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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.

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. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

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 polyanionic 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 ζ-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.

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 °C. The sol–gel transition temperature ( T gel ) could be controlled from 33 to 51 °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 °C for 60 days. This research provides a molecular design approach to create biodegradable thermo-gelling polymers with controllable T gel and mechanical toughness.

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 α-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 °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 α-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.© 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3892–3903, 2009

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 was 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 was 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.

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-...

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.

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.

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 sol 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 °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. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6317–6332, 2008

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 °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 20 wt% hydrogels are eroded gradually in phosphate buffered saline at 37 °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.

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.

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 Tg 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.

Amphiphilic ABA-type triblock copolymers were synthesized to develop a biodegradable anti-adhesive membrane. In this particular synthesis, poly[L-lactide(LA)- co-depsipeptide] (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 PLGLPEG-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 PLGLPEG-PLGL films were degraded and depleted gradually in vivo without inflammation.

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 PEG10K-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.

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(n) of PEG = 35 000, M(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.

Branched poly(lactide)(PLA)s with various lengths of graft chain were synthesized by ring-opening polymerization of l - or d -lactide ( l - or d -LA) in bulk using polyglycidol as a macroinitiator. 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 (Tg), melting temperature (Tm), 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 PDLA stereocomplex film could easily be controlled by changing the molecular weight of branched PLA.

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. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6402–6409, 2006

Specific sequential arrangements of three kinds of chromophores separated by regulated distances equaling approximately one pitch of the DNA duplex (34 A) 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 A).

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 °C for 10 min. Agarose gel electrophoresis and scanning electron microscope observation revealed that the PVA–DNA nanoparticles with average diameter of about 200 nm 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.

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 correspondin...

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.

A poly(aspartic acid)-block-polylactide (PAsp-block-PLA) diblock copolymer was synthesize through the polymerization of β-benzyl-L-asparate-N-carboxyanhydried [Asp(OBzl)-NCVA] with amino-terminating polylactide (NH 2 -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.

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.

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.

Poly(L-lactide) (PLLA) with terminal primary amino groups (ALLA-NH 2 ) 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-NH 2 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.

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 α-cyclodextrins (α-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 1H NMR, solid-state 13C 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 α-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 compl...

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 (Tm's), and crystallinities as well as higher viscosity properties as compared with poly-L-lactide film. The Tm and crystallinity and mechanical properties at 37 °C 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. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2462–2468, 2003

Polylactide (PLA)-grafted polysaccharides with various lengths and numbers of graft chains were synthesized using a trimethylsilyl protection method. The properties of the cast films prepared from graft-copolymers were investigated through thermal and dynamic mechanical analyses. The graft-copolymer films exhibited a lower glass transition temperature (Tg), melting temperature, and crystallinity, and higher viscosity properties compared to PLA films. Moreover, the usefulness of graft-copolymer as a plasticizer was investigated with 1:4 blend films prepared from the graft-copolymers and PLA. The blend films showed lower Tg and crystallinity, and higher viscosity properties compared to PLA films.

The synthesis of poly(L-lactide) (polyLA) end-capped with lactose residue was studied from the standpoint of development of a new bioabsorbable material. After the hydroxyl group of t-butoxycarbonyl(Boc)-aminoethanol was converted to Boc-aminoethanol-OK by using potassium/naphthalene, L-lactide was polymerized in tetrahydrofuran using Boc-aminoethanol-OK as an initiator at room temperature to prepare polyLA-NHBoc. Subsequently, the removal of the Boc group in terminal Boc-aminoethanol residue was performed by treatment of formic acid to obtain the amino group end-capped polyLA (polyLA-NH(2)) as a reactive polyLA derivative. The coupling reactions of lactose with polyLA-NH(2) were investigated by two methods; the synthetic method through reductive amination of lactose with polyLA-NH(2) in the presence of sodium cyanoborohydride as a reducing agent did not give high degree of substitution of end-capped lactose residue per polyLA molecule, whereas the synthetic method through the ester interchange reaction of lactonolactone with polyLA-NH(2) gave Lac-polyLA perfectly end-capped with lactose residue.

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, pro...

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 endcapped with branched peptides having four amino or carboxyl groups, respectively (K 3 -PLA and E 3 -PLA). K 3 -PLA and E 3 -PLA were converted to K 4+ 3 -PLA and E 4- 3 -PLA by acid or base treatment, respectively. MSs with charged surfaces were then prepared using K 4+ 3 -PLA or E 4- 3 -PLA as a surfactant [MS(K 4+ 3 -PLA) or MS(E 4- 3 -PLA)]. The ionic surface state of the MSs was confirmed by colloidal titration and zeta potential analysis.

The labeling of oligo- and polynucleotides with fluorescent probes is an important technique for the analysis of DNAs and RNAs. The effect of duplex formation with complementary oligo-DNA on the quenching behavior of two fluorescent chromophores (eosin, Eo and tetramethylrhodamine, TMR) attached to the 5′-terminal of various 10mer oligo-DNAs was investigated and the dependence of the quenching on DNA base sequence is discussed. We found that guanine residues played a major role in the quenching of the fluorescence of the chromophores. Guanine residues on the complementary DNA near the chromophores, in particular, had a significant influence on the quenching.

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. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 453–462, 2004

Poly(L-lactide)-based microspheres having cationic or anionic surfaces were prepared using polydepsipeptide-block-poly(L-lactide)s as surfactants. Polydepsipeptide-block-poly(L-lactide)s having amino or carboxylic acid groups on their side chains were synthesized through anionic ring-opening polymerizations of L-lactide using the corresponding protected polydepsipeptides as macroinitiators and consequent deprotections. Since these amphiphilic copolymers consisting of hydrophobic segments and hydrophilic segments with amino or carboxylic acid groups could be converted to cationic or anionic block copolymers, they could act as surfactants preparing poly(L-lactide)-based microspheres by an oil-in-water emulsion method. The amount of ionic groups located on the surfaces of the obtained microspheres was found to increase with increasing the feed of charged polydepsipeptide-block-poly(L-lactide)s in the blend of poly(L-lactide) and block copolymers. The average diameters of the dried microspheres estimated by scanning electron microscopy were found to decrease with an increase in feed of block copolymers in polymer blends.

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 (Mn) = 1240]-b-PLA (Mn = 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) (Mn = 1240)-b-PLA (Mn = 7000) micelles and their release with doxorubicin as a hydrophobic drug. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 1426–1432, 2002

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. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 1218–1225, 2002

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

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 HepG2 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 (3.1×10–4 and 2.3×10–4M, respectively) than the MeO-PEG-DA/CDDP conjugate (10.5×10–4M). 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.

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.

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 b...

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 enhancement and prolongation of activity of drugs, and reduced side-effects of drugs. In this review, 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 linkages and the drug-targeting by homing devices, with discussing about what kind of concepts proposed in the “Ringsdorf's model” have been achieved or progressed.

A sequential arrangement of chromophores using non-covalent interaction in aqueous media provides a good model for an artificial photosynthetic system. In order to construct sequential arrangements of chromophores having regulated distances and geometry on non-covalent molecular assembly systems in aqueous media, we designed chromophore/oligo-DNA conjugates having complementary sequences. Three different chromophores, fluorescamine (Fla), rhodamine B (Rho) and fluorescein (Flu) were employed as an energy donor, an acceptor and a mediator, respectively, and were attached to 5 or 10 residues of oligo-DNAs at their 5′-terminals via aminolinkers. Single-step photo-induced energy transfer from Fla to Flu or from Flu to Rho on the molecular assembly of the chromophore/oligo-DNA conjugates was confirmed. Then, the three kinds of conjugates having different chromophores were mixed with 15 or 25 residues of matrix oligo-DNA consisted of complementary sequences for the conjugates, or mixed in “alternative–complementary” combinations to form sequential array of three kinds of chromophores, Fla-(Flu)n-Rho (n = 1–3) having five residues distances. The multi-steps photo-induced energy transfer from Fla to Rho through Flu mediator(s) on the molecular assemblies were observed. Copyright © 2000 John Wiley & Sons, Ltd.

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 β-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 ms). 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 th...

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.