Synthesis Of Poly (Lactic-co-glycolic Acid)-g-dextran And The Characteristics As A Paclitaxel Carrier For Tumor Therapy

Amphiphilic block copolymers consisting of a hydrophilic and a hydrophobic segment self-assemble into polymeric micelles in aqueous solution with a hydrophobic core stabilized by a hydrophilic shell. Hydrophobic drugs can be loaded into their hydrophobic core. Due to their small size and hydrophilic surface, polymeric micelles are not easily recognized and captured by the reticuloendothelial systems (RES). Therefore, polymeric micelles have a relatively long circulation time after intravenous administration and passively target tumor site, which was called "enhanced permeability and retention (EPR)" effect.This study is to construct a compatibility micelle based on dextran (dextran-poly (lactic-co-glycolic acid), Dex-PLGA) to realize the effective delivery of anti-cancer drug paclitaxel. The amphiphilic graft was synthesized via an esterification reaction between the carboxyl group of poly (lactic-co-glycolic acid)(PLGA) and hydroxyl group of dextran (Dex). By changing the mole ratio of PLGA in feed, three types of graft were obtained, and the chemical composition and critical micelle concentration were investigated. The results showed the graft ratio of PLGA increased and the critical micelle concentration decreased with the increase of the mole ratio of PLGA in feed. Dex-PLGA could self-assemble to form nanoscaled micelles in aqueous medium. The CMC of synthesized Dex-PLGA and the micelle size decreased from50.3to27.7μg/mL and from48.00to24.23nm respectively when the graft ratio of PLGA increased. After loading water insoluble anticancer drug paclitaxel with dialysis method, different types of paclitaxel-loaded micelles were achieved through varying the graft types and paclitaxel in feed. After loading paclitaxel, micelle size increased slightly, but remained below100nm with relatively narrow size distribution. The micelles had high paclitaxel loading ability. The drug loading content could be reached up to above11wt%by enhancing the graft ratio of PLGA and the charged amounts of drug. In vitro paclitaxel release from Dex-PLGA micelles could be prolonged to48h. With human ovarian cancer cells (SKOV-3), drug sensitive cell (MCF-7) and multidrug resistant cell (MCF-7/Adr) human breast cancer as model cells, in vitro antitumor efficacy results showed, the cytotoxicity of graft was low, and had excellent internalization ability. Compared with Taxol, paclitaxel-loaded micelles could effectively inhibit the proliferation of SKOV-3cells and MCF-7cells, and overcome the drug resistance of MCF-7/ADR cells. The maximum tolerated dose study (MTD) results showed that the MTD of paclitaxel-loaded micelles in ICR mice after a single intravenous injection was higher than200mg PTX/kg, which was more than8-fold higher than that of Taxol. In vivo anti-tumor activity results showed that paclitaxel-loaded micelles treatments could effectively suppress the growth of tumor and improve the tolerance of paclitaxel in animal body.