Kenji Yasugi

Preparation and characterization of polymer micelles from poly(ethylene glycol)-poly(D,L-lactide) block copolymers as potential drug carrier

Poly(ethylene glycol)-poly(D,L-lactide) block copolymers (PEG-PLA) with varying composition were prepared through successive ring-opening polymerization of ethylene oxide and D,L-lactide using an anionic initiator, and their property of multimolecular micellization in aqueous milieu was examined in detail from the standpoint of designing carriers for hydrophobic drugs. The heterogeneity of PEG-PLA was found to crucially affect the size and distribution of micelles, and narrowly-distributed micelles with sizes of approximately 30 nm in diameter were formed only from PEG-PLA with a substantially narrow molecular weight distribution and an appropriate balance in the length ratio of the PEG and PLA segments in PEG-PLA, indicating the importance of establishing a reliable synthetic route for the block copolymers. PEG-PLA micelles have a considerably low critical association concentration (approximately 1.0 mg/l) which is apparently an advantage in utilizing these micelles as drug carriers in an extremely diluted condition.

Temperature-related change in the properties relevant to drug delivery of poly(ethylene glycol)-poly(D,L-lactide) block copolymer micelles in aqueous milieu

The block copolymers of poly(ethylene glycol) and poly(D,L-lactide) (PEG-PDLLA), the latter having a glass transition temperature (T(g)) around the physiological condition, was self-assembled into polymer micelles with a narrow and unimodal distribution in aqueous milieu either by dialysis or by the ultrasonication-aided dispersion method. The 1H NMR measurement of the PEG-PDLLA micelles in D(2)O revealed a gradual increase in the chain mobility of PDLLA segment in the core of the micelles at a temperature range above the T(g) of PDLLA. The critical association concentration (c.a.c.) of the PEG-PDLLA micelles was determined at various temperatures (25-55 degrees C) using pyrene as a probe to monitor the change in the polarity of the microenvironment in the micelle. An Arrhenius plot of the c.a.c. (ln(c.a.c.) versus 1/T) exhibited a break near T(g) of PDLLA. In sharp contrast with the linear decrease in ln(c.a.c.) versus 1/T in the region above the T(g), there was observed an almost constant c.a.c. (7-8 mg/l) regardless of the temperature change below the T(g). Furthermore, the chain exchange reaction between micelles was investigated based on the migration of the end-tagged block copolymers (alpha-lactosyl-PEG-PDLLA and omega-pyrenyl-PEG-PDLLA). The change in the binding affinity of the fluorescent micelles toward the RCA-1 lectin immobilized column was monitored with time to estimate the chain exchange. Consequently, appreciable acceleration in the chain exchange rate was revealed by increasing the surrounding temperature indicating the core mobility to be a substantial factor for inter-micellar chain migration. These results indicate that the engineering of the thermal characteristics of the core-forming segment of the block copolymer should be one of the crucial factors for optimizing the properties of the polymer micelles used for drug delivery.