Nanoparticles for the Targeted Delivery of Therapeutics to Mitochondria to Overcome Drug Resistance

Abstract

Overcoming drug resistance and improving the toxicity profile of drugs are major challenges in cancer chemotherapy. Targeted delivery along with detouring of drugs to cellular organelles and nano-vehicles have emerged as potential solutions to these challenges respectively. In this work, we aimed to deliver electron transport chain (ETC) damaging drug α-tocopheryl succinate and detour nuclear DNA damaging drugs namely cisplatin and camptothecin to mitochondria to overcome the resistance mechanisms against them. We developed sub-200 nm nanoparticles containing these three drugs. The nanoparticles have the zeta potential (ZP) value of 35.1 mV and are stable in phosphate buffer solution (PBS) at 37 o C and dulbecco’s modified eagle medium (DMEM) for 3 days. They were sub-200 nm in size in water at 4 o C after one month indicating good shelf-life. Their ZP value increased to 40.8 mV in pH 5.5. These nanoparticles are being evaluated for their anti-cancer efficacy and further, their mechanism of action will be studied. We also developed tertiary amine-functionalized nanoparticles based on α-tocopheryl succinate to study the localization of nanoparticles into mitochondria. These nanoparticles are also sub-200 nm in size and have the ZP value > 35 mV. The set of these nanoparticles will be expanded and will be evaluated for mitochondrial localization. Further, we checked the effect of sonication on the size and polydispersity of nanoparticles. We observed that with sonication time, the size decreases with increasing monodispersity.