Mitochondrial-Targeted Multifunctional Platinum-Based Nano “Terminal-Sensitive Projectile” for Enhanced Cancer Chemotherapy Efficacy

Abstract

Platinum-based anticancer drugs exert their effects by forming adducts within nuclear DNA (nDNA), inhibiting transcription and inducing apoptosis in cancer cells. However, tumor cells have evolved mechanisms to resist these drugs. Given mitochondria’s role in cancer and their lack of nucleotide excision repair (NER), targeting mitochondrial DNA (mtDNA) offers a strategy. Herein, a platinum-based terminal-sensitive projectile (TSB) which comprises a heterofunctional tetravalent platinum prodrug as the primary warhead, complemented by a guidance system incorporating triphenylphosphine (TPP) and a secondary warhead, FFa (Fenofibric acid) was developed. TSB was then encapsulated within IR780 coupling DSPE-PEG 2K for enhanced delivery (NTSB). This design allows the TSB to be precisely targeted into intertumoral mitochondria as its targeting terminal, releasing free oxaliplatin (OXA) and FFa upon reaching its terminal destination. The accumulation of OXA leads to cross-linking with mtDNA, causing mitochondrial dysfunction, while FFa disrupts the electron transport chain (ETC), impairing oxidative phosphorylation (OXPHOS). Furthermore, under near-infrared (NIR) irradiation, the IR780 component generates a phototherapeutic thermal effect and reactive oxygen species (ROS), which deplete intracellular glutathione (GSH) levels and facilitate Pt cross-linking with mtDNA. Both in vitro and in vivo studies have demonstrated that this comprehensive approach significantly enhances the sensitivity of tumor cells to platinum-based chemotherapeutic drugs.