Old Drugs in New Wraps

S. Dhar
University of Miami,
United States

Keywords: drug delivery, carrier

Summary:

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. I will describe a new methodology to construct prodrugs for cisplatin with mitochondrial association properties,1-3 incorporation of these prodrugs in biodegradable polymeric nanoparticles with mitochondria targeting and brain accumulating properties4, in vitro, and in vivo properties of this system. Cancer cells also maintain normal mitochondrial glutathione as one of the defense mechanisms to inhibit apoptosis. I will discuss mitochondrial delivery of cisplatin with additional functionalities in the form of prodrug using nano-formulations to modulate mitochondrial glutathione to control the fate of cancer cell death by apoptosis under cellular resistance.5,6 In another approach, I will describe the use of a targeted nano-cocktail of cisplatin and anti-inflammatory agents for combination therapy of advanced cancers.