Dual-Drug Backboned Polyprodrug With A Predefined Drug Combination For Synergistic Chemotherapy

The combination of various chemotherapeutic drugs with synergistic effect is an important way to overcome cancer cell drug resistance and reduce the chemotherapy’s side effects by reducing drug dose.Combination chemotherapy effect is closely related to the dosage ratio of drugs acting on target.In order to maximize the synergistic effect,the multi-drug delivery carrier needs to load and release the drug at a stable and controllable ratio.At present,the research on drug delivery system with tumor-targeting and response has been in-depth,but few cases can achieve stable and controllable drug release ratio,one of the most important reason is the different binding forces between drugs and carriers.In order to solve this problem,a dual-drug backboned poly-prodrug PEG-P(MTO-ss-CUR)was designed by our research.The poly-prodrug consists of hydrophilic block polyethylene glycol(PEG)and hydrophilic block P(MTO-ss-CUR)which is synthesized from mitoxantrone(MTO)and curcumin(CUR)via disulfide bond polymerization.CUR and MTO are antitumor drugs with synergistic effect.The combination of curcumin and mitoxantrone at an appropriate ratio can effectively overcome the tumor resistance caused by the high expression of P-glycoprotein(P-gp).PEG-P(MTO-ss-CUR)can self-assemble into nano-micelle in water environment,which can passively enhance to tumor tissues through enhanced permeability and retention(EPR)effect.Due to disulfide bond polymerization,the hydrophilic block P(MTO-ss-CUR)will degrade under reduction microenvironment provided by high concentration of glutathione(GSH)in tumor cells.Moreover,because the nano-micelle’ hydrophobic core skeleton is the poly-prodrug formed by the polymerization of mitoxantrone(MTO)and curcumin(CUR),the process of drug release activation accompany with the polymer backbone degradation,thus the problem of different binding forces between drugs and carriers can be solved.Experimental results show the dual-drug backboned deliver system can achieve drug release with the stable and controllable ratio at three main levels(solution,in vitro and in vivo).Therefore,the dual-drug delivery system developed in this work provides a novel and efficient strategy for combination chemotherapy.