Preparation And Evaluation Of D-α-Tocopherol Polyethylene Glycol Succinate-Based Prodrugs For Overcoming Multidrug Resistance Of Cancer

Objectives: Overexpression of the drug-efflux transporter like P-glycoprotein(P-gp) is a key responsible factor in tumor multidrug resistance(MDR) and thus leads to chemotherapy failure. To solve this problem, we designed two kinds of prodrug based on the P-gp inhibiting activity of D-α-tocopheryl polyethylene glycol 1000(TPGS). These prodrugs realized the rapid drug release and the P-gp inhibition in tumor cells, which made them suitable and good candidate for drug delivery and overcoming the MDR of cancer.Methods: The first prodrug(TPGS-S-S-PTX) is a redox-sensitive TPGS-paclitaxel conjugate and the second prodrug(TPGS-CH=N-DOX) is synthesized by conjugating doxorubicin onto TPGS via a pH triggered Schiff base. The chemical structure of prodrugs was confirmed by 1H NMR and FTIR. The redox/pH sensitivity, self-assembly and micelle stability were verified through the monitor of particle size by DLS. MTT assay of prodrugs against drug sensitive and resistant cancer cell was performed and the potential mechanism was further explored. In vivo antitumor evaluation was conducted on S180 tumor bearing mice and MCF-7/ADR xenografed model. After modifying TD with cRGD ligand, the tumor growth delay ability of RGD-TD was evaluated on B16F10 melanoma.Results: The prodrugs could self-assemble into micelles. The drug loading efficiency was about 20%~25% and the particle size was around 130 nm~150 nm. The prodrug micelles/hybrid micelles exhibited good redox/pH sensitivity and released drug fast in according environments. Increased cell cytotoxicity and higher cell apoptosis against MDR cells were observed compared to Taxol and insensitive TPGS-C-C-PTX prodrug. Improved drug uptake and decreased drug effluxin MDR cells were observed in TD compared to free DOX and the micelles also induced mitochondria associated apoptosis pathway. In vivo evaluation showed that prodrug significantly delayed MDR tumor growth and the decorated micelles improved the antitumor efficacy.Conclusions: These prodrugs combined the properties of P-gp inhibition and fast drug release together so that an enhanced anti-tumor efficacy could be achieved, which would provide valuable research results about smart nanodrug in overcoming MDR. Meanwhile, we provide a new insight of “Molecular Economy” in rational prodrug design, explore the original activity of biomaterial, relieve the carrier burden and maximize the therapy efficiency of nanomedicine so as to motivate the translation of nanomedicine to practical clinic application.