Corrole conjugates: a unique approach to tumor targeting

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 2328 The purpose of the studies described here is to test the hypothesis that a novel corrole compound can induce tumor-specific toxicity by forming a noncovalent assembly with a novel recombinant cell penetrating viral protein targeted to HER2+ breast cancer cells. Corroles are macrocyclic compounds that can bind and transport metal ions, and thus may be toxic to cells. While anionic corroles poorly enter cells, likely due to the negatively charged cell membrane, delivery via a targeted, membrane penetrating agent facilitates cell entry. Accordingly, we have demonstrated that a recombinant cell penetrating Ad capsid protein forms a noncovalent assembly with corroles that is stable in serum and facilitates target-specific delivery and cell death in vitro, while the equivalent concentration of either free corrole or free capsid protein has no effect on cell survival. Here we now demonstrate that heregulin-targeted corrole conjugates specifically impact HER2+ but not HER2- human breast cancer cells in a mixed cell culture at an efficacy that exceeds the equivalent concentration of adriamycin, and have begun in vivo testing. We have observed that delivery of corroles or corrole conjugates into established tumors yields shrinkage and prevention of tumor growth. The high fluorescence intensity of sulfonated corrole bound to gallium metal ion lends itself to live animal in vivo imaging, and has enabled us to examine the biodistribution of free and targeted corroles in mice. Furthermore, we have observed in vitro that the fluorescence of even nanomolar concentrations of corrole is measurable in 100% human serum, suggesting that this compound may be easily detected in blood samples. Finally, our ongoing studies investigating the mechanism of corrole-mediated cell death indicate that corroles remain excluded from the nucleus after cell entry and induce the appearance of apoptosis markers. Altogether, these findings indicate that corroles may serve dual purpose as both imaging and therapeutic agents, and, as we have observed from our studies, form unique conjugates with specialized carrier molecules that may enable a new and improved form of tumor targeted therapy.