School of Medicine, Nankai University, Tianjin 300071, China; Department of Urology, Tianjin First Central Hospital, Tianjin 300192, China.
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, and College of Life Sciences, Nankai University, Tianjin 300071, China.
J Control Release. 2021 Feb 10;330:715-725. doi: 10.1016/j.jconrel.2020.12.042. Epub 2020 Dec 28.
As a common method for postoperative adjuvant treatments of bladder tumor, chemotherapy encounters low tumor targeting, short tumor retention time and bad bioavailability in clinical applications, which result in unsatisfactory high chemotherapeutical doses, frequent administration and subsequent severe side effects. Herein, we innovatively introduced the enzyme-assisted assembly to construct a bladder tumor-specific transformable peptide prodrug (i.e. HCPT-FF-GFLG-EEYSA). The prodrug targeted bladder tumor through the specific binding capacity of YSA to EphA2 and underwent on-demand structural transformation intracellularly from micelles to fibrils catalyzed by cathepsin B (CtsB), of which EphA2 and CtsB are overexpressed on the outer membrane and in cytoplasm of bladder tumor cells, respectively. Comparing with hydroxycamptothecin (HCPT), the prodrug can prolong the drug retention time and release the active drug in a sustained manner, which in turn decrease the administration frequencies of chemotherapeutics and reduce the side toxicities, etc. This strategy provides an alternative for bladder tumor chemotherapeutics and shows great potential to inhibit the relapse of postoperative tumors.
作为膀胱肿瘤术后辅助治疗的常用方法，化疗在临床应用中存在肿瘤靶向性低、肿瘤滞留时间短、生物利用度差等问题，导致化疗药物剂量不理想、给药频繁、后续副作用严重。在此，我们创新性地引入酶辅助组装构建了一种膀胱肿瘤特异性可转化肽前药（即 HCPT-FF-GFLG-EEYSA）。该前药通过 YSA 与 EphA2 的特异性结合靶向膀胱肿瘤，并在细胞内由组织蛋白酶 B（CtsB）催化从胶束按需转化为纤维，EphA2 和 CtsB 分别在膀胱肿瘤细胞膜和细胞质中过度表达。与喜树碱（HCPT）相比，该前药可以延长药物滞留时间，并以持续的方式释放活性药物，从而减少化疗药物的给药频率，降低毒副作用等。该策略为膀胱肿瘤化疗提供了一种替代方法，显示出抑制术后肿瘤复发的巨大潜力。
