Cisplatin, a Food and Drug Administration (FDA) approved chemotherapeutic, is most extensively characterized as a DNA-damaging agent and its cytotoxicity is arises from the ability to form interstrand and intrastrand nuclear DNA (nDNA) cross-links.1 Chemoresistance of cisplatin therapy is related to various factors including extensive repair of cisplatin-modified DNA in the nucleus by the nucleotide excision repair (NER). Mitochondrial DNA (mtDNA) plays significant roles in cell death and metastatic competence. Limited studies have examined cisplatin activity on mtDNA of cancer cells.2 Delivering cisplatin to the mitochondria to attack mitochondrial genome lacking NER machinery can lead to a rationally designed therapy for metastatic, chemoresistant cancers and might overcome the problems associated with conventional cisplatin treatment. We engineered a hydrophobic mitochondria-targeted cisplatin prodrug, Platin-M, using a strain-promoted alkyne–azide cycloaddition (SPAAC) chemistry.3 Efficient delivery of Platin-M using a brain penetrating mitochondria targeted polymeric nanoparticle (NP) based on biodegradable poly(lactic-co-glycolic acid)-block-polyethyleneglycol functionalized with a terminal triphenylphosphonium cation4 resulted in controlled release of cisplatin from Platin-M locally inside the mitochondrial matrix to attack mtDNA. This unique dual-targeting approach to controlled mitochondrial delivery of cisplatin in the form of a prodrug to attack the mitochondrial genome lacking NER machinery and in vivo distribution of the delivery vehicle in the brain suggested previously undescribed routes for cisplatin-based therapy.5 References 1. Jamieson, E. R.; Lippard, S. J. Structure, recognition, and processing of cisplatin-DNA adducts. Chem. Rev. 1999, 99, 2467-2498. 2. Wisnovsky, S. P.; Wilson, J. J.; Radford, R. J.; Pereira, M. P.; Chan, M. R.; Laposa, R. R.; Lippard, S. J.; Kelley, S. O. Chem. Biol. 2013, 20, 1323−1328. 3. Pathak, R. K.; McNitt, C. D.; Popik, V. V.; Dhar, S. Copper-free click-chemistry platform to functionalize cisplatin prodrugs. Chem. Eur. J. 2014, 20, 6861-6865. 4. Marrache S, Dhar S. Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics. Proc Natl Acad Sci USA 2012, 109,16288-16293. 5. Marrache, S.; Pathak, R. K.; Dhar, S. "Detouring of cisplatin to access mitochondrial genome for overcoming resistance" Proc. Natl. Acad. Sci. USA, 2014, 111, 10444-10449.

Targeting mitochondrial genome by cisplatin prodrug and its nanoparticle formulation to overcome chemoresistance

249th National Meeting (2015)

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