Theranostic Metallodrugs for Imaging and Fighting Cancer
We propose to develop metallocorroles as versatile theranostic agents with fluorescence, NIR emission, and MRI contrast enhancement imaging modalities. Spectroscopic properties and biological activities can be tuned by judicious choice of the chelated metal ion and by functional group substitutions around the corrole periphery. Detailed studies of different chemical combinations have led to the design of new metallocorroles that exhibit efficient and irreversible endocytosis across a variety of cell types with wide ranging cytotoxicities. One major conclusion reached from the ongoing collaboration between us (my group at the Technion and John Termini’s group from COH) is that while lipophilic metallocorroles provide the greatest flexibility for the optimization of bioimaging and therapeutic properties, their limited aqueous solubility seriously impedes practical medical applications. The Technion group has now discovered an extremely facile and novel formulation methodology that provides water-soluble nanocages composed of lipophilic corroles and native serum proteins. Preliminary cytotoxicity screens performed at COH revealed IC50 values for gold corrole nanocages in the nanomolar range, an orders of magnitude improvement relative to the same reagent solubilized by DMSO, amphiphilic metallocorroles, or cis-platin. We will perform in depth research on the applicability of bio-nanocages for imaging as well as antitumor therapy, including examination of variables affecting size, solubility, and uptake; comparisons of cytotoxicity and mechanism of action relative to related formulations; as well as targeting effects exhibited by the proteins used for nanocage formulation. The non-toxic bio-nanocages will be used for the aforementioned imaging studies, with focus on evaluating both extra- and intracellular trafficking. During my sabbatical at COH, John Termini and I will co-supervise the experimental work performed by researchers from both groups, analyze the results and design new directions with the explicit intention of and using the newly acquired results as the foundation for writing and submitting research proposals to the NIH and/or similar peer-reviewed funding agencies.