Shanta Dhar NanoTherapeutics Research Laboratory Department of Chemistry University of Georgia Athens, GA 30602 shanta@uga.edu Mitochondria play significant roles in carcinogenesis process due to their active participation in energy production and maintenance of cellular apoptosis. The genome, which resides inside the mitochondrial lumen, mitochondrial DNA (mtDNA), is important in cell death and drives tumor towards a more metastatic stage. The most widely used nuclear DNA (nDNA) damaging agent cisplatin is highly effective in many cancers, however several types of malignant cells become resistant to cisplatin-based therapy. This resistance often results from accelerated nDNA repair by the nucleotide excision repair (NER) machinery. The lack of NER in the mitochondria and highly mutated mtDNA in aggressive cancers indicated that directing cisplatin in the form of a prodrug to the mitochondrial lumen can be beneficial to overcome resistance. Here, we describe a click chemistry based methodology to construct prodrugs for cisplatin with mitochondrial association properties, incorporation of these prodrugs in biodegradable polymeric nanoparticles, in vitro, and in vivo properties of this system. In another approach, we will describe the use of click chemistry to construct new polymers for delivery of a cocktail of cisplatin and anti-inflammatory agents. Reference: (1) Marrache, S.; Pathak, R. K.; and Dhar, S. Detouring of cisplatin to access mitochondrial genome for overcoming resistance, Proc. Natl. Acad. Sci. USA, 2014, 111, 10444-10449. (2) Pathak, R. K.; McNitt, C. D.; Popik, V. V. and Dhar, S. Copper-free click-chemistry platform to functionalize cisplatin prodrugs, Chem. Eur. J., 2014, 20, 6861-6865. (3) Pathak, R. K.; and Dhar, S. A nanoparticle cocktail: Temporal release of predefined drug combinations, J. Am. Chem. Soc., 2015, 137, 8324-8327.

Click chemistry tools for delivering cisplatin to cancer cells

251st National Meeting (2016)

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