Precious metal complexes are currently used and are actively being explored for use in cancer chemotherapy. Compounds of platinum have been especially successful in this regard with cisplatin, carboplatin and oxaliplatin forming the "front line" for the clinical treatment of many forms of human cancer. In an effort uncover the chemical basis behind the marketability and clinical effectiveness of the platinum drugs, we examined the factors that lead to stable drug formulations as well as studied the kinetics and mechanism of reaction of the agents under physiological conditions with biological targets such as DNA. We recently found that the high stability of commercial formulations of carboplatin and oxaliplatin is due to existence of hither to unknown drug association complexes in the ready to use infusion solution the nature of which protects the platinum compound from attack and degradation by water. We also recently found that carbonate, which is found in blood and the cell, readily reacts with platinum drugs to produce carbonato complexes that are likely the species circulating in blood and responsible for cancer cell death. An active area of platinum drug discovery is focused on complexes of Pt(IV) that serve a prodrugs for biologically active Pt(II) compounds. In an effort to understand how these interesting produgs may be activated in the body, we have been studying the kinetics and mechanism of the reduction of these agents with ascorbic acid and glutathione finding that the nature of the reducing agent controls the type of the cytotoxic platinum complex formed.
Nanotechnology is revolutionizing many aspects of medicine including cancer chemotherapy. Since gold nanoparticles (AuNP) have highly tunable surfaces and are inherently non-toxic to human cells, we have been exploring the use of surface-modified AuNPs for delivering clinically approved drugs to tumor sites. Current work is focused on coating 15 nm AuNPs with many copies of duplex DNA which are encoded to selectively bind the clinically used intercalating drugs doxorubicin (DOX) and actinomycin D (ActD). When equipped with targeting vectors, these drug-loaded nanoparticles act as vehicles for delivering high payloads of drug to cancer cells thereby enhancing the likelihood of cell death. In an effort to integrate platinum drugs into an effective delivery strategy involving gold nanoparticles, we are also studying cyclodextrin coated AuNPs that can surface interact through a guest-host interaction with adamantane appended cytotoxic Pt(II) and Pt(IV) complexes. Since the "armed" AuNP delivery vehicle can carry many platinum complexes, it can be used to deliver a high payload of toxic platinum compounds to cancer cells.
Collaborators on these research projects include, Professors, Jerry Goodisman, Mathew M. Maye and Yan Yeung Luk of the Department of Chemistry, Syracuse University.
Textbook, Dabrowiak, J. C., Metals in Medicine, John-Wiley & Sons, Ltd, Chichester, UK, 2009. » more info
Special Volume, Inorganica Chimica Acta, Dabrowiak, J. C. (Guest Editor) Metals in Medicine, December 2012.
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DNA-capped nanoparticles designed for doxorubicin drug delivery. Alexander, C. M., Maye, M. M., Dabrowiak, J. C. Chem. Commun., 2011, 47, 3418-20.
Stability of carboplatin and oxaliplatin in their infusion solutions is due to self-association. Di Pasqua, A. J., Kerwood, D. J., Shi, Y., Goodisman, J., Dabrowiak, J. C. Dalton Trans. 2011, 40, 4821-25.
Adamantane-platinum conjugate hosted in β-cyclodextrin: Enhancing transport and cytotoxicity by noncovalent modification. Prashar, D., Shi, Y., Bandyopadhyay, D., Dabrowiak, J. C., Luk, Y.-Y. Bioorg. Med. Chem. Lett. 2011, 21, 7421-25.
Pt(IV) complexes as prodrugs for cisplatin. Shi, Y., Lui, S.-A., Kerwood, D. J., Goodisman, J., Dabrowiak, J. C. J. Inorg. Biochem., 2012, 107, 6-14.
Understanding how the anticancer drug carboplatin works: From the bottle to the cell. Di Pasqua, A. J., Goodisman, J., Dabrowiak, J. C. Inorg. Chim. Acta, 2012, 389, 29-35.
Enhanced detection of gold nanoparticles in agarose gel electrophoresis. Hasenoehrl, C., Alexander, C. M., Azzarelli, N. N., Dabrowiak, J. C. Electrophoresis., 2012, 33, 1251-54.
Investigation of the Drug Binding Properties and Cytotoxicity of DNA-Capped Nanoparticles Designed as Delivery Vehicles for the Anticancer Agents Doxorubicin and Actinomycin D. Alexander, C. M., Dabrowiak, J. C., Maye, M. M. Bioconjug. Chem., 2012, 23, 2061-70.
Guest-host interactions involving platinum anticancer agents. DNA binding and cytotoxicity of a b-cyclodextrin-adamantane Pt(IV) complex. Shi, Y., Dabrowiak, J. C. Inorg. Chim. Acta, 2012, 393, 337-39.
Metals in Medicine, Dabrowiak, J. C. Inorg. Chim. Acta, 2012, 393, 1-2.
Gravitational sedimentation of gold nanoparticles. Alexander, C. M., Dabrowiak, J. C., Goodisman, J., J. Coll. Interf. Sci., 2013, in press.