Aberrant expression of the Hedgehog (Hh) pathway causes Basal Cell Carcinoma (BCC), the most commonly diagnosed cancer in North America and Europe. Current chemotherapeutic strategies against BCC target upstream regulator Smoothened (Smo), but Smo or downstream mutations ultimately lead to chemoresistant tumor recurrence. Gli transcription factors, the ultimate Hh regulators have been identified as valuable targets in BCC and belong to a family of zinc finger transcription factors (ZnFtfs) that are susceptible to inhibition by Co(III)-Schiff base complexes (Co(III)-Sb) developed in the Meade lab. Specificity for one ZnFtf is achieved by coupling the consensus DNA sequence to the Co(III)-Sb scaffold, resulting in a Co(III)-DNA complex. Herein, we report efforts towards improving cellular delivery of Co(III)-Gli, an specific Gli inhibitor, as a chemotherapeutic strategy against Hh signaling in BCC. We investigated polyethyleneimine functionalized graphene oxide (GOPEI) as a Co(III)-Gli delivery vehicle. GOPEI constructs were found to have quantifiable inhibitor loading and superior transfection into the ASZ BCC cell line than liposomal transfection agents. Inhibitor constructs were further investigated against the Hh pathway in cell migration assays, where 300 nM Co(III)-Gli reduced Hh-driven wound healing to the same degree as 5 mM GANT-61, the current gold standard Gli inhibitor.

Co(III)-DNA nanoconstructs against mammalian hedgehog signaling

ACS Spring 2022

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