Institute of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou 325027, PR China.
Institute of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou 325027, PR China.
Int J Pharm. 2022 Sep 25;625:122081. doi: 10.1016/j.ijpharm.2022.122081. Epub 2022 Aug 5.
Corneal neovascularization (CNV) is a sequela of anterior segment inflammation, which could lead to vision impairment and even blindness. In the present study, the dual delivery of anti-inflammatory agent (i.e., diclofenac; DIC) and anti-VEGF antibody (i.e., Avastin®; Ava) by the thermosensitive hydrogel (Poly(dl-lactide)-poly(ethylene glycol)-poly(dl-lactide); PDLLA-PEG-PDLLA) is expected to effectively inhibit CNV via their synergistic effects. The optimal DIC micelles were formulated and then mixed with Ava and PDLLA-PEG-PDLLA aqueous solution to generate various DIC@Ava-loaded hydrogels. The co-encapsulation of DIC micelles and Ava did not influence the gelling behavior of the system, and the resulting DIC@Ava-loaded hydrogel provided sustained drug release of both DIC and Ava without compromising their pharmacological activity over 19 days. As indicated by in vitro cytotoxicity and in vivo ocular biocompatibility test, the proposed PDLLA-PEG-PDLLA hydrogel caused minimal cytotoxicity against all tested cell lines at a polymeric concentration ranging from 0.05 mg/mL to 0.8 mg/mL and demonstrated good ocular biocompatibility after a single subconjunctival injection. Using the rabbit CNV model, we documented the superior anti-angiogenic effects of the DIC@Ava-loaded hydrogel over Ava alone medication (treatment with Ava solution and Ava-loaded hydrogel) due to synergistic effects of anti-VEGF and anti-inflammatory action. Overall, the proposed DIC@Ava-loaded hydrogel might be a powerful strategy to reduce CNV.
角膜新生血管（CNV）是眼前节炎症的后遗症，可导致视力损害甚至失明。在本研究中，通过温敏水凝胶（聚（dl-丙交酯）-聚（乙二醇）-聚（dl-丙交酯）；PDLLA-PEG-PDLLA）递呈抗炎剂（即双氯芬酸；DIC）和抗 VEGF 抗体（即阿瓦斯汀®；Ava）的双重递送，有望通过协同作用有效抑制 CNV。优化了 DIC 胶束的配方，然后将其与 Ava 和 PDLLA-PEG-PDLLA 水溶液混合，以生成各种载 DIC@Ava 的水凝胶。DIC 胶束和 Ava 的共包封并不影响体系的胶凝行为，所得的载 DIC@Ava 的水凝胶提供了 DIC 和 Ava 的持续药物释放，而不会损害其在 19 天内的药理活性。体外细胞毒性和体内眼相容性试验表明，所提出的 PDLLA-PEG-PDLLA 水凝胶在聚合物浓度为 0.05 mg/mL 至 0.8 mg/mL 时对所有测试的细胞系均表现出最小的细胞毒性，并且在单次结膜下注射后表现出良好的眼相容性。通过兔 CNV 模型，我们记录了载 DIC@Ava 水凝胶在抗血管生成方面优于 Ava 单药治疗（用 Ava 溶液和 Ava 载药凝胶治疗）的优越效果，这是由于抗 VEGF 和抗炎作用的协同作用。总体而言，所提出的载 DIC@Ava 水凝胶可能是减少 CNV 的有效策略。
