Single chemotherapeutic agent like paclitaxel (PTX) has shown some limitations in anti-tumor treatment, such as undesirable side effects, multidrug resistance, and high toxicity. In order to reduce the toxicity of PTX and increase the anti-tumor effect, folate-modified amphiphilic and biodegradable biomaterial was developed to co-deliver PTX and metformin (MET) for exerting the synergistic effect. PTX was physically entrapped in the hydrophobic inner core of the amphiphilic block copolymer by a solvent evaporation method, whereas MET was chemically conjugated to the hydrophilic terminals of copolymer via a pH-sensitive cis-aconityl linkage (Cis). The in vitro release behaviors of the drugs were analyzed by high-performance liquid chromatography (HPLC), and the synergistic effect of the drugs was evaluated by a Q value method. Results showed that drug-loaded micelles with an average size about 100 nm were successfully constructed. In acidic environments, the chemically conjugated MET was rapidly released after the breakage of sensitive bond between drug and copolymer. In vitro anti-tumor studies demonstrated that MET and PTX had a synergistic effect and co-delivery micelles induced higher cytotoxicity and apoptosis against 4T1 breast cancer cells than free drugs. Furthermore, folate-targeted co-delivery micelles increased the cellular uptake of drugs and were found to be effective for the treatment of solid tumor in vivo. These findings indicated that co-delivery of MET and PTX through the polymeric micelles is a promising strategy for cancer therapy.
Keywords: folic acid; metformin; pH-sensitive; paclitaxel; polymeric micelles.