Wang Qilong, Liu Zhe, Yao Jiale, Xie Haosheng, Liu Zhihui, Zhai Jianxiu, Li Sikai, Zhang Jia Ming, Han Na, Yin Jun
Development and Utilization Key Laboratory of Northeast Plant Materials, School of Traditional Chinese Meteria Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
College of Mechanical and Electrical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, 210016, China.
Drug Deliv Transl Res. 2025 Jan 20. doi: 10.1007/s13346-025-01793-0.
TXA9, a cardiac glycoside isolated from the root of Streptocaulon juventas (Lour.) Merr., with better therapeutic effect in vitro on non-small cell lung cancer (NSCLC) than cisplatin and has no toxic side effects on the body. However, poor water solubility and rapid metabolism limited its clinical application. Multi-arm star PEG have many advantages over linear PEG, such as high drug loading due to more terminals and better anti-hemodilution ability, which have become popular carriers for drug delivery. In this study, to improve the efficacy of TXA9, 6/8armPEG-Glycine Carbamate (Gly) (n = 10, 20, and 40 kDa) were used as carriers to prepare star PEG-TXA9 conjugates. The particle size and zeta potential of six prodrug NPs for effective tumor targeting, with suitable drug loading, and good water solubility. Compared with free TXA9, 6/8APG-T NPs had more significant anti-tumor effects in vitro. Since the multi-arm star PEG formed an "umbrella" structure on the surface of NPs, the 8APG-T NPs with the best pharmacokinetic properties increased half-life of TXA9 about 60 times in vivo. In addition, the arm numbers and molecular weight of multi-arm star PEGs significantly influenced the in vivo destiny of prodrugs. In vivo experiments showed that the same dose of 8APG-T NPs increased the tumor inhibition rate about 3.56 or 1.22 times compared with TXA9 or cisplatin, and had good biocompatibility. This study provides a simple but effective strategy to solve the challenges caused by the poor water solubility and short half-life of TXA9 for developing the TXA9 as a safe and effective drug against NSCLC.
TXA9是从马莲鞍（Streptocaulon juventas (Lour.) Merr.）根部分离得到的一种强心苷，其在体外对非小细胞肺癌（NSCLC）的治疗效果优于顺铂，且对机体无毒性副作用。然而，其水溶性差和代谢快限制了它的临床应用。多臂星形聚乙二醇（PEG）相比于线性PEG具有许多优势，例如由于末端更多而具有更高的载药量以及更好的抗血液稀释能力，已成为热门的药物递送载体。在本研究中，为提高TXA9的疗效，使用6/8臂PEG-氨基甲酸甘氨酸酯（Gly）（n = 10、20和40 kDa）作为载体来制备星形PEG-TXA9缀合物。六种前药纳米粒具有有效的肿瘤靶向性、合适的载药量和良好的水溶性，其粒径和zeta电位适宜。与游离TXA9相比，6/8臂APG-T纳米粒在体外具有更显著的抗肿瘤作用。由于多臂星形PEG在纳米粒表面形成了“伞”状结构，具有最佳药代动力学性质的8臂APG-T纳米粒使TXA9在体内的半衰期延长了约60倍。此外，多臂星形PEG的臂数和分子量显著影响前药在体内的命运。体内实验表明，相同剂量的8臂APG-T纳米粒与TXA9或顺铂相比，肿瘤抑制率提高了约3.56倍或1.22倍，且具有良好的生物相容性。本研究提供了一种简单而有效的策略，以解决TXA9水溶性差和半衰期短所带来的挑战，从而将TXA9开发成一种安全有效的抗NSCLC药物。
