The long-term goal of this research is to improve platinum-based cancer therapy. Platinum drugs are administered to nearly half of all cancer patients receiving chemotherapy. Despite the efficacy of these treatments, drug resistance, toxic side effects, and tumor recurrence are critical barriers that need to be addressed for the next generation of platinum chemotherapeutics. Overcoming these obstacles requires improved understanding of factors that stabilize platinum compounds en route to the tumor, the invention of better strategies for selective drug uptake and retention, and the design of constructs that eradicate cancerous tissue. The three specific aims of the proposed research address these objectives.
The first aim i s to deploy methods for directing platinum agents to cancer cells by targeting their unique biology. Tactics for achieving this goal include programmed delivery through cancer-specific receptors on the cell surface and the synthesis and evaluation of dual-threat constructs. The latter capitalize on the power of Pt-DNA adducts to arrest transcription and trigger apoptosis while simultaneously disabling factors that undermine efficacy, such as cancer stem cells in the tumor microenvironment. The approaches include linking cancer cell-targeting units or apoptosis-enhancing factors to a platinum(II) drug, or to a platinum(IV) prodrug that will release such a component upon platinum reduction in the cancer cell, as well as packaging the platinum and auxiliary modules in biodegradable nanoparticles.
The second aim of this proposal is to understand and improve phenanthriplatin, a recently discovered, uniquely potent cationic platinum complex derived from cisplatin by replacing one of its chloride ligands with phenanthridine. Phenanthriplatin is highly differentiated in the spectrum of cancer cells that it targets compared to any other platinum drug, indicating its potential to circumvent mechanisms that limit conventional platinum chemotherapy. The approaches include investigating the DNA interactions of phenanthriplatin and their effects on cellular function, experiments to probe and stimulate its mechanisms of inducing cell death, and chemically modifying it to install dual-threat features similar to those planned for the cisplatin drug family ultimately to establish the utility of phenanthriplatin in vivo.
The final aim i s to deliver a high bolus of platinum to cancer cells to improve the therapeutic response. This goal will be met by the synthesis of self-assembled supramolecular constructs based on Pt(II) centers that form a spherical cage with hydrophobic cavities that can accommodate an additional payload of Pt(IV) prodrugs. Taken together, research proposed in the three aims will give rise to a greater understanding of conventional and non-traditional platinum anticancer agents, providing information that will guide the generation of novel and more effective chemotherapeutic candidates. The results of these investigations will also be of value to other investigators in the rapidly expanding field of metal-based medicines, and it is expected that the innovative concepts introduced here for understanding and improving platinum anticancer agents can be readily adapted for other therapeutic DNA-binding metal complexes.
This project aims to increase the understanding of, and make improvements upon, cisplatin and related anticancer drugs, a family comprising three widely used and successful chemotherapeutic agents that contain platinum. The knowledge acquired will be used to design, synthesize, and evaluate new platinum-based anticancer drug candidates, and preliminary work toward these goals has aided Blend Therapeutics (blendtx.com) to advance two lead molecules through IND-enabling studies, each of which involves a novel platinum entity with new modes of action for cancer therapy.
|Czapar, Anna E; Zheng, Yao-Rong; Riddell, Imogen A et al. (2016) Tobacco Mosaic Virus Delivery of Phenanthriplatin for Cancer therapy. ACS Nano 10:4119-26|
|Patra, Malay; Johnstone, Timothy C; Suntharalingam, Kogularamanan et al. (2016) A Potent Glucose-Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells. Angew Chem Int Ed Engl 55:2550-4|
|Johnstone, Timothy C; Suntharalingam, Kogularamanan; Lippard, Stephen J (2016) The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs. Chem Rev 116:3436-86|
|Patra, Malay; Awuah, Samuel G; Lippard, Stephen J (2016) Chemical Approach to Positional Isomers of Glucose-Platinum Conjugates Reveals Specific Cancer Targeting through Glucose-Transporter-Mediated Uptake in Vitro and in Vivo. J Am Chem Soc 138:12541-51|
|Zheng, Yao-Rong; Suntharalingam, Kogularamanan; Bruno, Peter M et al. (2016) Mechanistic Studies of the Anticancer Activity of An Octahedral Hexanuclear Pt(II) Cage. Inorganica Chim Acta 452:125-129|
|Riddell, Imogen A; Johnstone, Timothy C; Park, Ga Young et al. (2016) Nucleotide Binding Preference of the Monofunctional Platinum Anticancer-Agent Phenanthriplatin. Chemistry 22:7574-81|
|Johnstone, Timothy C; Suntharalingam, Kogularamanan; Lippard, Stephen J (2015) Third row transition metals for the treatment of cancer. Philos Trans A Math Phys Eng Sci 373:|
|Johnstone, Timothy C; Alexander, Sarah M; Wilson, Justin J et al. (2015) Oxidative halogenation of cisplatin and carboplatin: synthesis, spectroscopy, and crystal and molecular structures of Pt(IV) prodrugs. Dalton Trans 44:119-29|
|Johnstone, Timothy C; Lippard, Stephen J (2015) Improvements in the Synthesis and Understanding of the Iodo-bridged Intermediate en Route to the Pt(IV) Prodrug Satraplatin. Inorganica Chim Acta 424:254-259|
|Suntharalingam, Kogularamanan; Awuah, Samuel G; Bruno, Peter M et al. (2015) Necroptosis-inducing rhenium(V) oxo complexes. J Am Chem Soc 137:2967-74|
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