Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
School of International Studies, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China and First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
Biomater Sci. 2019 May 28;7(6):2582-2599. doi: 10.1039/c9bm00341j.
Keratinocyte growth factor (KGF) has a good therapeutic effect on injured corneas. However, due to the washout of tears and blinking, locally administrated KGF usually has a short residence time on the surface of an injured cornea, resulting in its poor bioavailability. Herein, a bioadhesive hydrogel is described produced using cysteine-modified γ-polyglutamic acid (PGA-Cys) as the hydrogel-forming material to locally deliver KGF. A series of PGA-Cys polymers with different graft ratios of cysteine were firstly synthesized and carefully characterized. Thereafter, the PGA-Cys hydrogel was screened by changing the graft ratio of cysteine and polymer concentration, and the apparent viscosities and bioadhesive force were also carefully investigated. It was found that PGA-Cys polymers with different graft ratios of cysteine exhibited tunable apparent viscosity and bioadhesive properties at the same polymer concentration. When PGA-Cys with a graft ratio of 1.5 mmol g-1 of cysteine (PGA-Cys-1.5) was used as hydrogel-forming material, the hydrogel exhibited a good gelation property with an apparent viscosity of 5.2 Pa s and strong bioadhesive force of 167 ± 0.5 mN. In vitro release study showed that KGF was slowly released from PGA-Cys-1.5 hydrogel over a longer time in comparison to PGA solution alone. Moreover, PGA-Cys-1.5 hydrogel enabled most of the encapsulated KGF to be retained on the cornea and conjunctiva after local administration. Meanwhile, the morphology of the corneal epithelium in the alkali-injured cornea of mice was well repaired after 7 days of treatment with KGF-PGA-Cys-1.5 hydrogel. The therapeutic mechanism was strongly associated with inhibiting corneal inflammation and neovascularization, promoting proliferation of the corneal epithelium and inhibiting apoptosis. Overall, the use of the bioadhesive PGA-Cys hydrogel with a suitable KGF release profile may be a more promising approach than using PGA solution alone and KGF to repair injured corneas.
角质细胞生长因子（KGF）对受损角膜有很好的治疗效果。然而，由于眼泪的冲洗和眨眼，局部给予的 KGF 通常在受损角膜表面的停留时间很短，导致其生物利用度较差。本文描述了一种使用半胱氨酸修饰的γ-聚谷氨酸（PGA-Cys）作为水凝胶形成材料的生物粘附水凝胶，用于局部递送 KGF。首先合成了一系列具有不同半胱氨酸接枝比的 PGA-Cys 聚合物，并对其进行了仔细的表征。此后，通过改变半胱氨酸接枝比和聚合物浓度来筛选 PGA-Cys 水凝胶，并仔细研究了表观粘度和生物粘附力。结果发现，具有不同半胱氨酸接枝比的 PGA-Cys 聚合物在相同聚合物浓度下表现出可调节的表观粘度和生物粘附性能。当使用半胱氨酸接枝比为 1.5mmol g-1的 PGA-Cys（PGA-Cys-1.5）作为水凝胶形成材料时，水凝胶表现出良好的凝胶性能，表观粘度为 5.2Pa·s，生物粘附力为 167±0.5mN。体外释放研究表明，与单独的 PGA 溶液相比，KGF 从 PGA-Cys-1.5 水凝胶中缓慢释放更长时间。此外，局部给予 KGF-PGA-Cys-1.5 水凝胶后，大部分包封的 KGF 能够保留在角膜和结膜上。同时，KGF-PGA-Cys-1.5 水凝胶治疗 7 天后，可明显修复小鼠碱烧伤角膜的角膜上皮形态。其治疗机制与抑制角膜炎症和新生血管形成、促进角膜上皮增殖和抑制细胞凋亡密切相关。总之，使用具有合适 KGF 释放特性的生物粘附性 PGA-Cys 水凝胶可能比单独使用 PGA 溶液和 KGF 更有希望修复受损的角膜。
