Three platinum(II) complexes, cisplatin, carboplatin, and oxaliplatin, have been approved by the US FDA for the treatment of cancer. Structural and mechanistic studies have elucidated four early steps that describe their action, cell entry, activation, DNA binding, and transcription inhibition while eluding repair. In spite of the clinical success of cisplatin, there are many occasions where treatment must be discontinued due to drug resistance, acquired or intrinsic, arises from reduced cellular uptake, enhanced DNA repair, drug deactivation, or a combination of these mechanisms. One strategy to overcome resistance is to design specific functionalities onto platinum to enhance uptake and delivery via drug targeting. Oxidation of cisplatin affords Pt(IV) species, known as prodrugs, that can be derivatized with axial ligands for attaching the resulting complexes to carriers for targeted delivery to cancer cells. Upon entry into the cell, the platinum(IV) is reduced, liberating cisplatin and the axial ligands, which can potentiate the cell-killing properties of the construct. In this manner we have functionalized single-walled carbon nanotubes as “longboat” carriers of Pt(IV) constructs into cells, specifically targeted the folate receptor on cancer cells and delivered platinum complexes with extraordinary potency against folate receptor overexpressing cancer cells.1 Dose limiting toxicities or resistance also limit application of cisplatin in many types of cancer including prostate. We devised a unique strategy to deliver cisplatin to prostate cancer cells by constructing Pt(IV)-encapsulated prostate-specific membrane antigen (PSMA) targeted nanoparticles (NPs) of poly(D,L-lactic-co-glycolic acid) (PLGA)-poly(ethylene glycol) (PEG)-functionalized controlled release polymers. By using PLGA-b-PEG nanoparticles with PSMA targeting aptamers (Apt) on the surface as a vehicle for a platinum(IV) prodrug, a lethal dose of cisplatin was delivered specifically to prostate cancer cells.2 By appending axial ligands that destroy the mitochondrial function of the cancer cell while platinum simultaneously impeding DNA-mediated processes in the nucleus, we have synthesized a novel compound mitaplatin, and this new construct is currently being evaluated for anticancer activity vs. normal cells.3 Our technologies provide a potentially important platform for spatiotemporal, controlled release of two or more drugs for future applications in human cancer chemotherapy.4
1. Dhar, S.; Liu, Z.; Thomale, J.; Dai, H. and Lippard, S. J. “Targeted Single Walled Carbon Nanotube Mediated Pt(IV) Prodrug Delivery using Folate as Homing Device”, J. Am. Chem. Soc. 2008, 130, 11467‐11476.
2. Dhar, S.; Gu, F. X.; Langer, R.; Farokhzad, O. C. and Lippard, S. J. “Targeted Delivery of Cisplatin to Prostate Cancer Cells by Aptamer Functionalized Pt(IV) Prodrug‐PLGA–PEG Nanoparticles”,Proc. Natl. Acad. Sci. USA, 2008, 105, 17356‐17361.
3. Dhar, S. and Lippard, S. J. Proc. Natl. Acad. Sci. USA, 2009, 106, 22199‐22204.
4. Kolishetti, N.; Dhar, S.; Pedro, V.; Lin, L.; Karnik, R.; Lippard, S. J. Langer, R.; Farokhzad, O. C. and “Engineering of Self‐assembled Nanoparticle Platform for Precisely‐controlled Combination Drug Therapy”, Proc. Natl. Acad. Sci. USA, 2010, in press.