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.
STATEMENT OF SIGNIFICANCE: We believe that our study makes a significant contribution to the literature, because it demonstrated the potential application of cationic elastic
liposomes as topical delivery systems for
growth factors (GFs) that have certain limitations in their
therapeutic effects (e.g., low percutaneous absorption of GFs at the lesion site and the requirement for various GFs at different healing stages). Topical treatment with cationic elastic
liposomes loaded with highly skin-permeable low-molecular-weight
protamine (LMWP)-fused GFs-
hyaluronic acid (HA) complex synergistically enhanced the healing of diabetic
wounds, exerting both rapid and prolonged effects.