive gelation at 33°C. The Tgel could be controlled from 33 to 51°C by varying the PEG length and compositions without a decrease in mechanical strength of the hydrogels. This research provides a molecular design approach to creating biodegradable thermo-gelling polymers with controllable Tgel and mechanical toughness. ©2009 IEEE.

DOI： 10.1109/MHS.2009.5351825

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

DNA is one of the best candidates as building blocks for bottom-up approach to nanometre size architecture in nanotechnology. In natural photosynthetic system, the arrangement of porphyrin derivatives with regulated distances, orders and orientations provides an efficient photon-energy collecting and transmission. We have studied about chromophore arrangement on DNA assembly as a simple artificial model of photosynthetic and photo-energy transmission systems. In order to prepare DNAs containing porphyrin residues at desired sites, a hydrophilic porphyrin amidite derivative, which can be utilised on automatic DNA synthesizer, was synthesised. The porphyrin amidite derivative was applied for automatic DNA synthesizer to give single-strand DNA (ssDNA) containing porphyrin set in the chain. The obtained ssDNA was mixed with complementary counter strand having another chromophore black hole quencher-3 (BHQ-3) to form duplex by self-assembly. The quenching behaviour by energy transfer from the porphyrin to BHQ-3 was monitored by fluorescence measurement.

DOI： 10.1080/10610270802468462

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

We showed previously that poly(L-lactide)-grafted dextran could form biodegradable nanogels in water. In this paper, various properties of Dex-g-PLLA nanogels were compared with Dex-Chol (dextran-cholesterol conjugate) nanogels to investigate the effects of hydrophobic units. Dex-g-PLLA nanogels exhibited significantly lower CAC and higher colloidal stability, indicating a strong tendency to form nanogels. We prepared lysozyme-loaded Dex-g-PLLA nanogels, and they exhibited a sustained release of lysozyme for 1 week without denaturation in PBS at 37 degrees C. The Dex-g-PLLA nanogels therefore have great potential as a delivery vehicle for therapeutic protein.

DOI： 10.1002/mabi.200800175

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

Starburst triblock copolymers consisting of 8-arm poly(ethylene glycol) (8-arm PEG) and biodegradable poly(L-lactide) (PLLA) or its enantiomer poly(D-lactide) (PDLA), 8-arm PEG-b-PLLA-b-PEG (Stri-L), and 8-arm PEG-b-PDLA-b-PEG (Stri-D) were synthesized. An aqueous solution of a 1:1 mixture (Stri-Mix) of Stri-L and Stri-D assumed a so] state at room temperature, but instantaneously formed a physically crosslinked hydrogel in response to increasing temperature. The resulting hydrogel exhibited a high-storage modulus (9.8 kPa) at 37 degrees C. Interestingly, once formed at the transition temperature, the hydrogel was stable even after cooling below the transition temperature. The hydrogel formation process was irreversible because of the formation of stable stereocomplexes. In aqueous solution, gradual hydrolytic erosion was observed because of degradation of the hydrogel. The combination of rapid temperature-triggered irreversible hydrogel formation, high-mechanical strength, and degradation behavior render this polymer mixture system suitable for use in injectable biomedical materials, for example, as a drug delivery system for bioactive reagents or a biodegradable scaffold for tissue engineering. (C) 2008 Wiley Periodicals, Inc.

DOI： 10.1002/pola.22943

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Partially cholesterol-substituted 8-arm poly(ethylene glycol)-block-poly(L-lactide) (8-arm PEG-b-PLLA-cholesterol) has been prepared as a novel star-shaped, biodegradable copolymer derivative. The amphiphilic 8-arm PEG-b-PLLA-cholesterol aqueous solution (polymer concentration, above 3 wt%) exhibits instantaneous temperature-induced gelation at 34 degrees C, but the virgin 8-arm PEG-b-PLLA does not, irrespective of concentration. Moreover, an extracellular matrix (ECM)-like micrometer-scale network structure has been created with favorable porosity for three-dimensional proliferation of cells inside the hydrogel. This network structure is mainly attributed to specific self-assembly between cholesterol groups. The 10 and 20wt% hydrogels are eroded gradually in phosphate buffered saline at 37 degrees C over the course of a month, and after that the gel becomes completely dissociated. Moreover, L929 cells encapsulated into the hydrogel are viable and proliferate three-dimensionally inside the hydrogels. Thus, in-vitro cell culture studies demonstrate that 8-arm PEG-b-PLLA-cholesterol is a promising candidate as a novel injectable cellular scaffold.

DOI： 10.1002/adfm.200700587

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：SPIE-INT SOC OPTICAL ENGINEERING  

DNA is one of the best candidates as building blocks for bottom-up approach to nanometer size architecture in nanotechnology. In natural photosynthetic system, the arrangement of porphyrin derivative with regulated distances, orders and orientations provide ail efficient photon-energy collecting and transmittion. Sequential arrangement of chromophore (dye molecule) should therefore be a good model of artificial photosynthetic and photo-energy transmission systems. Sequential arrangements of three kinds of chromophores separated by regulated distances equaling approximately one pitch of the DNA duplex (3.4 nm) in non-covalent molecular assembly systems are constructed using chromophore/oligo-DNA conjugates. Vectorial photo-energy transmission along the DNA helix axis by fluorescence resonance energy transfer (FRET) in a sequential chromophore array was observed by fluorescence spectra measurements and analyzed by time-resolved fluorescence spectroscopy measurements using a femtosecond pulse laser system.

DOI： 10.1117/12.801489

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Language：English   Publishing type：Research paper (international conference proceedings)  

Starburst triblock copolymers consisting of 8-arm polyethylene glycol) (8-arm PEG), poly(L-lactide) (PLLA) or its enantiomer poly(D-lactide) (PDLA) and terminal PEG, 8-arm PEG-b-PLLA-b-PEG (Stri-L) and 8-arm PEG-Z-b-PDLA-b-PEG (Stri-D), were synthesized. An aqueous solution of a 1:1 mixture (Stri-Mix) of Stri-L and Stri-D assumed a sol state at room temperature, but instantaneously formed a physically cross-linked hydrogel in response to increasing temperature. The resulting hydrogel exhibited a high storage modulus at 37 °C. The rapid temperature-triggered hydrogel formation, high mechanical strength, and degradation behavior render this polymer system suitable for use in injectable drug delivery system or a biodegradable scaffold for tissue engineering. © 2008 IEEE.

DOI： 10.1109/MHS.2008.4752497

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Language：English   Publishing type：Research paper (scientific journal)  

Biodegradable polymers, which can be degraded into non-toxic elements, metabolized, absorbed and excreted, are utilized as drug carriers and depots in drug delivery systems. They are frequently used in injectable formulations such as soluble nanoparticles, microspheres, and gelling system. In this chapter, we focus on polylactide and the copolymers as popular biodegradable polymers, and the developments of drug delivery system by hybridization of polylactides with some hydrophilic polymers are introduced. © 2008, THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM. All rights reserved.

DOI： 10.2745/dds.23.618

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Cholesterol side-functionalized poly(depsipeptide-co-DL-lactide) (PGD-DL-LA-(cholesterol)(n)) and poly(depsipeptide) (PGD-(cholesterol)(n)) were prepared as novel biodegradable liquid crystalline (LC) polymers. These polymer films exhibited different LC phases depending on the cholesterol unit content in the polymers. The thermodynamic stability of these LC phases was quite high, and PGD-(cholesterol)(n) film exhibited continuous LC phases up to 202 degrees C. The resulting cholesterol LC phases were indicated to act as physical cross-linking points to form noncovalent network structures among the polymer chains. Therefore, PGD-DL-LA-(cholesterol)(n) film exhibited a rubbery and stretchy nature at 37 degrees C due to physical cross-linking points based on cholesterol LC phase well-dispersed in the film. The cholesterol side-group effects leading to rubbery character and hydrolytic resistance reported herein are rather unique. The biodegradable LC material exhibiting a soft and tenacious nature is a promising candidate for a new class of implant biomaterials used with dynamic organs of the body such as the heart and blood vessels.

DOI： 10.1021/bm700921h

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Monodisperse stereocomplex nanogels were obtained through the self-assembly of an equimolar mixture of dextran-graft-poly(L-lactide) (Dex-g-PLLA) and dextran-graft-poly(D-lactide) (Dex-g-PDLA) amphiphilic copolymers with well-defined composition in a dilute aqueous solution. The stereocomplex nanogel possessed partially crystallized cores of hydrophobic polylactide (PLA) and the hydrophilic dextran skeleton by intra- and/or intermolecular self-assembly between PLLA and PDLA chains. The stereocomplex nanogels exhibited significantly lower critical aggregation concentration (CAC) value as well as stronger thermodynamic stability compared with those of the corresponding L- or D-isomer nanogels. The mean diameter of the stereocomplex nanogels was 70 nm with narrow size distribution, implying they were well-defined and presumably nanogels. Furthermore, stereocomplex nanogel exhibited strong kinetic stability. The tunable degradation properties of Dex-g-PLA nanogels were achieved by varying the number of grafted PLA chains as well as applying stereocomplexation. This study demonstrates the advantage of stereocomplexation in the design of biodegradable nanogels with enhanced stability.

DOI： 10.1021/bm070206t

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Biodegradable stereocomplex film exhibiting soft and stretchy character was prepared by simply blending between enantiomeric 8-arms poly(ethylene glycol)-block-poly(L-lactide) (8-arms PEG-b-PLLA) and 8-arms PEG-b-PDLA copolymers with star-shaped structure. The stereocomplex film exhibited higher T-g and PLA crystallinity than those of original copolymer films. Effects of stereoregularity and stereocomplexation on protein adsorption and L929 cells attachment/proliferation behaviors onto the films were analyzed from the viewpoint to design a new class of implantable soft biomaterial. The stereocomplex film was found to exhibit large amount of protein adsorption than original films. Furthermore, cell attachment efficiency and proliferation rate on the film were significantly enhanced by stereocomplexation. This stereocomplex material is expected to be applicable as degradable temporary scaffold for soft tissue regeneration. Consequently, it was indicated that the stereocomplex formation could be proposed to be a novel method to control the protein- and cell-adhesive properties of biodegradable matrix composed of PEG-PLA copolymer. (c) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.polymer.2007.03.017

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS LTD  

Amphiphilic ABA-type triblock copolymers were synthesized to develop a biodegradable anti-adhesive membrane. In this particular synthesis, poly[L-lactide(LA)-co-depsipeptideI (poly[LA-co-(Glc-Leu)]: PLGL) was used as the A segment, and the poly(ethylene glycol)s (PEG)s, Mn = 10,000 and Mn = 20,500 were used as the B segment. The synthesis of the triblock copolymer (PLGL-PEG-PLGL) was carried out via a ring-opening copolymerization of L-lactide and cyclo(Glc-Leu) in the presence of hydroxytelechelic poly(ethylene glycol) using tin 2-ethylhexanoate as a catalyst. To evaluate the copolymer films as candidates for biodegradable anti-adhesive membranes, physicochemical properties such as degradation on behavior under physiological conditions and water absorption were investigated. The degradation rate of the PLGL-PEG-PLGL films varied with changes in the molecular architecture; specifically, the molecular weight of the hydrophilic B segment and the depsipeptide unit content in the A segment were more prominent. The biocompatibility and resorption of the PLGL-PEG-PLGL films were also evaluated. The PLGL-PEG-PLGL films were degraded and depleted gradually in vivo without inflammation.

DOI： 10.1177/0883911506070818

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

To develop novel biomedical soft materials with degradability, amphiphilic poly(L-lactide)-grafted dextrans (Dex-g-PLLAs) of relatively high sugar unit contents were synthesized with the trimethylsilyl protection method. The characteristic properties of solution-cast films prepared from the obtained Dex-g-PLLAs were investigated. The water absorption and degradation rate of the Dex-g-PLLA films increased with increasing sugar unit content. The morphology of the bulk phase and top surface of the Dex-g-PLLA films was evaluated with transmission electron microscopy and atomic force microscopy, respectively. The bulk phase of the Dex-g-PLLA films with a sugar unit content of 16-25 wt % was found by transmission electron microscopy to form a lamellar type of phase-separated structure composed of approximately 80-100-nm-wide nanodomains because of their amphiphilic and branched structures. The hydrophobic top surface for a Dex-g-PLLA film with a sugar unit content of 25 wt % covered with PLLA segments was confirmed by atomic force microscopy phase images to be easily converted to a wettable top surface covered with hydrophilic dextran aggregates showing an 8-10-nm-wide honeycomb pattern by means of annealing in water. (c) 2006 Wiley Periodicals, Inc.

DOI： 10.1002/pola.21750

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

To explore the potential of a star-shaped 8-armed poly(ethylene glycol)35K-block-poly(L-lactide)37K (8-armed PEG35K-b-PLLA37K:(M) over bar (n) of PEG = 35 000, (M) over bar (n) of PLLA = 37 000) film as a novel bioabsorbable adhesion-prevention membrane, the water structure, surface contact angle, protein adsorption, and cell and platelet anti-adhesion properties of such a hydrated film are investigated. Based on the results, it is found that the 8-armed PEG35K-b-PLLA37K film exhibits a biologically inert surface, which is the result of a large number of PEG chains and a free water layer on the film surface. This leads to a reduction in protein absorption and cell and platelet adhesion onto the film surface. This implies that the star-shaped 8-armed PEG35K-b-PLLA37K film can be utilized as a novel bioabsorbable adhesion-prevention membrane.

DOI： 10.1002/mabi.200500249

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Branched poly(lactide)(PLA)s with various lengths of graft chain were synthesized by ring-opening polymerization of L- or D-lactide (L- or DLA) in bulk. using polyglycidol as a macromitiator. The properties of polymer films of branched PLLA or PDLA obtained and their stereocomplex were investigated through thermal analysis and tensile testing. The branched PLLA or PDLA film exhibited a lower glass transition temperature (T-m), melting temperature (T-m). crystallinity, Young's modulus and a higher strain at break than the corresponding linear PLLA or PDLA film. The branched PLLA/branched PDLA stereocomplex film showed a high maximum stress and a high Young's modulus keeping its high strain at break. Moreover, the usefulness of branched PLLA or PDLA as a plasticizer of linear PLLA was investigated with 1:9 blend or stereocomplex film prepared from the branched PLLA or branched PDLA and linear PLLA. The blend or linear PLLA/branched PDLA stereocomplex film showed a higher strain at break compared with linear PLLA film. The mechanical properties of the blend or linear PLLA/branched PLLA stereocomplex film could easily be controlled by changing the molecular weight of branched PLA. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.polymer.2005.11.039

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Language：Japanese   Publisher：化学工業社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC POLYMER SCIENCE JAPAN  

Biodegradable star-shaped 8 arms PEG-b-PLLA block copolymer was synthesized to create a novel implantable soft material. The differences in physicochemical properties between star-shaped 8 arms PEG10K-b-PLLA35K film and linear 2 arms PEG10K-b-PLLA33K film having same compositions of PEG and PLLA units was investigated to reveal the architecture effects on their physicochemical properties. Thermal analysis of these copolymer films revealed that the crystallinity of PLLA in the 8 arms PEG10K-b-PLLA35K films (1.8%) was drastically low compared with that in the 2 arms PEG 10K-b-PLLA33K film (37.5%). Additionally, TEM observation of the copolymer films revealed that the larger PLLA domains (greater than 200 nm) with miscellaneous structure were formed in the 2 arms PEG10K-b-PLLA33K film while the smaller PLLA domains (80 nm) with lamellar structure were formed in the 8 arms PEG10K-b-PLLA35K film. Consequently, the 8 arms PEG10K-b-PLLA35K film showed higher swelling ability, lower tensile strength and higher elongation at break than the 2 arms PEG10K-b-PLLA33K film. Moreover, the 8 arms PEG35K-b-PLLA37K film showed higher elongation at break than the 8 arms PEG10K-b-PLLA35K film because of the fine PLLA domains with highly ordered structure. The 8 arms PEG35K-b-PLLA37K film which having the high swelling ability and desirable mechanical properties such as softness as well as tenacity was available as a novel implantable soft material.

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Publishing type：Research paper (international conference proceedings)  

The suppression of the transgene transcription caused by the carrier materials was found to be one of the biggest problems in nonviral gene transfer system. The electroporation enhances the permeability of plasma membrane and allows the polyplexes to enter into the cytosolic compartment. In this study, pEGFP-N1 was transfected into L929 cells by the electroporation using various carriers such as linear polyethylenimine (1-PEI) and stearyl-1-PEI. In order to investigate the transcription efficiency in the cells, the amount of pEGFP-N1 delivered into cells was measured by use of YOYO-1 labeling system, and the GFP expression was analyzed under the fluorescent microscope. The flow cytometer was also used for their evaluation. Stearyl-1-PEI was expected to lead to higher transcription than the 1-PEI, because the hydrophobic stearyl groups make the polyplex dissociation easy and enhanced the transcription efficiency.

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Publishing type：Research paper (international conference proceedings)  

Suppression of the transgene transcription caused by the carrier materials is one of the biggest problems in non-viral gene transfer system. However no experimental method has revealed its efficiency so far. We selected electroporation method, which enhances the permeability of plasma membrane and allows the polyplexes to enter into the cells, in order to quantify the transcription efficiency in the cells. In this study, pEGFP-N1 was transfected into L929 cells by the electroporation using various carriers such as polypeptides with different molecular weights, linear polyethylenimine (1-PEI), and stearyl-1-PEI. The amount of pEGFP-N1 delivered into cells was measured by use of YOYO-1 labeling system, and the transgene expression was evaluated by fluorescent microscopy and flow cytometer. As a result, stearyl-1-PEI was found to lead to higher transcription than the 1-PEI, suggesting that the hydrophobic stearyl groups made the polyplex dissociation easy and enhanced the transcription efficiency.

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The effect of cell-adhesion property of scaffold materials on the differentiation of mesenchymal stem cells (MSCs) was studied. Biodegrable PEG/PLLA multiblock copolymers, on which cells do not adhere due to its swelling property, was synthesized by polycondensation of PLLA, PEG, and DDA using SnO as a catalyst and subjected to the differentiation-induction experiments. The differentiation of the MSCs was monitored by real time PCR method in addition to the morphological and histological observation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Specific sequential arrangements of three kinds of chromophores separated by regulated distances equaling approximately one pitch of the DNA duplex (34 angstrom) in non-covalent molecular assembly systems are constructed using chromophore/oligo-DNA conjugates. Vectorial photoenergy transmission along the DNA helix axis by fluorescence resonance energy transfer (FRET) in a sequential chromophore array is observed and analyzed by time-resolved fluorescence spectroscopy and lifetime measurements using a femtosecond pulse laser system. The results suggest a FRET occurs on a picosecond scale between the donor chromophore and the acceptor chromophore through a mediator chromophore via a multi-step FRET over the molecular assemblies (two helical pitches, 68 angstrom).

DOI： 10.1080/10610270500054101

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

A poly(N-isopropylacrylamide) (PNIPAAm)-like biodegradable thermosensitive polydepsipeptide, poly-[Glc-Asn(N-isopropyl)], was synthesized by introducing an isopropyl amide group into poly[Glc-Asn]. Poly[Glc-Asn(N-isopropyl)] was degraded in vitro by cleavage of the ester bonds in the main chain in water at room temperature. The non-toxic nature of the polymer and its degradation products, coupled with a cloud point at 29 degrees C in water, make this polymer attractive for biomedical implant applications.

DOI： 10.1002/mabi.200400221

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：VSP BV  

To develop novel biodegradable biomedical materials, potylactide-grafted dextrans (Dex-g-PLA)s having various lengths, numbers of graft chains and sugar units were synthesized using the trimethylsilyl (TMS) protection method. To explore the possibility of using Dex-g-PLA as a biomedical soft-material, the contact angle, cell attachment and protein adsorption properties of the films prepared from these biodegradable and amphiphilic graft co-polymers were investigated. The poly-L-lactide (PLLA) film did not absorb water at all because of its high hydrophobicity, while the graft co-polymer films started immediately to swell after immersion in PBS. The percentage of water absorption at equilibrium increased with increasing sugar unit content. The receding contact angle of the Dex-g-PLA films against water was smaller than that of the PLLA film. The receding contact angle of Dex-g-PLA films against water decreased with increasing the sugar unit content. The top surface of the Dex-g-PLA film was suggested to be covered with hydrophilic Dex segments by means of annealing in water and to afford the wettable surface. Such a wettable surface led to the suppression of cell attachment and protein adsorption onto the film.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：VSP BV  

A novel hyaluronic acid (HA)-based hydrogel was prepared through polyion complex (PIC) formation between cationic polylactide (PLA)-based microspheres (MS+) and hyaluronic acid (HA(-)) as an anionic polyelectrolyte. The MS+ and HA formed a biodegradable PIC hydrogel (HA(-)/MS+) when mixed in aqueous media. The swelling behavior and mechanical properties of the PIC hydrogel could be controlled by changing the charge ratio between HA(-) and MS+. In addition, the HA(-)/MS+ PIC hydrogel resulted in a lower inflammatory response compared with a collagen hydrogel in vivo.

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We have studied the hydrogen bonding structures formed by ultra high pressure (UHP) technology because of hydrogen bonding interaction enphasized under UHP condition. Previously, we reported the formation of PVA hydrogels and PVA/DNA particles uptaken by cells. In this study, we studied that the formation of PVA/DNA hydrogels using UHP technology and DNA release from that. Various PVA/DNA hydogels were formed at different PVA concentration by UHP treatement (Fig). With lower PVA cone., fast release of DNA were observed, but slow DNA release were achieved using higher PVA conc.. These results incidated the application fo PVA/DNA hydrogels for gene delivery.

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Publishing type：Research paper (international conference proceedings)  

In order to form inorganic particles/polymers composites, nano-scaled hydroxyl apatite (HAp) and polyvinyl alcohol (PVA) having various molecular weights were mixed at different concentration and treated by ultra high pressure processing. In the case of higher PVA concentration, hydro gels containing nano-HAp particles were obtained. The good cell adhesion on the hydro gel was showed. At lower PVA concentration, the particles of the nano-HAp particles/PVA composites or nano-HAp/PVA/DNA composites were formed, which also showed effective DNA delivery.

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Publishing type：Research paper (international conference proceedings)  

Polyvinyl alcohol (PVA)/DNA complexes encupslating nano-scaled hydroxyl apatite (HAp) particles were formed by ultra high pressure processing. The good dispersiveness of them was showed comparison with the nano-HAp particles/DNA complexes. Using fluorescent labeled DNA molecules, the cellular uptake of the PVA/DNA complexes encupslating nano-HAP was investigated. The intracellular distribution of them was observed by fluorescent microscope. The high transfection efficiency was achieved using PVA/DNA complexes encupslating nano-HAP, suggesting the effective DNA release from endocytosis.

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Polylysine-block-polylactide amphiphilic diblock copolymer was synthesized. Biodegradable polymeric micelles having positively charged surfaces were prepared from the obtained diblock copolymer by dialysis method. Polyplex formation behavior between plasmid DNA and the biodegradable positively charged polymeric micelles and stability of the polyplex were investigated.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Polyvinyl alcohol (PVA)-DNA nanoparticles have been developed by ultra high pressure (UHP) technology. Mixture solutions of DNA and PVA having various molecular weights (Mw) and degree of saponifications (DS) were treated under 10,000 atmospheres (981 MPa) condition at 40 degreesC for 10 min. Agarose gel electrophoresis and scanning electron microscope observation revealed that the PVA-DNA nanoparticles with average diameter of about 200 run were formed. Using PVA of higher Mw and degree of saponifications, the amount of nanoparticles formed increased. The driving force of nanoparticle formation was the hydrogen bonding between DNA and PVA. In order to apply the PVA-DNA nanoparticles for gene delivery, the cytotoxicity and the cellular uptake of them were investigated using Raw264 cell lines. The cell viability was not influenced whether the presence of the PVA-DNA nanoparticles. Further, the nanoparticles internalized into cells were observed by fluorescent microscope. These results indicates that the PVA-DNA nanoparticles prepared by UHP technology showed be useful as drug carrier, especially for gene delivery. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.msec.2004.08.046

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

Poly(L-lactide) (PLLA) with terminal primary amino groups (PLLA-NH2) was synthesized and used to construct PLLA-grafted pullulan (Pul-g-PLLA). It consisted of a hydrophilic carboxymethyl Pul (CM-Pul) main chain and hydrophobic PLLA graft chains that were created through a direct coupling reaction between PLLA-NH2 and CM-Pul using 2-ethoxy-1-(ethoxycarbonyl)-1,2-dihydroquinoline as a condensation reagent. Pul-g-PLLAs with over 78 wt % sugar unit content were found to form nanometer-sized aggregates in water. (C) 2004 Wiley Periodicals, Inc.

DOI： 10.1002/pola.20336

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Polylactide (PLA)-grafted dextran (Dex-graft-PLA) of various contents of sugar units was synthesized by anionic polymerization Of L-lactide (L-LA) using the alkoxide of partially trimethylsilylated dextran (TMSDex) and subsequently removing the trimethylsilyl (TMS) groups. The copolymer showed different solubility from L-LA homopolymer with increasing the content of sugar units. We prepared bovine serum albumin (BSA)-loaded microspheres (MS)s according to a water-in-oil-in-water emulsion-solvent evaporation/extraction method using methylene chloride/DMSO as an organic cosolvent. MSs prepared from Dex-graft-PLA [MS(Dex-graft-PLA)s] exhibited higher loading efficiency of BSA than MSs prepared from PLLA [MS(PLLA)s]. The in vitro release rate of BSA from MS(Dex-graft-PLA) was faster than that from MS(PLLA). BSA released from MS(Dex-graft-PLA) maintained the secondary structure of native BSA to a great extent, compared with BSA released from MS(PLLA).

DOI： 10.1002/mabi.200300106

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

We synthesized two types of "anti-directed" oligo-DNA dimer conjugates consisting of a photo-functional core group, in this case naphthalene as a model, and two strands of sequential oligo-DNAs (pentamer, GCTGC or GCAGC) linked at the 1,5-positions of naphthalene and at the 5' ends of the oligo-DNAs through a phosphorodiester bond, forming Np(GCTGC)(2) and Np(GCAGC)(2). These conjugates are designed to be complementary to each other and are capable of forming a one-dimensional polymeric supramolecular assembly in aqueous solution. Duplex formation of the oligo-DNA strands in a solution of an equimolar mixture of the conjugates was confirmed by measurement of the hypochromicity, ethidium bromide (EB) intercalation tests, and circular dichroism (CD) spectra. From the CD spectra measurements of the solution, it was suggested that the oligo-DNA strands formed a B-type duplex-like conformation in aqueous solution. The equimolar mixture of the conjugates showed a temperature-dependent CD spectra change corresponding to the melting temperature of the B-type duplex. The formation of the polymeric assembly from the equimolar mixture of the conjugates was suggested by size-exclusion chromatography. The obtained results are useful for the construction of nanometre-scale structures using DNAs as building blocks.

DOI： 10.1080/10610270310001624989

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

A poly(aspartic acid)-block-polylactide- (PAsp-block-PLA) diblock copolymer was synthesized through the polymerization of beta-benzyl-L-aspartate-N-carboxyanhydride [Asp(OBzl)-NCA] with amino-terminating polylactide (NH2-PLA) as a macroinitiator. The chain length of the PAsp segment could be easily controlled by changing the. monomer/initiator ratio. Dynamic light scattering measurements of PAsp-block-PLA aqueous solutions revealed the formation of polymeric micelles. Changes in the micelles as a function of pH were investigated.

DOI： 10.1002/marc.200300259

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

To develop the preparative method for poly(DL-lactide-co-glycolide)-based microspheres containing proteins, we prepared microspheres from mixture of poly(DL-lactide-co-glycolide) and polydepsipeptide-block-poly(DL-lactide) having cationic or anionic pendant groups. Since the latter amphiphilic copolymers consisting of hydrophobic poly(DL-lactide) segment and hydrophilic polydepsipeptide segment with amino or carboxyl groups could be converted to cationic or anionic block copolymers, they could act as biodegradable surfactants on the preparation of poly(DL-lactide-co-glycolide)-based microspheres by water-in-oil-in-water emulsion method. The amphiphilic block copolymers were established to stabilize primary emulsions on the preparation of microspheres by scanning electron microscopy. We investigated the effects of the addition of the block copolymers on the entrapment efficiency of protein, the release behavior of protein from microspheres and the stability of protein. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1006/j.polymer.2003.12.067

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

A very important goal of researchers today is providing poly(L-lactide) (PLA)-based polymers with controllable degradation profiles, various (soft or elastic) mechanical properties, reactivity for chemical modification, and other functionalities while keeping the favorable characteristics of PLA. This article concerns the synthetic methods and properties of the following novel lactide copolymers: (1) random and block copolymers of depsipeptide and L-lactide with reactive (ionic) side-chain groups, (2) comb-type PLA and branched PLA, and (3) PLA-grafted polysaccharide and PLA with terminal saccharide residues. Poly(depsipeptide-random-L-lactide)s and polydepsipeptide-block-poly(L-lactide)s with reactive (ionic) side-chain groups should be useful for the preparation of matrices and microspheres with reactive surfaces because of their amphiphilic structures. Comb-type PLA and branched PLA show lower crystallinities than linear PLA. PLA-grafted polysaccharide should be useful for the preparation of matrices with various microstructures and mechanical and degradation properties through the introduction of hydrophilic segments. (C) 2003 Wiley Periodicals, Inc.

DOI： 10.1002/pola.10848

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The aggregation of polyions into microsphere (MS) complexes was studied as a preparative method for the construction of a biodegradable matrix. Aqueous suspensions of polylactide (PLA)-based MSs with positively and negatively charged surfaces, MS(K-3(4+)-PLA) and MS(E-3(4-)-PLA), respectively, immediately formed aggregates when mixed. The effects of the stoichiometry of the charged groups on the surfaces of the MSs and the ionic strength of the medium on aggregate formation, as well as the degradation behavior of the polyion complex (PIC) matrix over time, were investigated. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/jjcis.2003.10.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Recent studies have focused on the active targeting of drug delivery by combining a homing device and antitumor drug. For this purpose, synthesis of a well-designed vehicle (such as polymer/drug conjugates or nanoparticles) carrying a drug and a homing device requires many steps. We propose a new type of drug delivery system (DDS) by formation of a complex containing avidin (Av) plus biotinyl drug with a biotinyl homing device, which easily accommodates the combination of various drugs and homing devices. The targetable drug complex can be prepared by selecting an appropriate biotinyl drug derivative and a biotinyl homing device and mixing them with avidin. Fluorescent dye with 5-(and-6)-carboxytetramethylrhodamine (TAMRA) was used as a drug model, and galactose (Gal) recognized by liver parenchymal cells was used as a homing device. TAMRA and galactose were attached to biotin (Bio) through a triethyleneglycol (TEG) spacer group to give Bio-TEG-TAMRA conjugate and Bio-TEG-Gal conjugate, respectively. Confocal laser scanning microscopic studies suggest that the complexes prepared by mixing Bio-TEG-Gal conjugate and fluorescein isothiocyanate (FITC)-labeted Av (feed molar ratio 4:1), and mixing Bio-TEG-Gal conjugate, Bio-TEG-TAMRA conjugate and FITC-labeled Av are internalized into the hepatoma cells through a receptor-mediated endocytosis mechanism. (C) 2003 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jconrel.2003.09.020

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：VSP BV  

In tissue engineering, excellent biodegradable materials are desired as temporary scaffolds to support cell growth and disappear with the progress of tissue regeneration. We previously synthesized biodegradable poly(depsipeptide-co-lactide), poly [(Glc-Asp)-co-LA] and poly [(Glc-Lys)-co-LA], having reactive side-chain groups. Then, the effects of reactive and ionic side-chain groups on cell attachment and growth were investigated using co-polymer films with various amounts of carboxyl or amino groups. In this study, to evaluate the utility of these co-polymers as functional scaffolds for tissue regeneration, 3-dimensional porous sponges were prepared by freeze-drying method and the effects of reactive and ionic side-chain groups on cell growth and degradation behavior were investigated using co-polymer sponges with various amounts of carboxyl or amino groups. Good cell growth was observed on the co-polymer sponges. During cell culture, the co-polymer sponges exhibited various degradation rates related to the depsipeptide unit content. Three-dimensional biodegradable polymer matrices with reactive surface, controllable degradation behavior and good cell growth were successfully prepared using these co-polymers. Such kinds of co-polymer matrices are good candidate for scaffold for tissue engineering.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：VSP BV  

In tissue engineering, excellent biodegradable materials are desired as temporary scaffolds to support cell growth and disappear with the progress of tissue regeneration. We previously synthesized biodegradable poly(depsipeptide-co-lactide), poly [(Glc-Asp)-co-LA] and poly [(Glc-Lys)-co-LA], having reactive side-chain groups. Then, the effects of reactive and ionic side-chain groups on cell attachment and growth were investigated using co-polymer films with various amounts of carboxyl or amino groups. In this study, to evaluate the utility of these co-polymers as functional scaffolds for tissue regeneration, 3-dimensional porous sponges were prepared by freeze-drying method and the effects of reactive and ionic side-chain groups on cell growth and degradation behavior were investigated using co-polymer sponges with various amounts of carboxyl or amino groups. Good cell growth was observed on the co-polymer sponges. During cell culture, the co-polymer sponges exhibited various degradation rates related to the depsipeptide unit content. Three-dimensional biodegradable polymer matrices with reactive surface, controllable degradation behavior and good cell growth were successfully prepared using these co-polymers. Such kinds of co-polymer matrices are good candidate for scaffold for tissue engineering.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A variation of A-B-A-type triblock copolymers consisting Of poly(L-lactide) (PLLA) and poly(ethylene glycol) (PEG) was synthesized and examined for complexation with alpha-cyclodextrins (alpha-CDs). Although the PLLA block has bulky methyl groups as side chains, stable polypseudorotaxanes of PLLA-PEG-PLLA triblock copolymers as well as PLLA were obtained and confirmed by H-1 NMR, solid-state C-13 CP/MAS NMR, FT-IR, and X-ray spectroscopies. From the results, it was hypothesized that the guest molecules threaded into the hydrophobic CD cavities, and they form stable pseudorotaxanes in both PEG and PLLA blocks. The a-CDs slide over the flanking bulky PLLA blocks to form an inclusion complex with PEG block; in addition, they form very stick pseudorotaxanes with the end-blocks of PLLA parts. The copolymers confined to the CD channels lost their original crystalline properties but formed a channel-type hydrophobic crystalline structure with CDs due to long chain nature of the copolymers. Such a polymeric inclusion complex can have an important role for constructing supramolecular architectures such as polyrotaxanes and molecular tubes for the use of the bioactive agent delivery system.

DOI： 10.1021/ma035200k

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Sequential arrays of chromophores at regulated distances were constructed on a noncovalent DNA molecular assembly system in aqueous media. Photoinduced fluorescence resonance energy transfer (FRET) behaviors were then observed. We designed a number of chromophore/oligo-DNA conjugates with varying sequences. The chromophores eosin (Eo), TexasRed (TR), and tetramethylrhodamine (Rho) were employed as the energy donor, acceptor, and mediator, respectively, based on overlapping excitation and emission spectra. The chromophores were attached via aminolinkers to the 5'-terminals of 10mer oligo-DNAs consisting of AT rich sequences. The arrangement of Eo-Rho or Rho-TR with 10-residue (1 pitch of duplex) distances was ensured by duplex formation of the conjugates with a 20mer matrix oligo-DNA composed of complementary sequences to the conjugates. Single-step FRET from Eo to Rho and from Rho to TR was confirmed on the duplex. The three chromophore conjugates were then mixed with longer matrix oligo-DNAs (30 or 40mer) consisting of complementary sequences to the conjugates, producing Eo-(Rho)(n)-TR (n = 1 or 2) arrays with 10-residue distances. Multistep FRET from Eo to TR through the Rho mediator(s) was observed on the molecular assemblies. This photoenergy transmission system offers a good model for a photoenergy transmission system mimicking photosynthetic systems.

DOI： 10.1021/bc034028m

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

Polylactide (PLA)-grafted dextran was synthesized with a trimethylsilyl protection method to produce novel biodegradable, biomedical materials. PLA-grafted dextrans with various lengths and numbers of graft chains were synthesized. The properties of solution-cast films prepared from PLA-grafted dextrans were investigated with thermal and dynamic mechanical analyses. The graft-copolymer films exhibited lower glass-transition temperatures, melting temperatures (T-m's), and crystallinities as well as higher viscosity properties as compared with poly-L-lactide film. The T-m and crystallinity and mechanical properties at 37 degreesC could be adjusted by controlling the molecular structure such as the lengths and numbers of graft chains. Furthermore, the biodegradability of PLA-grafted dextran films was investigated through the weight change of film and the molecular weight change of polymer during the in vitro degradation test. PLA-grafted dextrans exhibited different degradation behavior from poly-L-lactide with the introduction of a polysaccharide segment and branched structure as well as the change of end-functional group. The degradation rate of PLA-grafted dextran and the cast film prepared from PLA-grafted dextran could be adjusted by controlling the sugar content or the length of graft chains. (C) 2003 Wiley Periodicals, Inc.

DOI： 10.1002/pola.10783

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DOI： 10.1016/S0032-3861(03)00308-2

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DOI： 10.1021/bm020110t

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

In tissue engineering related to the regeneration of damaged or lost tissue, excellent biodegradable materials are desired as temporary scaffolds to support cell growth and then disappear with the progress of tissue regeneration. We previously synthesized biodegradable poly(depsipeptide-co-lactide), poly[(Glc-Asp)-co-LA], and poly[(Glc-Lys)co-LA] with reactive side-chain groups. In this study, to evaluate the utility of these copolymers as functional scaffolds for tissue regeneration, the effects of reactive and ionic side-chain groups on cell attachment and growth were investigated using copolymer films with various numbers of carboxyl or amino groups. Poly[(Glc-Lys)-co-LA] and poly[(Glc-Asp)-co-LA] films having appropriate positive or negative charges exhibited higher cell attachment ability than did poly-L-lactide. Good cell growth was observed on the copolymer films. During cell culture, the copolymer films exhibited higher degradation rates related to the depsipeptide content. Biodegradable polymer matrices with reactive surfaces for cell growth successfully were prepared using copolymers with various numbers of depsipeptide units. Varying the depsipeptide unit numbers in the copolymer could change the degradation rate of these matrices. (C) 2003 Wiley Periodicals, Inc.

DOI： 10.1002/jbm.a.10446

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Sequential arrays of chromophores at regulated distances were constructed on a non-covalent DNA molecular assembly system in aqueous media. Photo-induced energy transfer behaviors were then observed. We designed a number of chromophore/oligo-DNA conjugates with varying residue sequences. The chromophores eosin (Eo), Texas Red (TR) and tetramethylrhodamine (TMR) were employed as energy donor, acceptor and mediator, respectively, based on overlapping excitation and emission spectra. The chromophores were attached to the 5-terminals of 10 residue oligo-DNAs using aminolinkers. Arrangements of Eo-TMR or TMR-TR were constructed by duplex formation of conjugates with a 20 mer matrix oligo-DNA comprising complementary sequences to the conjugates. Single-step photo-induced energy transfer from Eo to TMR and from TMR to TR was confirmed for the duplex. The three kinds of chromophore conjugates were then mixed with longer matrix oligo-DNAs (30 or 40 mer) consisting of complementary sequences to the conjugates, producing Eo-(TMR)(n)-TR (n = 1 or 2) arrays. Multi-step photoinduced energy transfer from Eo to TR through the TMR mediator(s) was observed on the molecular assemblies. This photo-energy transmission system offers a good model for artificial photosynthetic systems.

DOI： 10.1080/1061027021000002413

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

The syntheses of polylactides (PLAs) with branched peptide end groups containing reactive (ionic) moieties such as amino or carboxyl groups are described and were used to prepare PLA based microspheres (MSs) with positively or negatively charged surfaces. Branched peptides with hydroxyl end groups and four protected amino or carboxyl groups. Boc(4)K(3)-OH or Bn-4-E-3-OH, were synthesized, and the hydroxyl group converted to an alkoxide and was used as the initiation site for the ring opening polymerization of L-lactide. Subsequent deprotection gave PLAs end capped with branched peptides having four amino or carboxyl groups respectively (K-3(4) PLA and E-3 PLA) K-3-PLA and E-3-PLA were converted to K-3-PLA and E-3(4) PLA by acid or base treatment, respectively. MSs with charged surfaces were then prepared using K-3(4+) PLA or E-3(4)- PLA as a surfactant [MS(K-3(4)-PLA) or MS(E-3(4)-PLA)]. The ionic surface state of the MSs was confirmed by colloidal titration and zeta potential analysis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

Amphiphilic AB-type diblock copolymers composed of hydrophobic poly(L-lactide) (PLA) segments and hydrophilic poly(glycolic acid lysine) [poly(Glc-Lys)] segments with amino side-chain groups self-associated to form PLA-based polymeric micelles with amino surfaces in an aqueous solution. The average diameter of the loose core-shell polymeric micelles for poly(Glc-Lys) [number-average molecular weight (M-n) = 1240]-b-PLA (M-n = 7000) obtained by a dimethyl sulfoxide/water dialysis method was estimated to be about 50 nm in water by dynamic light scattering measurements. The size and shape of the obtained polymeric micelles were further observed with transmission electron microscopy and atomic force microscopy. To investigate the possibility of applying the obtained PLA-based polymeric micelles as bioabsorbable vehicles for hydrophobic drugs, we tested the entrapment of drugs in poly(Glc-Lys) (M-n = 1240)-b-PLA (M-n = 7000) micelles and their release with doxorubicin as a hydrophobic drug. (C) 2002 Wiley Periodicals. Inc.

DOI： 10.1002/pola.10226

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

The syntheses of amphiphilic AB-type diblock copolymers composed of hydrophobic polylactide segment and hydrophilic polydepsipeptide segment with amino or carboxyl groups were performed. The protected cyclodepsipeptides cyclo[Glc-Lys(Z)] and cyclo[Glc-Asp(OBzl)] (where Glc is glycolic acid, Lys is lysine, Asp is aspartic acid, Z is benzyloxycarbonyl, and OBzl is benzyl) were first polymerized in tetrahydrofuran (THF) with potassium ethoxide as an initiator to obtain the corresponding protected polydepsipeptides. After the terminal hydroxyl groups of the protected polydepsipeptides were converted into the potassium alcoholates with K/naphthalene, L-lactide was polymerized in the presence of the corresponding polymeric alcoholates as macroinitiators in THF to obtain poly [Glc-Lys(Z)]-block-poly(L-lactide) and poly [Glc-Asp(OBzl)] block-poly(L-lactide). Subsequent deprotection of Z and OBzl groups gave the objective amphiphiles poly(Glc-Lys)-block-poly(L-lactide) and poly(Glc-Asp)-block-poly(L-lactide), respectively. (C) 2002 Wiley Periodicals, Inc.

DOI： 10.1002/pola.10211

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Language：English   Publisher：Kansai University  

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Publishing type：Part of collection (book)  

© 2002 by CRC Press LLC. Science is knowledge we use to understand nature. People are always inspired by nature, and have tried to understand and utilize the laws of nature through scientific approaches. In the 20th century, technological innovation progressed at an accelerated pace and permeates almost every facet of our daily lives. The acceleration of both science and technology has led to remarkable advances, and this is especially true in the area of medicine. For example, surgery was used rarely as a therapeutic measure until the 19th century. A huge number of new therapeutic methodologies have been developed, and improvement and enhancement of the human body by artificial materials is one of the most successful innovations in the last century. These successes are largely due to fundamental scientific research into the interactions of artificial materials and living organisms. Technological effort has revolutionized our health care systems, surgery plays a prominent role in curing diseases, and further scientific exploration into these fields continues to bring about unique advances in medical treatment.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Communication: To develop the new-type poly(L-lactide)- based biomedical material having a wettable surface, Synthesis of poly(L-lactide) with one terminal D-glucose residue was investigated. After the hydroxyl group at 1-C of alpha-tetrabenzyl glucose, alpha-Glc(Bzl)(4),was converted to the corresponding potassium alkoxide by using tert-butoxide, L-lactide (L-LA) was polymerized in the,presence of alpha-Glc(Bzl)(4)-OK as an initiator in tetrahydrofuran at room temperature to prepare alpha-Glc(Bzl)(4)-polyLA. Subsequently, the removal of O-protecting benzyl groups in the terminal alpha-Glc(Bzl)(4) residue was carried put by hydrogenolysis with Pd/C to obtain the objective D-glucose-end-capped polyLA, alpha-Glc-polyLA. The wettability of surface of the alpha-Glc-polyLA material is discussed using the difference of the dynamic contact angle between a alpha-Glc-polyLA/homopolyLA blend film and a film of the polyLA homopolymer.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

To provide a macromolecular prodrug with recognition ability for hepatoma cells, we synthesized new conjugates of cisplatin (CDDP) and poly(ethylene glycol) (PEG) with galactose residues or antennary galactose units (Gal4A, four branched galactose residues) at the.-chain terminus, Gal-PEG-DA/CDDP or Gal4A-PEG-DA/ CDDP conjugates. An antennary (branched) structure of Gal4A was designed based on the fact that saccharide clusters with branched structures show highly effective binding with saccharide receptors, a phenomenon known as the 'cluster effect'. The cytotoxic activity of the conjugates was investigated against HepG21 human hepatoma cells in vitro and compared with a control conjugate without galactose, MeO-PEG-DA/CDDP. Gal-PEG-DA/ CDDP and Gal4A-PEG-DA/CDDP conjugates showed lower IC50 values (3.1 x 10(-4) and 2.3 x 10(-4) m. respectively) than the MeO-PEG-DA/CDDP conjugate (10.5 x 10(-4) m). The cytotoxic activities of these conjugates with galactose residues or antennary galactose units were inhibited as a result of the addition of galactose and strongly inhibited by the addition of Gal4A. however the inclusion of a methoxy group (the MeO-PEG-DA/CDDP conjugate) did not affect the activity. These results suggest that the Gal4A unit introduced to the conjugate has effective recognition ability against HepG2 human hepatoma cells.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Polylactide, which is a biodegradable and bio-absorbable polymer having low immunogenicity and good biocompatibility, has been mainly studied for biomedical applications. Branched polymers have different rheological and mechanical properties compared with their linear counterparts owing to their molecular architectures. we synthesized novel biodegradable polylactide having a branched structure composed of metabolically degradable and/or absorbable materials only. The branched polylactide was obtained from a one-pot copolymerization of L-lactide using metabolic intermediate DL-mevalonolactone as a bifunctional comonomer having both lactone ring and pendant hydroxy group. The glass transition point, melting point and crystallinity of the branched polylactide are lower than those of linear polylactide.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The control of biodegradation and the improvement of moldability of poly-L-lactide, PLA, have been difficult because of the high crystallinity and the lability of melt viscosity. The synthesis of biodegradable PLA having the branched structure, comb-type PLA, was carried out by using only metabolizable materials to obtain a new material showing the controlled degradation and good molding properties, and to provide information on correlation of branched structure with biodegradability. A depsipeptide-lactide random copolymer having pendant hydroxy groups, poly[(Glc-Ser)-LA], was obtained by ring-opening copolymerization of L-lactide, LA, with a protected cyclodepsipeptide, cyclo[Glc-Ser(OBzl)], and consequent deprotection. The obtained copolymer was used as a macroinitiator for graft-polymerization of LA to give comb-type PLA. The obtained comb-type PLA showed a lower glass transition point, melting point, and apparent crystallinity than linear PLA. Furthermore, it was suggested that the degradation rate of comb-type PLA could be adjusted by controlling the molecular architecture such as molecular weight of main chain and/or side chain and number of graft chain.

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Language：English   Publishing type：Research paper (scientific journal)  

In 1975 Prof. Ringsdorf already proposed the systematic model for polymeric drugs (polymer-drug conjugates or macromolecular prodrugs), so-called “Ringsdorf's model”, aiming at enhance ent and prolongation of activity of drugs, and reduced side-effects of drugs. In this reviewm, the authors introduce the recent advances in macromolecular prodrug researches, from the stand-points of the structures(shapes) of polymeric carriers, the controlled release by polymer-drug inkages and the drug-targeting by homing devices, with discussing about what kind l of concepts proposed in the “Ringsdorf's model” have been achieved or progressed. © 2001, THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM. All rights reserved.

DOI： 10.2745/dds.16.143

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Language：English   Publishing type：Research paper (scientific journal)  

We previously reported that a macromolecular prodrug synthesized by immobilizing cisplatin (CDDP) to dextran (Dex) through six-membered chelate-type coordination bond (DCM-Dex/CDDP conjugate) showed a significantly longer half-life in bloodstream and excellent in vivo tumor growth inhibitory effect against mice bearing Colon 26 cancer cells. In this report, to provide DCM-Dex/CDDP conjugate having targetability to hepatoma cells, we designed a new macromolecular prodrug of CDDP using dextran having branched galactose units (Gal4As, four branched galactose residues), DCM-Dex/Ga14A/CDDP conjugate. Galactose was employed as a homing device, because it is well-known that galactose receptors (asialoglycoprotein receptors) were exposed on the surface of liver parenchymal cells. The antennary (branched) structure of Gal4A was designed based on the fact that a saccharide cluster having a branched structure shows highly effective binding with the saccharide receptors, that is a "cluster effect". The apparent affinity constant per galactose residue against RCA120 lectin for dextran carrying Gal4As was higher than that for dextran carrying monomeric galactose residues. Moreover, the DCM-Dex/Gal4A/CDDP conjugate showed cell-specific cytotoxic activity against HepG2 human hepatoma cells in vitro. The cytotoxic activity of the conjugate was inhibited by the addition of galactose and strongly inhibited by the addition of Gal4A. The results suggest that the DCM-Dex/Gal4A/CDDP conjugate having branched galactose units has a higher affinity to hepatoma cells.

DOI： 10.1021/bm010053o

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The in vivo antitumor activity and toxicity of a newly synthesized polymeric prodrug of cisplatin was investigated and also compared with plain cisplatin. The prodrug included a dicarboxymethyl-dextran conjugate of cisplatin (DCM-Dex/CDDP). DCM-Dex/CDDP was i.v. injected in mice bearing s.c. Colon 26 mouse colon cancer cells. The tissue distribution of platinum was thereafter determined by flameless atomic absorption spectrophotometry. The platinic concentration of the organs showed a high rate of retention at 24 h after injection in the DCM-Dex/CDDP-treated mice. No biochemical or hematologically adverse effects were observed. In addition, DCM-Dex/CDDP showed a significantly higher antitumor activity than cisplatin alone. These results indicate that DCM-Dex/CDDP may therefore be a potentially effective cancer chemotherapy. [(C) 2000 Lippincott Williams & Wilkins.].

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EDITIONS SANTE  

It has recently become very important to develop drug delivery systems for water-soluble natural macromolecules, such as peptides, proteins and polynucleotides. We have found that poly(ethylene glycol)-grafted chitosan, PEG-g-chitosan, formed nanoparticles through intermolecular hydrogen bonding in an aqueous solution. PEG-g-chitosan nanoparticles can be expected to incorporate water-soluble, polar or anionic molecules, which can then interact with chitosan by hydrogen bonds or electrostatiscally. We therefore decided to investigate the incorporation of a peptide hormone, insulin, as a model peptide drug into PEG-g-chitosan nanoparticles. PEG-g-chitosan nanoparticles incorporated a certain quantity of insulin molecules spontaneously but this depended on the degree of introduction of PEG chain on chitosan. The release rate also depended on the degree of introduction of PEG chain on chitosan. The sustained release of insulin from nanoparticles was also observed. PEG-g-chitosan nanoparticles are can be expected to be applied as delivery vehicles for peptide drugs.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：VSP BV  

In order to develop a new type of lactic acid copolymer having pendant reactive groups as a biodegradable biomaterial, the synthesis of an AB-type diblock copolymer of L-lactide (L-LA) and depsipeptide with pendant thiol groups was investigated. Cyclodepsipeptide consisting of glycolic acid (Glc) and beta -methoxybenzyl L-cystine (Cys), cyclo[Glc-Cys(MBzl)], was polymerized in tetrahydrofuran (THF) solution using potassium ethoxide as an initiator. The terminal hydroxyl group of the poly[Glc-Cys(MBzl)] obtained was converted to potassium alkoxide by K/naphthalene. L-LA was polymerized in THF using the polymer alkoxide as a macro-initiator to obtain poly[Glc-Cys(MBzl)]- block-polyLA showing two melting temperatures (T(m)8). Through subsequent deprotection of the methoxybenzyl groups, the objective biodegradable amphiphilic AB-type block copolymer, poly(Glc Cys)-block-polyLA, was obtained. The accumulation ability of thiol groups located on the surface of the block copolymer film was evaluated to be higher than that of the random copolymer film.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Poly(L-lactic acid)-based microspheres having chemically reactive groups on their surfaces, MS(LAGA) and MS(LAGL), were prepared front the respective biodegradable L-lactic acid (LA)-depsipeptide copolymers, poly[LA-(Glc-Asp)] and poly[LA-(Glc-Lys)], having low contents of depsipeptide units, by an oil-in-water (O/W) emulsion and solvent evaporation method. The average diameters of the dried microspheres obtained were estimated to be 390-450 nm by scanning electron microscopy (SEM). The amounts of functionalized groups located on their surfaces were found to increase with an increase in the content of depsipeptide units in the used copolymers as determined by a colloidal titration method. The zeta potential values of the MS(LAGA) and MS(LAGL) surfaces increased negatively and positively in proportion to the amount of carboxyl and amino groups, respectively. As one example of the chemical modification of the obtained microspheres. the immobilization of galactose residues onto the surface of MS(LAGA) was demonstrated. Moreover, the entrapment of l-naphthalenesulfonic acid as a hydrophilic model drug into MS(LAGA) and MS(LAGL). and its release behavior were investigated.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pharmaceutical Society of Japan  

In vitro release behavior and cytotoxic activity, and in vivo plasma disposition of newly synthesized macromolecular derivatives of cisplatin (CDDP) were investigated and compared with CDDP. The derivatives included oxidized dextran conjugate of CDDP (OX-Dex/CDDP) and dicarboxymethylated dextran conjugate of CDDP (DCM-Dex/CDDP). In vitro release of platinum complex from dextran conjugated CDDP was determined by an equilibrium dialysis method. These dextran conjugates showed sustained release of the platinum complex. In vitro release half-life for DCM-Dex/CDDP was significantly longer (4.5 times) than that for OX-Dex/CDDP. In vitro cytotoxic activity of CDDP and dextran conjugated CDDP against colon 26, mouse colon cancer cell line, was measured using the MTT assay method. OX- Dex/CDDP showed a similar cytotoxic activity to CDDP. However, both cytotoxic activities were markedly decreased when preincubated with the medium containing serum. On the other hand, DCM-Dex/CDDP retained residual cytotoxic activity at a significantly higher level than OX-Dex/CDDP after preincubation with the medium containing serum, although it showed the lowest cytotoxic activity. This indicated longer maintenance of the in vitro antitumor activity of DCM-Dex/CDDP in serum compared with OXDex/CDDP. Plasma disposition of CDDP and dextran conjugated CDDP was determined by intravenous administration to rats. Although the total platinum plasma concentration-time profile for OX-Dex/CDDP was similar to that for CDDP, its markedly higher profile was achieved when DCM-Dex/CDDP was administered. The values of the total platinum AUC and MRT, where AUC is the area under the platinum concentration-time curve and MRT is the mean residence time, for DCM-Dex/CDDP were 11.2 times and 4.8 times significantly higher than with OXDex/CDDP in plasma, respectively. DCM-Dex/CDDP also showed a significantly lower total clearance compared with OX-Dex/CDDP. These results from the in vivo experiments revealed that retention of DCM-Dex/CDDP in blood circulation was much greater than that for OX-Dex/CDDP. DCM-Dex/CDDP thus has potential as a macromolecular derivative of CDDP for passive tumor targeting.

DOI： 10.1248/bpb.22.756

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARCEL DEKKER INC  

Graft polymerization of styrene on chitosan derivative was carried out in order to obtain a new amphiphilic hybrid material of synthetic and natural polymers using N,N-dimethylformamide (DMF) soluble 6-O-tritylchitosan and azo compound having carboxylic acid groups. 6-O-Tritylchitosan was coupled with 4,4'-azobis(4-cyanovaleric acid) (ACVA). Graft polymerization of styrene on the 6-O-tritylchitosan was carried out in DMF using the pendant ACVA moiety as an initiator. After deprotection of trityl groups of the polymerization products, graft copolymer (PSt-g-chito) was obtained. Contact angle measurement and transmission electron microscope observation for the films of the PSt-g-chito were carried out. The obtained PSt-g-chito showed a micro phase separated morphology.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Chitosan (deacetylated chitin), which is a naturally occurring polysaccharide having primary amino groups, is known to be insoluble in water because of its strong intermolecular hydrogen bonds. We prepared water-soluble poly(ethylene glycol) grafted chitosan (PEG-g-chitosan) through the chemical modification of chitosan and investigated its aggregation phenomenon in aqueous solutions. The solution properties of PEG-g-chitosans differ depending on the degree of introduction of PEG in aqueous solution, and were studied by measuring transmittance and light scattering. The PEG-g-chitosans could form aggregates spontaneously by means of their intermolecular hydrogen bonds in the aqueous solution. The PEG-g-chitosan aggregates could also uptake N-phenyl-1-naphthylamine (PNA) as a hydrophobic substance in neutral conditions and this PNA could be released from the aggregates in acidic conditions. (C) 1998 Elsevier Science Ltd. All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Biodegradable poly(lactic acid)-grafted amylose was synthesized using a trimethylsilyl (TMS) protection method. Tehrahydrofuran soluble, mostly trimethylsilyl protected amylose was prepared and reacted with potassium tert-butoxide to give the corresponding alkoxide. Poly(lactic acid)-grafted amyloses were obtained by ring-opening anionic polymerization of lactide using the polymeric alkoxides as initiators and subsequent removal of the TMS groups. The obtained graft copolymers show biodegradability and a microphase-separated morphology.

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Language：English   Publisher：Nagasaki University  

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Other Link： http://search.jamas.or.jp/link/ui/1999000688

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

alpha-1,4-Polygalactosamine (PGA) purified from the culture fluid of Paecilomyces sp. I-1 strain and N-acetylated alpha-1,4-polygalactosamine (NAPGA) are chitosan- and chitin-like biodegradable, compatible alpha-1,,4-linked polysaccharides, respectively. Partially N-acetylated PGA was found to show the stronger binding activity onto MH134Y hepatoma cells than three kinds of normal lymphocytes, bone marrow, T and B cells from the results of binding assay of C-14-50% N-acetylated PGA in vitro. Since PGA and NAPGA have the unreducing end groups of galactosamine and N-acetyl galactosamine, respectively, they were suggested to exhibit the receptor-mediated affinities to hepatoma cells. In order to provide the lysosomotropic macromolecular prodrug of fluorouracil (5FU) having a targeting ability to hepatoma, we synthesized water-soluble 6-O-carboxymethyl-NAPGA-immobilized 5FUs through Gly-Phe-Leu-Gly, monomethylene spacer groups. The obtained conjugate showed the cathepsin-B-susceptible release behavior of 5FU and then exhibited the stronger cytotoxic activity than free 5FU against HLE hepatoma cells in vitro. (C) 1998 Elsevier Science B.V. All rights reserved.

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DOI： 10.1021/ma980377d

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Sci Ltd  

The synthesis a novel single chain lipid (SP-16A), containing a photo-sensitive spiropyran group at its hydrophobic terminus is described. The photoisomerization behavior of SP-16A has been studied by UV-Vis spectroscopy. The lipid has been incorporated into small unilamellar vesicles (SUVs) in quantities up to 10 mol% by mixing with dipalmitoylphosphatidylcholine (DPPC) and consequent sonication. The photo-induced membrane perturbation of the SP-16A/DPPC mixed SUV liposome was observed by monitoring of leakage of carboxyfluorescein(CF), a water soluble fluorescent dye, from the interior aqueous phase of the SUV. SUVs containing 5-10 mol% of SP-16A showed drastic leakage of CF by UV irradiation at 465 nm, however, neither liposome rupture nor release of the lipid from the SUV was observed after the UV irradiation. On/off switching of the leakage of interior material from the vesicle could also be demonstrated. In order to discuss the mechanism and kinetics of the photo-sensitive membrane perturbation behavior for the SP-16A/DPPC mixed SUV, the isomerization behavior of the SP-16A molecule and the leakage of CF from the SUV over time were investigated using a pulsed excimer laser. These experiments suggested that the main factor involved in membrane perturbation by SP-16A is a conformational change of the lipid in the membrane, which occurs after isomerization of the molecule. This new lipid molecule is thus a novel and useful photo-sensitive switching system, and may have future applications in drug delivery systems.

DOI： 10.1016/S0968-5677(97)00070-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：John Wiley and Sons Inc.  

To obtain water-soluble oligodepsipeptide with pendant thiol groups, the alternating co-oligomer [oligo(Glc-alt-Cys)], consisting of glycolic acid (Glc) and L-cysteine (Cys) residues as α-hydroxy acid and α-amino acid residues, respectively, was prepared by means of ring-opening homo-oligomerization of cyclo[Glc-Cys(MBzI)] and subsequent deprotection of methoxybenzyl groups. Moreover, to modify the properties of poly (lactic acid) [poly(LA)] and to introduce pendant thiol groups to poly(LA), the terpolymer of LA, Glc, and Cys (poly[LA-(Glc-Cys)]) was synthesized through ring-opening and copolymerization of L-lactide with the protected cyclodepsipeptide, cyclo[Glc-Cys(MBzl)] and subsequent deprotection of methoxybenzyl groups. By changing the mol fraction of (Glc-Cys) unit, the solubility, thermal transition, degradation behavior of the modified poly(LA), and the water contact angle of its film could be varied. © 1998 John Wiley &amp
Sons, Inc.

DOI： 10.1002/(SICI)1099-0518(199806)36:8<1283::AID-POLA11>3.0.CO;2-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

It is well-known that some kinds of saccharide play the important roles in biological recognition on cellular surface. So, they are expected to be applied for cellular recognition devices. Recently, it was reported that cluster glycosides were effective in the specific interaction between oligosaccharide chains and receptors. Since chitosan is a cationic natural polysaccharide, having formation ability of polyelectrolyte complex with DNA, it is expected to be used as a carrier of DNA in gene delivery systems. So, in order to achieve an efficient gene delivery via receptor-mediated endocytosis, the synthesis of novel polycationic polysaccharide derivative having recognizable branched saccharide residues, N,N,N-trimethyl(TM)-chitosan/tetragalactose antenna conjugate (TC-Ga14A20), was carried out. The cellular recognition ability of TC-Ga14A20 conjugate were tested, and then the possibility of its application as a gene delivery tool was investigated. TC-Ga14A20 conjugate showed high affinity to RCA(120) lectin and its polycation-DNA complex had the ability of specific gene delivery to hepatocyte. (C) 1997 Elsevier Science Ltd.

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Since poly(ethylene glycol) (PEG) is a water-soluble and biocompatible polymer, PEG is a very interesting material as a carrier of macromolecular prodrug. Although doxorubicin (DXR) is one of the most prominent antitumor agents in cancer chemotherapy, its very strong side-effects, its poor water-solubility, and its instability have been cited as unsolved problems. In order to solve the defects of DXR, the design of a DXR-terminated PEG conjugate as a macromolecular prodrug of DXR was investigated. The MeO-PEG/Schiffs base/DXR conjugate showed a lysosomotropic release behavior of free DXR, very good stability in PBS for a long period, and exhibited a significant cytotoxic activity against p388D(1) lymphocytic leukemia cells in vitro. Moreover, this conjugate exhibited stronger cytotoxic activity than free DXR against DXR-resistant p388D, leukemia cells. Furthermore, the Lactose/PEG/amide/DXR conjugate showed stronger cell-specific cytotoxic activity against HLE human hepatoma cells than MeOPEG/amide/DXR conjugate. The cytotoxic activity of Lactose/PEG/amide/DXR conjugate against HLE cells was inhibited by addition of galactose.

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N-Acetylmuramyl-L-alanyl-D-isoglutamine (MDP) is the minimum required structure responsible for the immunoadjuvant activity of the bacterial cell wall. The D-glucose analogue of MDP (GADP) was reported to show a higher immunoadjuvant activity than MDP itself. Although the mechanism of activation by MDP and the existence of receptor against MDP are not clear, the patch formation and cluster formation of receptors are important steps on the signal transduction by such bioactive molecules. It is expected that the cluster effect such as antennary oligosaccharides reported by Lee et al. increased the affinity of ligand against receptor and accelerated the patch formation and cluster formation of receptors. In order to discuss the effect of multivalent-ligand formation of GADP on the activation of immunocompetent cells in more detail, we have synthesized GADP dimers combined through various lengths of alkyl and poly(ethylene glycol) (PEG) spacer groups as the simple models of multivalent-ligand molecule of GADP and evaluated their immunological enhancement activities in vitro. The GADP dimers showed a higher level stimulatory activities against macrophage-like cells than free GADP and monomeric GADP derivatives.

DOI： 10.1016/S0008-6215(96)00261-3

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It is well known that muramyl dipeptide is a minimum required structure of bacterial peptidoglycan responsible for immunoadjuvant activity. Since mannose receptors exist on the surface of macrophages, polymers with branched mannose residues are expected to target moieties to macrophages. To achieve an efficient delivery of D-glucose analogue of muramyl dipeptide (GADP) via receptor-mediated endocytosis by mannose receptors on the surface of macrophages, GADP/carboxymethyl-dextran (CM-Dex)/Man conjugate was synthesized. Moreover, to study the effect of the introduction of mannose residues, we also synthesized GADP/CM-glucomannan (CM-GM) and GADP/CM-Dex conjugates. The immunological enhancement activities of their conjugates were evaluated by measurements of glucose consumption and beta-D-glucuronidase activity from macrophage-like cells. The GADP/CM-Dex/Man and GADP/CM-GM conjugates showed higher immunological enhancement activity than the GADP/CM-Dex conjugate. The immunological enhancement activity of GADP/CM-Dex/Man and GADP/CM-GM conjugates was decreased to the same level of immunological enhancement activity of GADP/CM-Dex conjugate under the presence of excess mannose. These results suggested that the introduction of mannose residues into GADP/CM-Dex conjugate could increase the affinity against macrophage and the immunological enhancement activity of GADP/CM-Dex conjugate itself.

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Many polysaccharides are expected to apply as biomaterials because they generally show good biocompatibilities and biodegradabilities. It has recently been reported that the saccharides play important roles in biological recognition and the transmission of biological information on a cellar surface. Galactomannan (GalM) is a polysaccharide whose main chain is composed of beta-1,4-linked mannose units only. It has some branching alpha-galactose residues at the C-6 position of mannose units. Therefore, it was of interest of us to use GalM as a drug carrier which was targeted to hepatocyte having a galactose receptor on its cellar surface. Dicarboxy-galactomannan (DC-GalM), which has reactive functional groups and is a carboxylic acid derivative of galactomannan, was prepared by IO4-/ClO2- oxidation of GalM. The obtained DC-GalM showed specific binding with maclura pomifera (MPA) [1] which has a specificity to alpha-galactose. Moreover, DC-GalM showed selective incorporation into hepatocyte. Adriamycine (ADR), which is one of the most prominent anticancer agents, was immobilized to DC-GalM. The DC-GalM/ADR conjugate showed specific cytotoxic activity against HepG2 human hepatoma cells which have a galactose receptor on the cell surface, compared with Hela utrocervical carcinoma cells which have no galactose receptor.

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The catalytic activity of bovine serum albumin (BSA) modified physically by molecular imprinting using transition-state analogue (TSA) as a template molecule was studied. The resultant imprinted serum albumin (Imp-BSA) showed the rate acceleration of dehydrofluorination reaction from (4R,4S)-4-fluoro-4-(4-nitrophenyl)butan-2-one (1) and followed the type of Michaelis-Menten reaction in ethyl acetate solution. The enzymatic activity of Imp-BSA was competitively inhibited by (4R,4S)-4-hydroxy-4-(4-nitrophenyl)butan-2-one (4).

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Chitosan and 6-O-glycolchitosan, a water-soluble chitosan derivative, were oxidized by periodate. In the case of chitosan, only degradation products were obtained. With 5-O-glycolchitosan, however, water-soluble amphoteric polyelectrolyte derivatives of chitosan having higher molecular weight were obtained. The oxidized 6-O-glycolchitosan (OX-GC) showed a pH sensitive change of viscosity in aqueous solution. Moreover, the OX-GC hydrogel, cross-linked with glutaraldehyde, showed a pH sensitive swelling behavior. The OX-CC showed biodegradation behavior by lysozyme after acetylation.

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Water-soluble polydepsipeptides with functionalized side-chain groups, i.e., alternating copolymers, consisting of glycolic acid (Glc) and L-lysine (L-Lys), L-aspartic acid (L-Asp) or L-glutamic acid (L-Glu) residues as a-hydroxy acid and a-amino acid residues, respectively, were synthesized, and their biodegradation behavior was investigated. Three kinds of polydepsipeptides, poly(Glc-alt-lys), poly(Glc-alt-Asp) and poly(Glc-alt-Glu), were synthesized by means of ring-opening polymerization of the corresponding cyclodepsipeptides and subsequent deprotection of benzyl and benzyloxycarbonyl groups. In order to estimate the main-chain cleavage behavior of polydepsipeptides with functionalized side-chain groups, the hydrolysis behavior of the obtained water-soluble polydepsipeptides was first investigated in phosphate buffer solution with or without an enzyme in vitro.

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Since the mannose receptors exist on the surface of macrophages, the branched mannose residues of glucomannan are expected to act as targeting moieties to macrophages. So, in order to achieve an efficient delivery of D-glucose analogue of muramyl dipeptide (GADP) via receptor-mediated endocytosis by mannose receptors on the surface of macrophages, the GADP/carboxymethyl(CM)-glucomannan conjugate was synthesized. Moreover, in order to study the relationship between the immunological enhancement activity of the conjugates and their mannose residues, we synthesized the GADP/CM-glucomannan conjugates having various degrees of substitution of carboxymethyl group in mol% per sugar unit (DCM) and GADP/CM-dextran conjugate through hybridization of GADP with dextran. The immunological enhancement activities of GADP/CM-glucomannan conjugates and GADP/CM-dextran conjugate were evaluated by measurements of the glucose consumption, the superoxide anion production and the beta-D-glucuronidase activity from PMA (phorbol-12-myristate-13-acetate)-differentiated HL-60 (human promyelocytic leukemia) or U937 (human monoblast leukemia) cells as macrophage-like cells. Copyright (C) 1996 Elsevier Science Ltd

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Since chitosan is a cationic natural polysaccharide having the formation ability of a polyelectrolyte complex with DNA, it is expected to be used as a carrier of DNA in gene delivery systems. So, in order to achieve an efficient gene delivery via receptor-mediated endocytosis, the synthesis of a novel polycationic polysaccharide derivative having recognizable saccharide residues, N,N,N-trimethyl(TM)-chitosan/galactose conjugate, was performed. The formation of a polyelectrolyte complex with DNA and the cellular recognition ability of TM-chitosan/galactose conjugate were tested, and then the possibility of its application as a gene delivery tool was investigated. Copyright (C) 1996 Elsevier Science Ltd

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cis-Dichloro(cyclohexane-trans-l-1,2-diamine)platinum(II):Dach-Pt(chlorato) is a platinum complex which is expected to exhibit higher antitumor activity than cisplatin and which shows no cross-resistance with cisplatin. However, its strong side-effects and low water solubility have been noted. We have reported that polymer/antitumor drug conjugates show reduced side-effects and high antitumor activity. In order to provide a macromolecular prodrug of Dach-Pt having reduced side-effects and high water solubility, we synthesized dextran derivatives containing dicarboxylic acid groups to immobilize Dach-Pt via a chelate-type co ordination bo nd, dicarboxymethyl-dextran(DCM-Dex)/Dach-Pt conjugate. We investigated the release behavior of the platinum complex from the carrier polymer and the cytotoxic activity of the conjugate against p388D(1) lymphocytic leukemia cells in vitro compared with the carboxymethyl-dextran (CM-Dex)/Dach-Pt conjugate. The DCM-Dex/Dach-Pt conjugate showed almost the same level of cytotoxic activity as free Dach-Pt(chlorato) or Dach-Pt(malonato). Although the cytotoxic activity of free Dach-Pt(chlorato) was decreased by incubation in a medium with serum, the DCM-dextran/Dach-Pt conjugate kept its higher level of cytotoxic activity after incubation in a medium with serum. These results suggested that the stability of the Dach-Pt moiety in the medium was increased and cytotoxic activity of Dach-Pt was not decreased by fixation to dextran through a chelate-type coordination bond.

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p-Hydroxybenzene was. coupled with tetrathymidine or tetraadenosine through phosphodiester bonds to give symmetric oligo-DNA dimers, (T4)(2)Bz and (A4)(2)Bz, as components for a polymeric supramolecular assembly, The equivalent mixture of them formed a high-molecular-weight aggregate in aqueous media via complemental hydrogen bonds.

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cis-Dichloro(cyclohexane-trans-l-1,2-diamine)platinum(II) (Dach-Pt(chlorato)), is a platinum complex which is expected to exhibit higher antitumor activity than, and show no cross resistance with. cisplatin. However, its strong side-effects and low water-solubility have also been cited. We report that polymer/antitumor drug conjugates shows reduced side-effects and high antitumor activity. In order to provide a macromolecular prodrug of Dach-Pt having reduced side-effects and high water-solubility, we synthesized polymer conjugates of Dach-Pt and dextran derivatives having carboxylic acid groups, oxidized-dextran (OX-Dex)/Dach-Pt conjugate, and carboxymethyl-dextran(CM-Dex)/Dach-Pt conjugate. The cytotoxic activities of the conjugates were investigated against p388D(1) lymphocytic leukemia cells in vitro. The OX-Dex/Dach-Pt conjugate showed almost the same level of cytotoxic activity as free Dach-Pt(chlorato). Although the cytotoxic activity of free Dach-Pt(chlorato) was decreased by incubation in medium with serum, the OX-Dex/Dach-Pt conjugate kept its cytotoxic activity in higher level after 24 h incubation in medium with serum. These results suggested that the stability of Dach-Pt molecule in the medium was increased and cytotoxic activity of Dach-Pt was not decreased by Axing to OX-Dex.

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：CONTROLLED RELEASE SOCIETY INC  

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：A T L PRESS, SCIENCE PUBL, INC  

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：SPRINGER-VERLAG  

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In vivo and in vitro antitumor activities of macromolecular prodrugs of doxorubicin (DXR) using 6-O-carboxymethylchitin (CM-chitin) as a carrier polymer were investigated. In order to determine the effect of a spacer group between a drug and a carrier polymer on the antitumor activity, we employed two different spacer groups, a lysosomal digestible tetrapeptide (Gly-Phe-Leu-Gly) and a simple hydrophobic pentamethylene to immobilize DXR molecules to CM-chitin. The cytotoxic activity of the conjugates obtained were investigated against four kinds of tumor cell lines, p388D(1) lymphocytic leukemia, L1210 leukemia HLE human hepatoma and Hela utrocervical carcinoma cell in vitro The CM-chitin/Gly-Phe-Leu-Gly/DXR conjugate 1 with lysosomal digestible tetrapeptide spacer groups showed slightly higher in vitro cytotoxic activity against these tumor cells than CM-chitin/C-5/DXR conjugate 2 with a simple pentamethylene spacer group. However, the cytotoxic activity of these two conjugates was weaker than that of the free DXR. The survival effects of these conjugates were investigated against p388 lymphocytic leukemia bearing mice in vivo by intraperitoneal (i.p.) implantation and intravenous (i.v.) injection. Although these conjugates did not show very high cytotoxic activities in vitro compared with the free DXR, conjugate 1, with the lysosomal digestible tetrapeptide spacer groups, exhibited survival effects against p388 lymphocytic leukemia in mice i.p./i.v. However, conjugate 2, with the simple pentamethylene spacer group, did not show any survival effects under the same conditions. These conjugates did not display an acute toxicity in the high dose ranges.

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Doxorubicin (adriamycin; ADR) which is one of the most clinically used antitumor agent, has undesirable side-effects. To reduce these side-effects, a macromolecular prodrug of ADR exhibiting high antitumor activity, the conjugate of PEG end-capped with ADR was developed. To effect intracellular release of ADR from the conjugate, ester, amide and Schiff's base bonds were employed as modes of bonding ADR to PEG. The MeO-PEG/Schiff's base/ADR conjugate readily released ADR under the lysosomal acidic conditions in vitro and very slowly ADR under physiological conditions. Moreover, the MeO-PEG/Schiff's base/ADR conjugate showed strong cytotoxic activity similar to free ADR against p388D1 lymphocytic leukemia cells in vitro. Fluorescence measurements suggest that the conjugate forms self-aggregates in aqueous solution.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARCEL DEKKER INC  

In order to provide biodegradable poly(hydroxy acid)s by a simple process, fundamental studies on the polycondensation of alpha-hydroxy acids by enzymes and polyethylene glycol (PEG)-modified enzymes in organic media were carried out. The oligomer formation by unmodified hog liver esterase proceeded well using glycolic acid as a substrate in cyclohexanone. Lipase from Aspergillus niger gave the best result for the polycondensation of glycolic acid among the unmodified enzymes used. The effects of the PEG-modification of enzyme on the polycondensation of alpha-hydroxy acids are also discussed. When the enzyme modified with a small amount of low-molecular-weight PEG was used, the conversion by polycondensation was relatively high. In particular, by using ethyl glycolate as a substrate, which allows an ester exchange reaction, and 1,4-dioxane as a solvent, polycondensation by PEG-modified enzyme proceeded effectively to give the pentamer of poly(glycolic acid).

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Chitin is a non-toxic biodegradable polysaccharide. 6-O-Carboxymethylchitin (CM-chitin) is a water-soluble chitin derivative. In order to provide a water-soluble macromolecular prodrug of doxorubicin (DXR) reducing the side-effects and exhibiting high antitumor activity, the fixation of DXRs to CM-chitin through covalent bonds was carried out. Especially, a lysosomally digestible tetrapeptide (Gly-Phe-Leu-Gly) was used as spacer groups between CM-chitin and DXRs. In this paper, two kinds of conjugates, CM-chitin/Gly-Phe-Leu-Gly/DXR conjugate 5 having lysosomally digestible tetrapeptide spacer groups and CM-chitin/C5/DXR conjugate 6 having pentamethylene spacer groups, were synthesized. The effect of introduction of the spacer groups on the release behavior of DXR from the conjugate was investigated. The conjugate 5 having tetrapeptide spacer groups showed a distinct increase in the release rate of DXR in the presence of the lysosomal enzyme cathepsin B at 37-degrees-C in vitro; however, the conjugate 6 did not show such specific release behavior.

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Language：Japanese   Publisher：関西大学工業技術研究所  

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：PLENUM PRESS DIV PLENUM PUBLISHING CORP  

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In order to provide a novel synthetic biological response modifier exhibiting high antitumor activity, GADP (D-glucose analogue of muramyl dipeptide (MDP)) has been conjugated with carboxymethyl (CM)-curdlan (normal chain (1 --&gt; 3)-beta-D-glucan) which has antitumor activity through stimulation of the host immunosystem. The immunological enhancement activities of the conjugate obtained were investigated against macrophage-like HL-60 (human promyelocytic leukemia) or U937 (human monoblast leukemia) cells to be enlarged by means of coupling of GADP with CM-curdlan. In this paper, in order to discuss the relationship between the immunological enhancement activities of the conjugate and its molecular structure, we synthesized GADP/CM-curdlan conjugates having various degrees of substitution of the carboxymethyl group (DCM) and degree of substitution of the GADP group (DGADP) per sugar unit. The GADP/CM-curdlan conjugate showed higher immunological enhancement activities than GADP derivative, CM-curdlan, or a mixture of GADP derivative and CM-curdlan in all the concentration ranges tested. The immunological enhancement activities of the GADP/CM-curdian conjugate increased with increasing DGADP value. Although the immunological enhancement activities of CM-curdlan decreased with increasing in DCM value, those of GADP/CM-curdlan conjugate increased with increasing DCM value. We also synthesized the GADP/CM-dextran conjugate to investigate the effect of conjugation of GADP with immunologically active CM-curdlan. The immunological enhancement activities of GADP/CM-dextran conjugate was not higher than those of the mixture of GADP derivative and CM-dextran, or CM-dextran itself. These results suggested that the high immunological enhancement activities of GADP/CM-curdlan conjugates were due not only to giving polymeric character to GADP but also to the hybridization of GADP with immunologically active polysaccharide, curdlan. Moreover, from the results of the effect of DGADP and DCM values of the conjugate on activities and the results of the effect of the addition of calmodulin inhibitor to the macrophage-like cells activated by the conjugate on activities, the path of the activation of immunocompetent cells by the GADP/CM-curdlan conjugate was found to be different from that by CM-curdlan or free GADP derivative itself.

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alpha-1,4-Polygalactosamine (PGA) and N-acetyl-alpha-1,4-polygalactosamine (NAPGA) have been reported to be low toxic and biodegradable polymers and to act as growth inhibitors of certain tumor cells through stimulation of the host immune system. Moreover, these polysaccharides can be expected to have affinities for hepatocytes. A water soluble macromolecular prodrug of 5-fluorouracil (5FU) with affinity for tumor cells and without side-effects was obtained as CM-NAPGA/amide/pentamethylene/ester/monomethylene/5FU conjugate. The release behavior of 5FU from this conjugate and its antitumor activity were investigated in vitro at 37 degrees C in physiological saline. The release of free 5FU was observed, while no 5FU derivative was detected. The cytotoxicity of CM-NAPGA/amide/pentamethylene/ester/monomethylene/5FU conjugate was lower than that of free 5FU against p388D1 lymphocytic leukemia, while the conjugate was more potent than the free 5FU against HLE hepatoma cells in vitro. The administration of CM-NAPGA/amide/pentamethylene/ester/monomethylene/5FU conjugate via intraperitoneal (i.p.) transplantation/i.p. injection in mice resulted in a significant survival effect against p388 lymphocytic leukemia. The conjugate in the high dose range caused neither rapid decrease of body weight of the treated mice, nor acute toxicity in the treated mice.

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Small-sized chitosan-gel nanospheres, CNSs (average diameter 250 nm), containing 5-fluorouracil (5FU) or immobilizing 5FU derivatives (aminopentyl-carbamoyl-5FU or aminopentyl-ester-methylene-5FU) were prepared by the glutaraldehyde crosslinking technique and the emulsion method. When chitosan was crosslinked with glutaraldehyde, these 5FU derivatives were simultaneously immobilized to CNSs by means of Schiff's base formation. The CNSs were coated with anionic polysaccharides, such as 6-O-carboxymethyl-N-acetyl-alpha-1,4-polygalactosamine/Na (CM-NAPGA/Na), 6-O-carboxymethyl-chitin/Na (CM-chitin/Na), and sodium hyaluronate, through formation of a polyelectrolyte complex membrane to give CNS/polyanion, i.e., CNS/G, CNS/C, and CNS/H, respectively. The polyelectrolyte complex of polysaccharide was employed to achieve the controlled release and effective targeting of 5FU by the CNSs. The release rate of 5FU from the CNSs could be controlled by immobilization of 5FU, degree of deacetylation of chitosan used and coating with polysaccharides. Since very few galactosamine residues are known to be able to cross-react with ligands for galactose, the galactosamine residues on the surface of CNS/Gs are expected to act as the targeting moieties for hepatocyte. The CNS/G showed the lectin mediated aggregation phenomenon by the addition of APA lectin. Moreover, CNS/G had the highest cytotoxic activity among the three kinds of CNS/polyanion and CNS in HLE human hepatoma cell culture system in vitro.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Recently, it has been reported that some polysaccharides showed interesting biological or immunological activities. Glucomannan (GM) purified from Amorphophallus Konjac is a copolymer of 1,4-linked beta-D-glucose and beta-D-mannose, which has some mono-residual D-glucose or D-mannose branches at the 3-position of D-mannose units of the main chain. We prepared dicarboxy-glucomannan (DC-GM), a carboxylic acid derivative of glucomannan, by 10(4-)/ClO2- oxidation. The number-average molecular weight (M(n)) of the DC-GM obtained was about 2.0 x 10(4). The chemical structure of DC-GM was investigated by gas-chromatography. It showed high water-solubility and enzymatic degradation behavior by cellulase and beta-D-glucosidase. The enzymatic degradation rate of the DC-GM was dependent on the degree of introduction of carboxylic acid group. The immunological enhancement activity of the DC-GM was evaluated in vitro by testing glucose consumption and beta-D-glucuronidase activity against cultured macrophages, PMA (phorbol-12-myristate-13-acetate)-differentiated HL-60 (human promyelocytic leukemia) or U937 (human monoblast leukemia) cells. The DC-GM showed higher stimulating effects against such cultured macrophages than the other polysaccharide derivatives.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TECHNOMIC PUBL CO INC  

To provide a new synthetic biological response modifier which exhibits a high immunopotentiation activity and antitumor activity, a hybrid conjugate of chitin with immobilized D-glucose analogue of muramyl dipeptide (MDP) (GADP) was synthesized. The stimulation activity of the conjugate against cultured macrophages was evaluated as an immunopotentiation activity in vitro by glucose consumption using PMA (phorbol-12-myristate-13-acetate)-differentiated HL-60 (human promyelocytic leukemia) cells and by superoxide anion (O2-) production from PMA-differentiated HL-60 cells. The stimulation activity of the GADP/chitin conjugate against cultured macrophages was greater than that of GADP derivative, carboxymethyl-chitin and a mixture of these two. The stimulation activity of GADP against cultured macrophages was increased by conjugation with chitin.

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Language：Japanese   Publisher：化学工業社  

CiNii Books

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Language：Japanese   Publisher：日本化学会  

CiNii Books

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Grant-in-Aid for Scientific Research on Priority Areas

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Language：Japanese   Publisher：高分子刊行会  

CiNii Books

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

In order to provide a device releasing drugs in a controlled manner and having targetability to specific organs or cells, chitosan-gel microspheres, CMS, crosslinked with glutaraldehyde, immobolizing 1-[N-(5-aminopentyl) carbamoyl]-5-fluorouracil, 1, coated with anionic polysaccharides, such as 6-O-carboxymethyl-N-acetyl-alpha-1,4-polygalactosamine (CM-NAPGA), 6-O-carboxymethyl-chitin, alginic acid and heparin, by polyelectrolyte complex membrane formation were prepared. When chitosan was crosslinked with glutaraldehyde, 1 was simultaneously immobilized into CMS by Schiffs base formation. Average diameter of CMS obtained was estimated to be about 0.5-1.0 mum by SEM observation. In physiological saline media, only free 5-FU was released from the CMS but 1 and any 5-FU derivative was not. Release rate of 5-FU from the CMS was reduced by coating with polyelectrolyte complex membrane of cationic chitosan and anionic polysaccharides. CMS coated with CM-NAPGA showed a lectin-mediated specific aggregation phenomenon by addition of Abrus precatorius agglutinin. Moreover, the CMS immobilizing 1 coated with CM-NAPGA showed higher growth-inhibitory effect against SK-Hep-1 (human hepatoma) cells in vitro than the CMS coated with other polysaccharides.

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It is well known that N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) is a minimum required structure of bacterial peptidoglycan responsible for immunoadjuvant activity. Although MDP itself has no antitumor activity, the MDP derivatives modified with lipophilic groups are reported to exhibit antitumor activities in vivo. On the other hand, curdlan (normal chain (1 --&gt; 3)-beta-D-glucan) is known to exhibit an antitumor activity through stimulation of the host immuno-system. In order to provide the novel synthetic biological response modifier exhibiting high antitumor activity, we synthesized a hybrid type conjugate of curdlan immobilizing D-glucose analogue of MDP (GADP). The immunological enhancement activity of the conjugate obtained was evaluated by the test of glucose consumption of DMSO-differentiated HL-60 (human promyelocytic leukemia) cells. the test of superoxide anion (O2-) production from PMA (phorbol-12-myristate-13-acetate)-differentiated HL-60 cells, and the test of cytotoxic factor production from PMA-differentiated U937 (human monoblast leukemia) cells. These results suggested that the immunological enhancement activity of GADP was increased by the hybridization with curdlan.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HUTHIG & WEPF VERLAG  

Poly(alpha-malic acid) is of interest for the application as a biodegradable and bioadsorbable drug carrier, which has pendent reactive carboxylic acid groups. In order to provide a biodegradable macromolecular prodrug of doxorubicin (adriamycin, ADR), reducing the side-effects of ADR and exhibiting effective antitumor activity, ADR residues were covalently attched to poly(alpha-malic acid) via ester or amide bonds to give poly(alpha-malic acid)/ester/ADR conjugate 1 or poly(alpha-malic acid)/amide/ADR conjugate 2, respectively. The release rate of ADR from the poly(alpha-malic acid)/ester/ADR conjugate 1 was faster than that from the poly(alpha-malic acid)/amide/ADR conjugate 2 in buffer solution (pH 7,4) at 37-degrees-C. While the cytotoxic activity of poly(alpha-malic acid)/ester/ADR conjugate 1 is as strong as that of free ADR against p388D1 lymphocytic leukemia cells in vitro, the cytotoxic activity of poly(alpha-malic acid)/amide/ADR conjugate 2 is much lower.

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In order to provide a device that would release anticancer drugs in response to temperature, chitosan microspheres with immobilized 1-[N-(5-aminopentyl)urea]-5-fluorouracil (Ap-5FU) and coated with dipalmitoyl phosphatidyl choline (DPPC) multilayers were prepared. The chitosan-DPPC-chitosan microspheres were prepared by coating chitosan-DPPC microspheres with polyelectrolyte complex membrane of chitosan. Good distributive stability of microspheres in aqueous solution was achieved with the DPPC multilayers coating. When chitosan was crosslinked with glutaraldehyde, Ap-5FU was simultaneously immobilized to the microspheres by means of Schiff's base formation. In physiological saline media, free 5FU released from the microspheres was detected, but the 5FU derivative was not. The release rate of 5 FU from the microspheres was decreased by coating with DPPC multilayers, and further depressed by the formation of polyelectrolyte complex membrane. The thermo-sensitive release behavior of 5FU from chitosan-DPPC microspheres and chitosan-DPPC-chitosan microspheres was observed in vitro across the phase transition temperature (T(m)) of the DPPC multilayer (41.4-degrees-C).

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Language：English   Publisher：PHARMACEUTICAL SOC JAPAN  

In order to provide the water-soluble and biodegradable macromolecular prodrug of 5-fluorouracil (5FU), the fixation of 5FUs to 6-O-carboxymethyl chitin(CM-chitin) through pentamethylene, monomethylene spacer groups via amide, ester bonds was carried out. The obtained CM-chitin/5FU conjugate showed the slow release of 5FU and exhibited remarkable antitumor activity against P388 lymphocytic leukemia in mice by intraperitoneal(i.p.) implantation / i.p. injection.

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：ELSEVIER APPL SCI PUBL LTD  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARCEL DEKKER INC  

The homopolymerization of vinyl monomer immobilized 5-fluorouracils (5FU) through organosilicon-amine spacer groups via urea bonds (KY-20) and the copolymerization of KY-20 with vinyl monomer were carried out by a radical technique to give the homopolymer [Poly(KY-20)] and copolymer [Poly(KY-20/vinyl monomer)], respectively. The antitumor activities of Poly(KY-20) and Poly(KY-20/vinyl monomer) were tested against p388 lymphocytic leukemia by intraperitoneal (i.p.) transplantation/i.p. or oral (p.o.) administration and against Meth-A fibrosarcoma or MM46 mammary adenocarcinoma in mice by subcutaneous (s.c.) implantation/p.o. administration. These 5FU/organosilicon-amine hybrid polymer conjugates exhibited significant survival effects against p388 leukemia in mice i.p./i.p. or i.p./p.o. Poly(KY-20/HPMA) also showed stronger growth-inhibitory effects against Meth-A fibrosarcoma and MM46 mammary adenocarcinoma in mice s.c./p.o.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Poly(malic acid) is of interest for application as a bioresorbable carrier of polymeric drugs, which can be modified chemically. In order to provide the biodegradable macromolecular prodrug of 5-fluorouracil (5FU) reducing the side effects of 5FU, having targetability into tumor cells and exhibiting effective antitumor activity, 5FU residues and some kinds of saccharide residues were attached to poly(alpha-malic acid) to give poly (alpha-malic acid)-5FU-saccharide conjugates. Galactosamine, glucosamine, N-acetyl-D-glucosamine, mannose and mannosamine were used as saccharide residues. The antitumor activities of the obtained conjugates were tested against p388 leukemia in mice by intraperitoneal (i.p.) transplantation/i.p. injection. The obtained poly(alpha-malic acid)-5FU-saccharide conjugates showed significant survival effects against p388 leukemia mice and did not display an acute toxicity in the dose range 200-800 mg/kg. The survival effects tended to increase with an increase with the degree of substitution of 5FU on the polymer based on the number of carboxylic acid groups (D5FU). The effect of saccharide units on the growth inhibition of hepatoma cells and the other tumor cells was investigated in vitro. Poly(alpha-malic acid)-5FU-galactosamine conjugate tended to exhibit higher growth-inhibitory effect against hepatoma cells than the other poly(alpha-malic acid)-5FU-saccharide conjugates. The cell specific targeting of the conjugate to hepatoma cells was suggested to be possible by using a galactosaminyl chain.

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/0923-1137(91)90159-l

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

In order to provide a macromolecular prodrug of 5-fluorouracil (5FU) with reduced side-effects, having an affinity for tumor cells and exhibiting strong antitumor activity, the covalent attachment of 5FUs to alpha-1,4-polygalactosamine (PGA), N-acetyl-alpha-1,4-polygalactosamine (NAPGA) and their oligomers (GOS, NAGOS) through hexamethylene spacer groups via urea, urea bonds was carried out. The survival effect against p388 lymphocytic leukemia in female CDF1 mice by intraperitoneal (ip) transplantation/ip injection in vivo and the growth-inhibitory effect on Meth-A fibrosarcoma in male BALB/c SPF mice by subcutaneous (sc) implantation/intravenous (iv) injection in vivo were evaluated. The effects of the degree of substitution of 5FU based on the number of galactosamine groups and the degree of N-acetylation of amino groups of PGA based on the number of galactosamine groups on prolongation of life were investigated. The PGA/5FU and NAPGA/5FU conjugates exhibited strong survival effects against p388 lymphocytic leukemia and the GOS/5FU conjugate showed significant growth-inhibitory effect on Meth-A fibrosarcoma. The obtained PGA/5FU, NAPGA/5FU, GOS/5FU and NAGOS/5FU conjugates did not display any acute toxicity even in the high dose ranges.

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：AMER CHEMICAL SOC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARCEL DEKKER INC  

Small-sized albumin gel microspheres, MSs, containing 5-fluorouracil (5FU) with targeting moieties on their surfaces (average diameter: 1.5-mu-m) were prepared by the glutaraldehyde crosslinking method and suspension technique. Since galactose is known to interact specifically with the asialoglycoprotein receptor on hepatocyte, the galactose residues were introduced on the surface of MSs as the targeting moieties for hepatoma through polyethylene glycol (PEG) spacers. PEG spacers were employed to depress the immunogenicity of albumin, to keep the mobility of the galactose residues, and to heighten the distributive stability of the MSs in aqueous solution. It was confirmed by ESCA analysis that the PEG chains were introduced onto the surfaces of MSs. The amount of galactose residues introduced to MS were estimated to be 0.013 wt%. The intra-MSs aggregation was observed by the addition of Ricinus Communis Agglutinin I (RCA 120) into the MS suspension, and then the aggregation of MSs was dissociated by addition of free lactose. Moreover, by incubation of the MSs with human hepatoma HLE cells, the phenomena of MS's specific binding onto HLE cell surfaces and phagocytosis of MSs by HLE cells were observed. These results suggested that the galactose residues on the surface of MSs were recognized with the galactose receptors on hepatoma cell surfaces. The release rate of 5FU from MSs was investigated in vitro in physiological saline at 37-degrees-C. About 90% of encapsulated 5FU were found to be released from MSs through incubation for 8 h.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

In order to provide a macromolecular prodrug of 5-fluorouracil(5FU) with reduced side-effects, having affinity for tumor cells and exhibiting a high antitumor activity, the design of polysaccharide-5FU conjugates was investigated. Chitin-5FU, chitosan-5FU, alpha-1,4-polygalactosamine-5FU, partially N-acetylated alpha-1,4-polygalactosamine-5FU, hyaluronic acid-5FU and dextran-5FU conjugates exhibited significant survival effects against p388 lymphocytic leukemia in mice by intraperitoneal(ip) transplantation/intraperitoneal(ip) injection. Chitosan-5FU, chitosamino-oligosaccharide-5FU, and galactosamino-oligosaccharide-5FU conjugates showed higher growth-inhibitory effects against MH134Y hepatoma and Meth-A fibrosarcoma in mice than 5FU, chitin, oligosaccharides and their blends by subcutaneous(sc) implantation/intravenous(iv) injection. The obtained conjugates did not display an acute toxicity in the high dose ranges.

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Language：Japanese   Publisher：吹田 : 関西大学先端科学技術推進機構  

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Language：Japanese   Publisher：日本バイオマテリアル学会  

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Language：Japanese   Publisher：日本DDS学会  

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Language：Japanese   Publisher：日本DDS学会  

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