Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China.
State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Shaanxi, China.
Int J Pharm. 2021 Sep 5;606:120871. doi: 10.1016/j.ijpharm.2021.120871. Epub 2021 Jul 9.
This study demonstrates the development of topotecan (TCN) loaded thermosensitive nanocargos (TCN-TS-NC) for intramuscular (IM) administration with enhanced antitumor activity. In this regards, TCN loaded temperature dependent solid lipid nanoparticles (SLNs) were prepared with micro-emulsion method, which were then incorporated into temperature sensitive poloxamer solution to develop TCN-TS-NC. The particle size, entrapment efficiency (%EE), zeta potential and transmission electron microscopy (TEM) analysis of the TCN-TS-NC were performed. Moreover, the inject-ability, release pattern, apoptosis, cellular uptake, pharmacokinetics and antitumor studies of the TCN-TS-NC were attained and compared with TCN solution and TCN-Emulgel (poloxamer solution containing TCN). At room temperature, the TCN loaded SLNs were solid and poloxamer solution remains liquid, however, TCN loaded SLNs melted to liquid and Emulgel converted into gel from, at body temperature, resulting controlled release of the incorporated drug. The TCN-TS-NC showed enhanced cellular uptake and better apoptosis. Similarly, it reduces C and sustained its level for a significantly longer time in rats, as compared to the TCN-Emulgel and TCN solution. Moreover, a significantly improved antitumor activity was observed in TCN-TS-NC treated tumor bearing athymic nude mice when compared with the control, TCN solution and TCN-Emulgel applied mice. Thus, the TCN-TS-NC system showed control release of the drug with no initial fast effect. Furthermore, it enhanced the antitumor activity of TCN with comparatively no toxicity. It is therefore concluded that TCN-TS-NC could be a potentially more suitable drug delivery system for the delivery of TCN.
本研究旨在开发拓扑替康（TCN）负载的温敏纳米载体（TCN-TS-NC），用于增强抗肿瘤活性的肌肉内（IM）给药。在这方面，采用微乳液法制备了 TCN 负载的温度依赖性固体脂质纳米粒（SLNs），然后将其掺入温敏泊洛沙姆溶液中以开发 TCN-TS-NC。对 TCN-TS-NC 的粒径、包封效率（%EE）、Zeta 电位和透射电子显微镜（TEM）分析进行了研究。此外，对 TCN-TS-NC 的可注射性、释放模式、细胞摄取、药代动力学和抗肿瘤研究进行了研究，并与 TCN 溶液和 TCN-Emulgel（含 TCN 的泊洛沙姆溶液）进行了比较。在室温下，负载 TCN 的 SLNs 是固态的，而泊洛沙姆溶液是液态的，然而，负载 TCN 的 SLNs 在体温下融化成液态，Emulgel 从液态转变成凝胶，从而控制了包裹药物的释放。TCN-TS-NC 表现出增强的细胞摄取和更好的细胞凋亡。同样，与 TCN-Emulgel 和 TCN 溶液相比，它在大鼠体内能够更有效地降低 Cmax 并延长其维持时间。此外，与对照组、TCN 溶液和 TCN-Emulgel 应用的小鼠相比，在荷瘤裸鼠中观察到 TCN-TS-NC 治疗的肿瘤具有显著改善的抗肿瘤活性。因此，TCN-TS-NC 系统表现出药物的控制释放，没有初始快速作用。此外，它增强了 TCN 的抗肿瘤活性，毒性相对较低。因此，可以得出结论，TCN-TS-NC 可能是一种更适合 TCN 给药的潜在药物传递系统。
