pH-Triggered Charge-Reversal Polypeptide Nanoparticles for Cisplatin Delivery: Preparation and In Vitro Evaluation

A series of pH-responsive random copolymer poly(l-glutamic acid-co-L-lysine) [P(Glu-co-Lys)] were synthesized through the ring-opening polymerization (ROP) of gamma-benzyl-t-glutamate N-carboxyanhydride (BLG-NCA) and 3-benzyloxycarbonyl-L-lysine N-carboxyanhydride (ZLys-NCA) and the subsequent deprotection. The chemical structure of the P(Glu-co-Lys)s was confirmed by NMR. Critical aggregation concentration and transmission electron microscopy measurements indicated that the P(Glu-co-Lys)s could self-assemble into aggregates in phosphate buffer. The surface charge of P(Glu-co-Lys) aggregates was greatly affected by the solution's pH and L-glutamic acid/L-lysine ratio because the carboxyl and amino groups present on the P(Glu-co-Lys) aggregates could be protonated or deprotonated to become charged. The pH value of the solution at which the surface charge of the P(Glu-co-Lys) aggregates reversed could be manipulated by the feed ratio of BLG-NCA and ZLys-NCA. In vitro methyl thiazolyl tetrazolium assays demonstrated that negatively charged P(Glu-co-Lys)s were nontoxic and biocompatible. Positive charged P(Glu-co-Lys)s showed some cytotoxicity to He la cells. Cisplatin (CDDP) was used as a model anticancer drug to evaluate the charge-reversal drug delivery system. By the manipulation of CDDP loading content, the surface charge of the CDDP/P(Glu-co-Lys) nanoparticles could be reversed to positive from negative at tumor extracellular pH (pH, 6.5-7.2). An enhanced drug uptake and inhibition of cancer cell proliferation were observed for the tumoral pH(e) triggered charge-reversal CDDP/P(Glu-co-Lys) drug delivery system. These indicated that the CDDP/P(Glu-coLys) nanoparticles could be used as intelligent drug delivery systems for cancer therapy.