To enhance the therapeutic effects of exogenous administration of growth factors (GFs) in the treatment of chronic wounds， we constructed GF combinations of highly skin-permeable epidermal growth factor (EGF)， insulin-like growth factor-I (IGF-I)， and platelet-derived growth factor-A (PDGF-A). We genetically conjugated a low-molecular-weight protamine (LMWP) to the N-termini of these GFs to form LMWP-EGF， LMWP-IGF-I， and LMWP-PDGF-A. Subsequently， these molecules were complexed with hyaluronic acid (HA). Combinations of native or LMWP-fused GFs significantly promoted fibroblast proliferation and the synthesis of procollagen， with a magnification of these results observed after the GFs were complex... More
To enhance the therapeutic effects of exogenous administration of growth factors (GFs) in the treatment of chronic wounds， we constructed GF combinations of highly skin-permeable epidermal growth factor (EGF)， insulin-like growth factor-I (IGF-I)， and platelet-derived growth factor-A (PDGF-A). We genetically conjugated a low-molecular-weight protamine (LMWP) to the N-termini of these GFs to form LMWP-EGF， LMWP-IGF-I， and LMWP-PDGF-A. Subsequently， these molecules were complexed with hyaluronic acid (HA). Combinations of native or LMWP-fused GFs significantly promoted fibroblast proliferation and the synthesis of procollagen， with a magnification of these results observed after the GFs were complexed with HA. The optimal proportions of LMWP-EGF， LMWP-IGF-I， LMWP-PDGF-A， and HA were 1， 1， 0.02， and 200， respectively. After confirming the presence of a synergistic effect， we incorporated the LMWP-fused GFs-HA complex into cationic elastic liposomes (ELs) of 107±0.757nm in diameter and a zeta potential of 56.5±1.13mV. The LMWP-fused GFs had significantly improved skin permeation compared with native GFs. The in vitro wound recovery rate of the LMWP-fused GFs-HA complex was 23% higher than that of cationic ELs composed of LMWP-fused GFs alone. Moreover， the cationic ELs containing the LMWP-fused GFs-HA complex significantly accelerated the wound closure rate in a diabetic mouse model and the wound size was maximally decreased by 65% and 58% compared to cationic ELs loaded with vehicle or native GFs-HA complex， respectively. Thus， topical treatment with cationic ELs loaded with the LMWP-fused GFs-HA complex synergistically enhanced the healing of chronic wounds， exerting both rapid and prolonged effects.
