The knowledge of metabolic re-programming in cancer cells with differences from their normal counterparts has resulted in the investigation of alternative therapeutic approaches. Mitochondria serve as a central hub for responses to cellular stress as well as injury and thus mitochondrial dysfunction is implicated in several human disorders including cancer. Thus, it stands imperative to target bio-active molecules to the mitochondria and develop robust nanotechnology platforms for effective delivery of such molecules (1). The resistance of cisplatin or its analogues to various cancers can be partially explained by the extensive repair of the Pt-DNA adducts by nucleotide excision repair (NER) pathway which significantly reduces the efficacy of the drugs. A rationally designed hydrophobic mitochondria-targeted Pt(IV) prodrug, Platin-M, was constructed using strain promoted alkyne-azide cycloaddition (SPAAC) chemistry (2). Further, the efficient delivery of Platin-M was achieved using a biocompatible polymeric nanoparticle based on biodegradable and FDA approved poly(lactic-co-glycolic acid)-block-polyethyleneglycol polymer functionalized with a terminal triphenylphosphonium cation to target the mitochondria of cells owing to its lipophilic character and ability to take advantage of the negative mitochondrial membrane potential which exists across the double membrane (3). The entire formulation showed promising activity in neuroblastoma cells. Following the mammoth potential of the nanotechnology platform to deliver Platin-M to the mitochondria, our aim is to develop a unique approach to target the prostate cancer cells using a dual targeting strategy. The cisplatin prodrug containing the mitochondria targeting ligands is encapsulated in a bio-degradable polymeric nanoparticle which also bears prostrate specific membrane antigen (PSMA) and mitochondria targeting ligands on its surface in two layers. The NPs are thought to undergo endocytosis by interaction of the PSMA peptide with the antigens in PCa cells. The mitochondria-targeted NP containing Platin-M released in the acidic pH of the endosomes and cause disruption of endosomal membrane through ionic imbalance, and the released mitochondria targeted NPs will be able to associate with the mitochondria of the prostate cancer cells.<br/>

Precise delivery of a chemotherapeutic Prodrug to mitochondria of prostate cancer cells to bypass repair induced resistance

253rd National Meeting (2017)

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