A Gli-Targeted Cobalt Complex and Nanoparticle Delivery Agents for Hedgehog Pathway Inhibition

Bajema, Elizabeth Amber

doi:https://doi.org/10.21985/n2-eazj-j621

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A Gli-Targeted Cobalt Complex and Nanoparticle Delivery Agents for Hedgehog Pathway Inhibition

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Many transcription factors (TFs) regulate oncogenic processes and are therefore desirable targets for drug intervention. However, few TF inhibitors have been developed to date due to a lack of specificity and few TF binding pockets. The Meade Lab has overcome these challenges by using cobalt-based complexes that disrupt Cys2His2 zinc finger structural motifs. The cobalt-Schiff base complexes are specific and irreversible inhibitors of zinc finger TFs. In the work presented here, a cobalt-Schiff base complex targeted to Gli TFs was generated. Gli is a known oncogene and the ultimate effector of Hedgehog pathway signaling, heavily implicated in basal cell carcinoma, medulloblastoma, and pancreatic adenocarcinoma. To allow for activatable fluorescence imaging, the cobalt-Schiff base inhibitor was fluorescently modified and was delivered to cells with spherical gold nanoparticles (AuNP) and graphene oxide nanosheets (GO). This allows for facile visualization and tracking of the fluorescent active agent in vitro. Because the fluorophore is quenched by proximity to the AuNP or GO when attached, the presence of fluorescence indicates successful release of the drug payload. This work demonstrates in vitro specificity for Gli protein and successful delivery and visualization of Co-DNA constructs in live cells.

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