Cell specific mitochondria targeted metabolic alteration for precision medicine

Abstract

Mitochondria play important roles in the maintenance of cellular health. In cancer, these dynamic organelles undergo significant changes in terms of membrane hyperpolarization, altered metabolic functions, fusion–fission balance, and several other parameters. These alterations promote cancer growth, proliferation and spread, and the eventual development of metastatic disease and therapeutic resistance. Thus, routing therapeutics to the mitochondrial compartments can be one of the most promising methodologies for tackling such changes to achieve cancer control. Over the last decade, targeted cancer medicine has experienced tremendous growth, enabling the targeting of mitochondria for greater therapeutic specificity. Here, we demonstrate a feasibility method to specifically target the mitochondria of prostate cancer cells. We achieve such dual targeting by utilizing two functionalized polymers and constructing a single blended nanoparticle (NP). Such a targeting strategy was developed utilizing a polymeric platform that differed in terms of the length of the amphiphilic portions, the linker between the hydrophobic portions, and the attached targeting moieties. In doing this, we demonstrate prostate cancer specific mitochondrial delivery of a chemotherapeutic prodrug to create repair-resistant adducts within mitochondrial DNA promoting cellular death. This article documents the synthetic strategy, optimization of blended NPs for cell specific mitochondria targeting, and the utility of the proof-of-concept design was demonstrated using a combination of analytical and in vitro studies.