Star-shape copolymer of lysine-linked di-tocopherol polyethylene glycol 2000 succinate for doxorubicin delivery with reversal of multidrug resistance.

A star-shape copolymer of nanostructure-forming material, P-glycoprotein (P-gp) reversible inhibitor and anticancer enhancer, lysine-linked di-tocopherol polyethylene glycol 2000 succinate (PLV(2K)), was synthesized to overcome multidrug resistance (MDR) in cancer chemotherapy. The critical micellar concentration of PLV(2K) was as low as 1.14 μg/mL, which can endow nanoassemblies good physical stability. Doxorubicin (DOX) was encapsulated into the hydrophobic core of PLV(2K) (PLV(2K)-DOX), with encapsulation efficiency as high as 94.5% and a particle size of 16.4 nm. DOX released from PLV(2K)-DOX nanomicelles was pH-dependent, which ensures micelles stable in blood circulation and releases DOX within tumor cells. Facilitated by the cytotoxicity and uncompetitive P-gp ATPase inhibition by PLV(2K), PLV(2K)-DOX showed greater cytotoxicity compared with DOX solution with increased intracellular accumulation in resistant MCF-7/Adr cells. PLV(2K)-DOX nanomicelles were uptaken into MCF-7/Adr cells via macropinocytosis and caveolae-mediated endocytosis, which further facilitate escapement of P-gp efflux. The anticancer efficacy in vivo was evaluated in 4T1-bearing mice and inhibition of tumor by PLV(2K)-DOX was more effective than TPGS-DOX and DOX solution. In summary, PLV(2K) copolymer has striking functions such as uncompetitive P-gp ATPase reversible inhibitor and anticancer efficacy, and could be a promising nanocarrier in improving the chemotherapy of hydrophobic anticancer drugs.