PH-triggered prodrug micelles for cisplatin delivery: Preparation and In Vitro/Vivo evaluation

Abstract

A novel copolymers based on glycidyl azide polymer (GAP) and polyethylene glycol (PEG) with comb-linear-comb architecture were synthesized via atom transfer radical polymerization (ATRP) and then linear GAP segment modified to generate polymers with pendant thiol groups. Subsequent thiol-ene reaction with maleic anhydride leads to polymers with carboxylate functionalities, which were conjugated with cisplatin to generate polymer-cisplatin conjugates (PCPtCs). Due to the hydrophobicity of the drug conjugated block, the copolymers took on amphiphilic character leading to micelle formation in aqueous solution with an average diameter of 142 nm. As an environmentally sensitive drug delivery vehicle, these conjugates can potentially minimize the drug loss during PCPtCs circulation in the blood, where the pH value is neutral, and trigger rapid intracellular drug release after the PCPtCs are endocytosed by the target cells. This characteristic drug release profile holds the promise to suppress cancer cell chemoresistance by rapidly releasing a high dose of chemotherapy drugs inside the tumor cells, thereby improving the therapeutic efficacy of the drug payload. In addition, PCPtCs also showed excellent cytotoxicity effect on MCF-7 cell line whereas the copolymer had no significant toxicity effects on MCF-7 cell line due to which cell viability maintain over 80% at all concentration. As well as, the copolymer did not show noticeable toxicity on A. salina and synthesized PCPtCs showed hemolysis effect lower than 9%. Moreover, this result was repeat in LD50 and all mice which treat with 5000 mg/Kg were still alive after 24 and 168 h, which confirmed the safety of the carrier. All of these results show that this unique pH sensitive PCPtCs may offer a very promising approach for drug delivery of cisplatin.