title: Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model.
abstract: Exogenous administration of growth factors has potential benefits in wound healing; however, limited percutaneous absorption, inconsistent efficacy, and the need for high doses have hampered successful clinical use. To overcome these restrictions, we focused on the development of a topical formulation composed of highly skin-permeable multimeric nanocomplex of growth factors. In the present study, we fused low-molecular-weight protamine (LMWP) with epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-I), and platelet-derived growth factor A ligand (PDGF-A) (producing recombinant [r]LMWP-EGF, rLMWP-IGF-I, and rLMWP-PDGF-A, respectively) via genetic modification. Then, we used in vitro cell proliferation studies to assess the biological activity and the benefits of the combination. The LMWP-conjugated growth factors were complexed with low-molecular-weight heparin (LMWH) and formulated with Poloxamer 188 as a delivery vehicle. After confirming the enhanced skin permeability, in vivo studies were performed to assess whether the LMWP-conjugated growth factor nanocomplex formulations accelerated the healing of full-thickness wounds in mice. The LMWP-conjugated growth factors were biologically equivalent to their native forms, and their combination induced greater fibroblast proliferation. rLMWP-EGF showed significantly enhanced permeability and cumulative permeation, and the rates for rLMWP-IGF-I and rLMWP-PDGF-A, across excised mouse skin, were 124% and 164% higher, respectively, than for the native forms. The LMWP-fused growth factors resulted in formation of nanocomplexes (23.51±1.12 nm in diameter) in combination with LMWH. Topical delivery of growth factors fused with LMWP accelerated wound re-epithelialization significantly, accompanied by the formation of healthy granulation tissue within 9 days compared with a free-growth factor complex or vehicle. Thus, the LMWP-conjugated growth factor nanocomplex can induce rapid, comprehensive healing and may be a candidate wound-healing therapeutic.
authors.affiliation: College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Il-Hong
authors.initials: IH
authors.lastname: Bae
authors.affiliation: College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, Republic of Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Park
authors.affiliation: College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Dae-Yong
authors.initials: DY
authors.lastname: Kim
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006495:Heparin, Low-Molecular-Weight; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D049329:Nanostructures / Q000737:chemistry*; D020442:Poloxamer; D011479:Protamines / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012867:Skin / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D012869:Skin Absorption; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D006495:Heparin, Low-Molecular-Weight; D036341:Intercellular Signaling Peptides and Proteins; D011479:Protamines; D020442:Poloxamer
keywords: epidermal growth factor; insulin-like growth factor; platelet-derived growth factor