Mitochondria-targeting self-assembly based on drug-loaded polymeric nanogel for combination therapy

Abstract

Mitochondria are important suborganelle that play a critical role in diverse cellular processes. Mitochondria-targeted therapeutic system has been emerged as potential novel strategy in cancer therapy. Mito-1, a small molecule containing triphenylphosphonium (TPP) and quaternary ammonium group, can target and accumulate in mitochondria due to its positive charge, leading to polymerization-induced self-assembly, PISA at high concentration in aconfined space. However, small molecule is exposed to biological environment before arrival at the desired tissue and cell. Herein, we designed mitochondria-targeting self-assembly derived from drug-loaded polymeric nanogel to maximize the therapeutic efficacy by combination therapy using anticancer drug, camptothecin (CPT), and self-assembly molecule, Mito-1. CPT loaded in the nanogel induces damage on nuclei DNA and apoptosis finally, while Mito-1 on the surface of nanogel as a crosslinker forms fibrous structure inside mitochondria which is large enough to disrupt the mitochondrial membrane, resulting necroptosis. By combined effect of apoptosis and necroptosis, nanogel system has shown cytotoxicity on HeLa cell and efficient mitochondrial membrane disruption was proved by mitochondria-related indicators.