Hyaluronate-Epidermal Growth Factor Conjugate for Skin Wound Healing and Regeneration
Hyaluronate-Epidermal Growth Factor Conjugate for Skin Wound Healing and Regeneration
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DOI：
10.1021/acs.biomac.6b01216
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发表时间：
2016-11-01
影响因子：
6.2
通讯作者：
Hahn, Sei Kwang
中科院分区：
文献类型：
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作者：
Kim, Hyemin;Kong, Won Ho;Hahn, Sei Kwang
表皮生长因子（EGF）因其刺激皮肤细胞生长、增殖和分化的治疗功能而被认为是一种优良的伤口愈合剂。然而，EGF的透皮递送由于其半衰期短和缺乏有效的制剂而构成了重大挑战。在这里，为了提高透皮递送效率，EGF与透明质酸盐（HA）结合，其被配制成用于皮肤伤口愈合的贴片型膜。通过醛修饰的HA与EGF的N端氨基偶联反应合成HA-EGF偶联物，以最大限度地减少生物活性的损失。HA-EGF缀合物表现出与天然EGF相似的生物活性，如通过ELISA和使用鼠和人成纤维细胞的增殖试验所证实的。为了有效的局部递送，将HA-EGF缀合物掺入高分子量HA的基质膜中。双光子显微镜清楚地可视化HA-EGF缀合物更有效地透皮递送到伤口区域周围的正常皮肤和外周组织，而不是EGF。光学成像和ELISA后，在体内透皮给药表明，共轭的表皮生长因子HA延缓其降解，并延长其在伤口区域的停留时间。此外，在贴片型HA膜中的HA-EGF缀合物的体内透皮递送导致皮肤组织的再生显著改善，甚至进入皮下组织。
Epidermal growth factor (EGF) has been recognized as an excellent wound healing agent due to its therapeutic function stimulating skin cell growth, proliferation and differentiation. However, the transdermal delivery of EGF poses a significant challenge due to its short half-life and lack of efficient formulation. Here, to improve the transdermal delivery efficiency, EGF was conjugated to hyaluronate (HA), which was formulated into a patch-type film for skin wound healing. HA-EGF conjugate was synthesized by coupling reaction between aldehyde-modified HA and N-terminal amine group of EGF to minimize the loss of biological activities. The HA-EGF conjugates exhibited similar biological activities with native EGF as confirmed by ELISA and proliferation tests using murine and human fibroblasts. For the efficient topical delivery, HA-EGF conjugates were incorporated into a matrix film of high molecular weight HA. Two-photon microscopy clearly-visualized more efficient transdermal delivery of HA-EGF conjugates to both normal skin and peripheral tissues around the wound area rather than that of EGF. Optical imaging and ELISA after in vivo transdermal delivery showed that the conjugation of EGF to HA retarded its degradation and extended its residence time in the wound area. Furthermore, in vivo transdermal delivery of HA-EGF conjugate in the patch-type HA film resulted in significantly improved regeneration of skin tissues even into hypodermis.