Heterogeneous Surface Architectured pH Responsive Metal-Drug Nano-conjugates for Mitochondria Targeted Therapy of Glioblastomas: A Multimodal Intranasal Approach

Abstract Inorganic materials have lot of attention owing to their unique properties which can be explored for multiple biomedical application. Recently, alloy nanoparticles have been shown as potential candidate for multimodal therapy and imaging of cancer. In the present study, a novel pH responsive poly-l-lysine coated Fe3O4@FePt core shell nanoparticles have been developed for mitochondria targeted (Mito-PANPs) therapy of glioblastoma. The surface of synthesized nanoparticles was modified with mitochondria directing triphenylphsphonium ion (TPP) and hypoxic cancer cell directing protein chlorotoxin (CTX). An attempt has been made to provide multimodal therapy of GBM by targeting hypoxic tissue in combination with chemotherapeutic agent and chemo-photothermal therapy. The synthesized nanoconjugates were extensively characterized and evaluated. The obtained results demonstrated enhanced localization of mitochondria both in vitro and in vivo. A superior proliferation suppressing ability was observed via multiple molecular mechanism involving disruption in mitochondrial energetics. Considering the mitochondria targeting ability, along with specificity for glioma cells and hypoxic region of glioma, multimodal therapeutic approach (chemotherapy, ROS generation by Fe, photothermal therapy, radiotherapy and DNA strand breakage by Pt) and pH responsive drug release, Mito-PANPs can prove to be a promising nanotheranostic platform for tumor imaging and therapy with externally guided monitoring.