Multivariate Metal-Organic Frameworks based pH-responsive dual-drug delivery system for chemotherapy and chemodynamic therapy

Combination therapy has emerged as a promising strategy due to its synergistic therapeutic pathways that enhance anticancer efficacy and limits the emergence of drug resistance. In this work, MIL-88B type multivariate (MTV-1) nanocarriers based on mixed linker (1, 4-benzenedicarboxylic acid and biphenyl-4,4'-dicarboxylic acid ) and metals (iron and cobalt) were synthesized. Presence of the distinct linkers modified the pore makeup of MTV-1 and facilitated the co-encapsulation of two anticancer drugs of varying molecular sizes; 5-Fluorouracil (5-FU) and Curcumin (CUR). The drug loading measurements on MTV-1@5-FU+CUR represented a loading capacity of 15.9wt% for 5-FU and 9.3wt% for CUR, respectively. They further exhibited a pH-responsive drug release pattern with higher concentrations of 5-FU and CUR released at pH 5.5 (simulating cancer microenvironment) compared to pH 7.4 (physiological environment). Moreover, we also demonstrated that MTV-1 MOFs, due to the presence of mixed valence metal ions, could perform peroxidase-like activity and catalyzes H2O2 decomposition to produce •OH radicals for chemodynamic therapy. Cell cytotoxicity assays exhibited significant inhibitory effects of MTV-1@5-Fu+CUR against HepG2 cells with an IC50 of 78.7 g/mL. Together with dual-drug loading, pH-responsive release, and chemodynamic therapy, MTV-1 show excellent potential for multifunctional anticancer treatment.