Year: 2022
Type: article
Abstract: The Hedgehog (Hh) signaling pathway is integral for embryonic development and normal cell maintenance. However, aberrant expression of the Hh pathway is recognized as the oncogenic driving force for basal cell carcinoma (BCC). Current chemotherapeutic treatments that inhibit Hh signaling allow treatment of only locally advanced and metastatic BCCs via inhibition of the transmembrane protein, smoothened. It is further recognized that downstream mutations often lead to chemoresistant tumor recurrence. The Gli proteins are the ultimate regulators of Hh signaling and belong to a family of Cys 2 His 2 zinc finger transcription factors (ZnFTFs) that we have shown can be irreversibly inhibited by a series of cobalt(III) Schiff base–DNA (CoSB–DNA) conjugates. However, a significant challenge is the delivery of CoSB–DNA complexes in mammalian tissues. Herein, we report a polyethyleneimine-functionalized graphene oxide nanoconjugate (GOPEI) that delivers CoGli, a CoSB–DNA complex that targets Gli specifically. We describe the characterization of the surface functionalization of GOPEI and accumulation in ASZ murine BCC cells via confocal microscopy and inductively coupled plasma-mass spectrometry (ICP-MS). Lysosomal escape of CoGli is further confirmed by confocal microscopy. We report the successful targeting of Gli by CoGli and a 17-fold improvement in potency over small-molecule Gli inhibitor GANT-61 in inhibiting Hh-driven migration of ASZ murine BCC cells. This study provides a promising starting point for further investigating CoGli inhibitors of Hh signaling in developed mammalian tissues.
Source: Bioconjugate Chemistry
Authors: Meghan W. Dukes, Elizabeth A. Bajema, Tyler J. Whittemore, Robert A. Holmgren, Thomas J. Meade
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, National Aeronautics and Space Administration, Northwestern University, Ames Research Center, Materials Research Science and Engineering Center, Harvard University, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Division of Materials Research, Division of Electrical, Communications and Cyber Systems
Awards: G1169090945, NNCI: Soft Hybrid Nanotechnology Experimental (SHyNE) Resource, G2233802770, G3010471893, G3454132534, G3520039678, G4082334743, G4285583887, G4289625387, A Highly Specific, Tissue-Permeable Inhibitor of Gli Transcription Factors, MRSEC: Center for Multifunctional Materials, G4912152698, G4958141111, G5218300437, Irreversible Inhibtion of Cerebellar Gli Transcription Factors by Cobalt (III) Complexes, G6540817556, Cancer Nanotechnology Training Program, Real-Time Tracking of Gene Therapy by Bioactivated MR contrast Probes, G7898102844, INSTITUTE FOR PROTEOMICS AND NANOBIOTECHNOLOGY AT NORTHWESTERN UNIVERSITY IN EVANSTON, IL
OpenAlex ID: W4220850767