title: Multivalent Conjugates of Sonic Hedgehog Accelerate Diabetic Wound Healing.
abstract: Despite their preclinical promise, few recombinant growth factors have been fully developed into effective therapies, in part, due to the short interval of therapeutic activity after administration. To address this problem, we developed nanoscale polymer conjugates for multivalent presentation of therapeutic proteins that enhance the activation of targeted cellular responses. As an example of this technology, we conjugated multiple Sonic hedgehog (Shh) proteins onto individual hyaluronic acid biopolymers to generate multivalent protein clusters at defined ratios (i.e., valencies) that yield enhanced Shh pathway activation at equivalent concentrations relative to unconjugated Shh. In this study, we investigated whether these multivalent conjugates (mvShh) could be used to improve the therapeutic function of Shh. We found that a single treatment with mvShh significantly accelerated the closure of full-thickness wounds in diabetic (db/db) mice compared to either an equivalent dose of unconjugated Shh or the vehicle control. Furthermore, we identified specific indicators of wound healing in fibroblasts and endothelial cells (i.e., transcriptional activation and cell migration) that were activated by mvShh in vitro and at concentrations approximately an order of magnitude lower than the unconjugated Shh. Taken together, our findings suggest that mvShh conjugates exhibit greater potency to activate the Shh pathway, and this multivalency advantage improves its therapeutic effect to accelerate wound closure in a diabetic animal model. Our strategy of multivalent protein presentation using nanoscale polymer conjugates has the potential to make a significant impact on the development of protein-based therapies by improving their in vivo performance.
authors.affiliation: 1 Department of Bioengineering, University of California at Berkeley , Berkeley, California.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Han
authors.affiliation: 2 Department of Surgery, University of California at San Francisco , San Francisco, California.
authors.forename: Hans
authors.initials: H
authors.lastname: Layman
authors.affiliation: 3 Department of Materials Science and Engineering, University of California at Berkeley , Berkeley, California.
authors.forename: Nikhil A
authors.initials: NA
authors.lastname: Rode
authors.affiliation: 4 Department of Chemical and Biomolecular Engineering, University of California at Berkeley , Berkeley, California.
authors.forename: Anthony
authors.initials: A
authors.lastname: Conway
authors.affiliation: 1 Department of Bioengineering, University of California at Berkeley , Berkeley, California.|4 Department of Chemical and Biomolecular Engineering, University of California at Berkeley , Berkeley, California.
authors.forename: David V
authors.initials: DV
authors.lastname: Schaffer
authors.affiliation: 2 Department of Surgery, University of California at San Francisco , San Francisco, California.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Boudreau
authors.affiliation: 1 Department of Bioengineering, University of California at Berkeley , Berkeley, California.
authors.forename: Wesley M
authors.initials: WM
authors.lastname: Jackson
authors.affiliation: 1 Department of Bioengineering, University of California at Berkeley , Berkeley, California.|3 Department of Materials Science and Engineering, University of California at Berkeley , Berkeley, California.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Healy
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000473:pathology*; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D053823:Hedgehog Proteins