Mitochondria targeting self-assembly derived from drug-loaded polymeric nanogel for combination therapy

Abstract

Nanogels can be fabricated to have stimuli-responsive properties responding to tumor microenvironment. Those selective disassembly of nanogel not only enables the tumor-targeting drug delivery, but also the cargo stabilization. To develop the distinctive nanogel, the collaboration with other systems like small molecules, peptides, or proteins, can be one strategy. Recently, Kim et al. reported mitochondria-targeting small molecule, Mito-1, which accumulates in mitochodnria due to its positive charge and undergoes the polymerization via self-assembly, leading to mitochondrial damage. However, small molecule is exposed to biological environment before arrival at the desired site and its therapeutic efficiency is limited. 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, while Mito-1 on the surface of nanogel as a crosslinker maintains the encapsulation stability of nanogel before cell internalization and 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.