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（cardiovascular disease）的内科与外科治疗手段已取得诸多进展，但其死亡率与发病率仍居高不下。治疗性血管生成（Therapeutic angiogenesis）便是针对这一亟需更高效治疗方案的临床需求所探索的途径之一，但当前血管生成药物递送领域的研究进展仍存在局限：难以在实现足够生物利用度的同时规避安全性风险。本研究开发了一种由聚脲与聚(N-异丙基丙烯酰胺)（poly(N-isopropylacrylamide)）、磺酸基团结合而成的可注射磺化可逆温敏凝胶，用于血管生成因子的静电结合与递送。该温敏凝胶可实现血管内皮生长因子（vascular endothelial growth factor）释放的时空精准调控，在体外实验中可降低初期突释效应并放缓释放速率。研究采用小鼠皮下注射模型，评估其有效血管生成能力以及异物引发的炎症反应。小鼠皮下注射该温敏凝胶后，可通过诱导血管形成、血管内皮细胞的招募与分化，以及周细胞介导的血管稳定，展现出显著的血管生成特性；同时因凝胶注射引发的浸润性巨噬细胞数量随时间推移逐渐减少。上述结果证实，该递送系统可实现血管生成因子的有效定位与递送，为治疗性血管生成提供了可行方案。