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.
