Synthesis and Characterization of Folate-Modified Cell Membrane Mimetic Copolymer Micelles for Effective Tumor Cell Internalization.

Abstract

The inefficient targeting and phagocytic clearance of nanodrug delivery systems are two major obstacles in cancer therapy. Here, inspired by the special properties of zwitterionic polymers and folic acid (FA), a partly biodegradable copolymer of FA-modified poly(ε-caprolactone) block poly(2-methacryloxoethyl phosphorylcholine), PCL-b-PMPC-FA, was synthesized via atom transfer radical polymerization (ATRP) and click reaction. Non-FA-modified copolymer PCL-b-PMPC was also synthesized as a control. The hydrodynamic diameter of the PCL-b-PMPC-FA micelles is 158 nm (PDI 0.261), slightly larger than that of the PCL-b-PMPC micelles (139 nm, PDI 0.242). The drug doxorubicin (DOX) could be entrapped in the micelles, and as the pH decreased from 7.4 to 5.0, DOX release (in vitro) was accelerated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that both the PCL-b-PMPC and the PCL-b-PMPC-FA micelles showed low toxicity to L929, HeLa, and MCF-7 cells. In addition, the DOX-loaded micelles, PCL-b-PMPC/DOX and PCL-b-PMPC-FA/DOX micelles, exhibited low toxicity to L929 cells but high toxicity to HeLa and MCF-7 cells, especially the PCL-b-PMPC-FA/DOX micelles. HeLa and MCF-7 cell uptakes of the PCL-b-PMPC-FA/DOX micelles were 4.8 and 4.5 times higher than that of the PCL-b-PMPC/DOX micelles, respectively. Therefore, PCL-b-PMPC-FA micelles have great potential for developing drug delivery systems with extended circulation times and tumor-targeting properties.