Akihiro Takahashi

Biodegradable Polymeric Assemblies for Biomedical Materials

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(e-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.

Design of Biodegradable Injectable Polymers Exhibiting Temperature-Responsive Sol-Gel Transition

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 °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.

The effects of molecular structure on sol-to-gel transition of biodegradable poly(depsipeptide-co-lactide)-g-PEG copolymers.

We report on the effects of number and length of PEG chains in poly(depsipeptide-co-dl-lactide)-g-poly(ethylene glycol) (P(DG-dl-LA)-g-PEG) copolymers on their sol-to-gel transition behavior. The graft-type copolymer is suitable for the systematic study of the effects of molecular structure and hydrophilic/hydrophobic balance on its sol-to-gel transition. We prepared various P(DG-dl-LA)-g-PEG copolymers through coupling reactions between the pendant carboxylic acid groups of P(GD-dl-LA) and the end hydroxyl group of MeO-PEG having various molecular weights. Temperature-responsive sol-to-gel transition of the obtained copolymer solution in phosphate-buffered solution (pH 7.4, ionic strength = 0.14) was investigated by the test tube inverting method and rheological measurements. P(GD-dl-LA)-g-PEG copolymer prepared from higher molecular weight PEG showed higher sol-to-gel transition temperatures compared with the copolymers prepared from lower molecular weight PEG, although these copolymers have similar weight content of PEG (23–24u2009wt.%). Similar trends were observed for groups of copolymers whose PEG contents were 27 or 30u2009wt.%. These results are informative for providing strategies on rational design of thermo-gelling polymers.

Impact of Core-Forming Segment Structure on Drug Loading in Biodegradable Polymeric Micelles Using PEG-b-Poly(lactide-co-depsipeptide) Block Copolymers

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.

Preparation of Biodegradable Oligo(lactide)s-Grafted Dextran Nanogels for Efficient Drug Delivery by Controlling Intracellular Traffic

Nanogels, nanometer-sized hydrogel particles, have great potential as drug delivery carriers. To achieve effective drug delivery to the active sites in a cell, control of intracellular traffic is important. In this study, we prepared nanogels composed of dextran with oligolactide (OLA) chains attached via disulfide bonds (Dex-g-SS-OLA) that collapse under the reductive conditions of the cytosol to achieve efficient drug delivery. In addition, we introduced galactose (Gal) residues on the nanogels, to enhance cellular uptake by receptor-mediated endocytosis, and secondary oligo-amine (tetraethylenepentamine) groups, to aid in escape from endosomes via proton sponge effects. The obtained Dex-g-SS-OLA with attached Gal residues and tetraethylenepentamine (EI4) groups, EI4/Gal-Dex-g-SS-OLA, formed a nanogel with a hydrodynamic diameter of ca. 203 nm in phosphate-buffered solution. The collapse of the EI4/Gal-Dex-g-SS-OLA nanogels under reductive conditions was confirmed by a decrease in the hydrodynamic diameter in the presence of reductive agents. The specific uptake of the hydrogels into HepG2 cells and their intercellular behavior were investigated by flow cytometry and confocal laser scanning microscopy using fluorescence dye-labeled nanogels. Escape from the endosome and subsequent collapse in the cytosol of the EI4/Gal-Dex-g-SS-OLA were observed. These biodegradable nanogels that collapse under reductive conditions in the cytosol should have great potential as efficient drug carriers in, for example, cancer chemotherapy.