A sulfonated reversible thermal gel for the spatiotemporal control of VEGF delivery to promote therapeutic angiogenesis

Despite medical and surgical advancements for the treatment of cardiovascular disease, mortality and morbidity remain high. Therapeutic angiogenesis has been one approach to address the major clinical need for a more effective treatment, but current progress in angiogenic drug delivery is inadequate at providing sufficient bioavailability without causing safety concerns. An injectable sulfonated reversible thermal gel composed of a polyurea conjugated with poly(N-isopropylacrylamide) and sulfonate groups has been developed for the electrostatic binding and delivery of angiogenic factors. The thermal gel allowed for the spatiotemporal control of vascular endothelial growth factor release with a decreased initial burst release and reduced release rate in vitro. A subcutaneous injection mouse model was used to evaluate efficacious vascularization and assess the inflammatory response due to a foreign body. Thermal gel injections showed substantial vascularization properties by inducing vessel formation, recruitment and differentiation of vascular endothelial cells, and vessel stabilization by perivascular cells, while infiltrating macrophages due to the thermal gel injections decreased over time. These results demonstrated effective localization and delivery of angiogenic factors for therapeutic angiogenesis.尽管心血管疾病的临床与外科治疗技术已取得长足进步，但其患者的死亡率与致残率仍居高不下。治疗性血管生成（Therapeutic angiogenesis）曾被视为满足更高效治疗这一核心临床需求的潜在方案之一，但当前血管生成药物递送领域的进展仍存在明显局限：无法在保证足够生物利用度的同时规避安全性隐患。本研究开发了一种可注射磺化可逆温敏凝胶（sulfonated reversible thermal gel），该凝胶由聚脲与聚(N-异丙基丙烯酰胺)（poly(N-isopropylacrylamide)）结合磺酸盐基团构建而成，可通过静电结合作用绑定并递送血管生成因子（angiogenic factors）。该温敏凝胶可在体外实现对血管内皮生长因子（vascular endothelial growth factor, VEGF）释放的时空精准调控，能够降低初始突释效应并放缓整体释放速率。研究采用小鼠皮下注射模型，评估该凝胶的有效血管生成能力以及异物反应引发的炎症应答。结果显示，注射该温敏凝胶可显著促进血管生成：能够诱导血管形成、募集并分化血管内皮细胞，还可通过血管周细胞（perivascular cells）稳定血管结构；同时因凝胶注射引发的浸润巨噬细胞数量随时间推移逐渐减少。上述结果证实，该递送系统可有效定位并递送血管生成因子，为治疗性血管生成提供了切实可行的解决方案。