Choi Jeong Uk, Lee Seong Wook, Pangeni Rudra, Byun Youngro, Yoon In-Soo, Park Jin Woo
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Acta Biomater. 2017 Jul 15;57:197-215. doi: 10.1016/j.actbio.2017.04.034. Epub 2017 May 2.
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.
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.
为增强外源性生长因子（GFs）在慢性伤口治疗中的疗效，我们构建了具有高皮肤渗透性的表皮生长因子（EGF）、胰岛素样生长因子-I（IGF-I）和血小板衍生生长因子-A（PDGF-A）的GF组合。我们将低分子量鱼精蛋白（LMWP）基因偶联到这些GF的N端，形成LMWP-EGF、LMWP-IGF-I和LMWP-PDGF-A。随后，这些分子与透明质酸（HA）复合。天然或LMWP融合的GF组合显著促进成纤维细胞增殖和前胶原合成，在GF与HA复合后观察到这些结果的放大。LMWP-EGF、LMWP-IGF-I、LMWP-PDGF-A和HA的最佳比例分别为1、1、0.02和200。在确认存在协同作用后，我们将LMWP融合的GF-HA复合物掺入直径为107±0.757nm、ζ电位为56.5±1.13mV的阳离子弹性脂质体（ELs）中。与天然GF相比，LMWP融合的GF具有显著改善的皮肤渗透性。LMWP融合的GF-HA复合物的体外伤口愈合率比仅由LMWP融合的GF组成的阳离子ELs高23%。此外，含有LMWP融合的GF-HA复合物的阳离子ELs在糖尿病小鼠模型中显著加速伤口闭合率，与载有载体或天然GF-HA复合物的阳离子ELs相比，伤口大小分别最大减少65%和58%。因此，用载有LMWP融合的GF-HA复合物的阳离子ELs进行局部治疗可协同增强慢性伤口的愈合，发挥快速和持久的作用。
我们认为我们的研究对文献做出了重大贡献，因为它证明了阳离子弹性脂质体作为生长因子（GFs）局部递送系统的潜在应用，这些生长因子在治疗效果上有一定局限性（例如，GF在病变部位的经皮吸收低以及在不同愈合阶段对各种GF的需求）。用载有高皮肤渗透性的低分子量鱼精蛋白（LMWP）融合的GF-透明质酸（HA）复合物的阳离子弹性脂质体进行局部治疗可协同增强糖尿病伤口的愈合，发挥快速和持久的作用。
