Ma Jizhuang, Li Wenhan, Ding Yu, Chen Yongfeng, Huang Xiaoyu, Yu Tong, Song Di, Niu Haoran, Li Bao, Xie Huichao, Zhang Keda, Yang Tianzhi, Zhao Xiaoyun, Yang Xinggang, Ding Pingtian
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China.
Mater Today Bio. 2024 Nov 30;29:101376. doi: 10.1016/j.mtbio.2024.101376. eCollection 2024 Dec.
Vascular malformations are common vascular lesions in infants and seriously affect their health and quality of life. Vascular sclerotherapy is an effective treatment for vascular malformations. However, current sclerosants have difficulty achieving both high efficiency and low toxicity, and their dosing forms make it difficult to achieve long-term retention in the affected blood vessels. Therefore, exploring a safe and effective sclerosant and its delivery strategy is the key to clinical sclerotherapy. To address the above issues, this study developed sclerosants that could form an in-situ gel based on a dual mechanism of vascular injury and plasmin (PLA) inhibition. By linking the non-ionic surfactant sclerosant polyoxyethylene alkyl ether (PAs) and the PLA inhibitor tranexamic acid (TA) through an ester bond, a cationic surfactant sclerosant polyoxyethylene alkylether tranexamate derivatives (PATDs) were constructed. The cationic charge of PATDs enhanced its cytotoxicity to HUVEC-TIE2-L914F cells, and the ester bond of PATDs could be degraded by esterase in the blood, reducing its systemic toxicity. The degradation product TA inhibited the activation of the PLA-matrix metalloproteinase (MMPs) system induced by vascular injury, thereby promoting the deposition of collagen and the proliferation and differentiation of fibroblasts to promote vascular fibrosis. In addition, an injectable solution (PATDs/GA) was prepared by mixing PATDs with glycerol formaldehyde (GA), and PATDs/GA could form a low-molecular-weight gel automatically in an aqueous solution, which was beneficial to increase its retention in the affected blood vessels and reduce the risk of drug entering non-targeted sites. At the same time, this gel automatically dissolved, reducing the risk of immune rejection caused by long-term retention. This study provided a new and precise approach for the treatment of vascular sclerosis with high efficiency and low toxicity.
血管畸形是婴儿常见的血管病变，严重影响其健康和生活质量。血管硬化治疗是治疗血管畸形的有效方法。然而，目前的硬化剂难以同时实现高效和低毒，其给药形式也难以在受影响的血管中实现长期保留。因此，探索一种安全有效的硬化剂及其给药策略是临床硬化治疗的关键。为了解决上述问题，本研究开发了一种基于血管损伤和纤溶酶（PLA）抑制双重机制形成原位凝胶的硬化剂。通过酯键将非离子表面活性剂硬化剂聚氧乙烯烷基醚（PAs）与PLA抑制剂氨甲环酸（TA）连接，构建了阳离子表面活性剂硬化剂聚氧乙烯烷基醚氨甲环酸衍生物（PATDs）。PATDs的阳离子电荷增强了其对HUVEC-TIE2-L914F细胞的细胞毒性，且PATDs的酯键可被血液中的酯酶降解，降低其全身毒性。降解产物TA抑制血管损伤诱导的PLA-基质金属蛋白酶（MMPs）系统的激活，从而促进胶原蛋白的沉积和成纤维细胞的增殖与分化，以促进血管纤维化。此外，将PATDs与甘油甲醛（GA）混合制备了一种可注射溶液（PATDs/GA），PATDs/GA可在水溶液中自动形成低分子量凝胶，这有利于增加其在受影响血管中的保留率，并降低药物进入非靶向部位的风险。同时，这种凝胶会自动溶解，降低了长期保留引起免疫排斥的风险。本研究为高效低毒治疗血管硬化提供了一种新的精准方法。
