Metal-based anticancer agents

Current cancer research within the Lippard lab is focused on understanding platinum anticancer drugs and developing non-classical anticancer complexes, including monofunctional Pt(II), dual threat Pt(IV), and other third row transition metal complexes. Our work has influenced clinical outcomes by revealing the mechanism of action of platinum drugs and holds promise to provide cures, considering the potential of new agents to display better efficacy, reduced drug resistance or tumor recurrence in comparison to current anticancer treatments. Research on platinum complexes led to the co-founding of Blend Therapeutics in 2011. Blend (now Placon Therapeutics) recently had an IND cleared by the FDA to take a new platinum compound into a Phase I clinical trial for cancer treatment.

The discovery of phenanthriplatin, [Pt(NH3)2(phenanthridine)Cl]+, a monofunctional Pt(II) complex provided a cisplatin derivative with significantly improved in vitro anticancer activity over the FDA approved platinum drugs with complimentary spectrum of activity. The mode of action for phenanthriplatin involved DNA damage followed by transcription stalling, as a result of the bulky phenanthridine ligand impeding procession of RNA Pol II. A role in ribosomal biosynthesis stress has also been implicated. Incorporation of phenanthriplatin into tobacco mosaic virus in collaborative work allowed this potency to be translated to efficacy in animals. Detailed structural investigations into phenanthriplatin binding to its biological targets are ongoing.

Consistent with our observation that bifunctional adduct formation is not required to impart the anticancer activity of metal constructs, the Lippard lab began investigations into the effects of octahedral transition metal complexes, focusing specifically on high oxidation state osmium and rhenium complexes. Osmium(VI) nitrido complexes containing a variety of bidentate ligands were initially accessed and found to demonstrate excellent anticancer activity. Further investigations revealed that osmium(VI) nitrido complexes selectively kill cancer stem cells over bulk tumor cells, through a combination of DNA damage and endoplasmic reticulum stress. In addition, rhenium(V) oxo complexes also containing bidentate ligands were shown to selectively kill cancer cells over normal cells by programmed necrosis, commonly referred to as necroptosis.

Another active area of research within the Lippard lab is the development of novel delivery strategies for Pt anticancer agents. Passive and active cancer targeting approaches have been employed including biodegradable nanoparticles, self-assembled platinum-based nanoclusters, and the use of glucose, folic acid, and peptides as homing devices.

Platinum(IV) prodrugs show increased inertness with respect to platinum(II) and must undergo reduction before aquation and subsequent reaction with a biological nucleophile. As a result, the circulation lifetime of Pt(IV) species in blood can be extended and can simultaneously target elements of cancer cell biology that distinguish them from normal cells of which we term “dual threat”.  A variety of dual threat constructs have been employed in the Lippard lab to impact efficacy. Notable among them are mitochondria targeting constructs, amphiphilic platinum (IV) constructs that bind human serum albumin non covalently for delivery into cancer cells, and Pt-immune checkpoint inhibitor constructs that preferentially target the immunosuppressive enzyme, indoleamine-2,3-dioxygenase for cancer immuno-chemotherapy.