制备并体内评价一种包含高透皮生长因子、槲皮素和氧载体的局部水凝胶系统，以增强糖尿病创面愈合治疗。
Preparation and in vivo evaluation of a topical hydrogel system incorporating highly skin-permeable growth factors, quercetin, and oxygen carriers for enhanced diabetic wound-healing therapy.
机构信息
College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.
College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam 58554, Republic of Korea.
出版信息
Int J Nanomedicine. 2019 Jul 18;14:5449-5475. doi: 10.2147/IJN.S213883. eCollection 2019.
PURPOSE
We created and evaluated an enhanced topical delivery system featuring a combination of highly skin-permeable growth factors (GFs), quercetin (QCN), and oxygen; these synergistically accelerated re-epithelialization and granulation tissue formation of/in diabetic wounds by increasing the levels of GFs and antioxidants, and the oxygen partial pressure, at the wound site.
METHODS
To enhance the therapeutic effects of exogenous administration of GFs for the treatment of diabetic wounds, we prepared highly skin-permeable GF complexes comprised of epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), platelet-derived growth factor-A (PDGF-A), and basic fibroblast growth factor (bFGF), genetically attached, via the N-termini, to a low-molecular-weight protamine (LMWP) to form LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, and LMWP-bFGF, respectively. Furthermore, quercetin (QCN)- and oxygen-carrying 1-bromoperfluorooctane (PFOB)-loaded nanoemulsions (QCN-NE and OXY-PFOB-NE) were developed to improve the topical delivery of QCN and oxygen, respectively. After confirming the enhanced penetration of LMWP-GFs, QCN-NE, and oxygen delivered from OXY-PFOB-NE across human epidermis, we evaluated the effects of combining LMWP-GFs, QCN-NE, and OXY-PFOB-NE on proliferation of keratinocytes and fibroblasts, and the chronic wound closure rate of a diabetic mouse model.
RESULTS
The optimal ratios of LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, LMWP-bFGF, QCN-NE, and OXY-PFOB-NE were 1, 1, 0.02, 0.02, 0.2, and 60, respectively. Moreover, a Carbopol hydrogel containing LMWP-GFs, QCN-NE, and OXY-PFOB-NE (LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL) significantly improved scratch-wound recovery of keratinocytes and fibroblasts in vitro compared to that afforded by hydrogels containing each component alone. LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL significantly accelerated wound-healing in a diabetic mouse model, decreasing wound size by 54 and 35% compared to the vehicle and LMWP-GFs, respectively.
CONCLUSION
LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL synergistically accelerated the healing of chronic wounds, exerting both rapid and prolonged effects.
目的
我们开发并评估了一种增强型局部递送系统，该系统结合了高透皮生长因子（GFs）、槲皮素（QCN）和氧气；这些通过增加 GFs 和抗氧化剂的水平以及伤口部位的氧气分压，协同加速糖尿病伤口的再上皮化和肉芽组织形成。
方法
为了增强外源性 GFs 治疗糖尿病伤口的治疗效果，我们制备了高透皮 GF 复合物，该复合物由表皮生长因子（EGF）、胰岛素样生长因子-I（IGF-I）、血小板衍生生长因子-A（PDGF-A）和碱性成纤维细胞生长因子（bFGF）组成，通过 N 末端与低分子量鱼精蛋白（LMWP）连接，分别形成 LMWP-EGF、LMWP-IGF-I、LMWP-PDGF-A 和 LMWP-bFGF。此外，开发了携带槲皮素（QCN）和载氧 1-溴全氟辛烷（PFOB）的纳米乳液（QCN-NE 和 OXY-PFOB-NE），分别提高 QCN 和氧气的局部递送。在确认 LMWP-GFs、QCN-NE 和 OXY-PFOB-NE 增强穿透人体表皮后，我们评估了 LMWP-GFs、QCN-NE 和 OXY-PFOB-NE 联合使用对角质形成细胞和成纤维细胞增殖以及糖尿病小鼠模型慢性伤口闭合率的影响。
结果
LMWP-EGF、LMWP-IGF-I、LMWP-PDGF-A、LMWP-bFGF、QCN-NE 和 OXY-PFOB-NE 的最佳比例分别为 1、1、0.02、0.02、0.2 和 60。此外，含有 LMWP-GFs、QCN-NE 和 OXY-PFOB-NE 的 Carbopol 水凝胶（LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL）与单独含有每种成分的水凝胶相比，显著改善了体外角质形成细胞和成纤维细胞划痕伤口的恢复。LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL 显著加速了糖尿病小鼠模型的伤口愈合，与载体和 LMWP-GFs 相比，伤口面积分别减少了 54%和 35%。
结论
LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL 协同加速慢性伤口愈合，具有快速和持久的作用。
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