Receptor-mediated, tumor-targeted gene delivery using folate-terminated polyrotaxanes

摘要

Safe and effective gene delivery is essential to the success of gene therapy. We synthesized and characterized a novel nonviral gene delivery system in which folate (FA) molecules were functioned as blockers on cationic polyrotaxanes (PR) composed of poly(ethylenimine) (PEI) 600-grafted α-cyclodextrin rings linearized on polyethylene glycol to form FA-terminated PR-PEI 600 (FPP). The FA terminal caps of FPP target cell surfaces abundant in FA receptor (FR), a common feature of tumor cells. The structure of FPP was characterized by using 1H nuclear magnetic resonance ( 1H NMR). The delivery particle was composed of chemically bonded PEG (4000), α-cyclodextrins (CD), and PEI (600 Da) at a molar ratio of 1:17:86.7, and the particle size and zeta potential of FPP/pDNA polyplexes were measured using dynamic light scattering. FPP/pDNA exhibited a lower cytotoxicity, strong specificity to FR, and high efficiency of delivering DNA to target cells in vitro and in vivo with the reporter genes. Furthermore, the FPP/DNA complex showed an enhanced antitumor effect in the nude mice compared with other delivery systems, such as PEI-25K. Together, these results suggest that FPP may be useful for gene therapy.