Chen Yang, Yang Cejun, Mao Juan, Li Haigang, Ding Jinsong, Zhou Wenhu
Xiangya School of Pharmaceutical Sciences, Central South University Changsha Hunan 410013 China
Department of Radiology, The Third Xiangya Hospital, Central South University Changsha 410013 P. R. China.
RSC Adv. 2019 Apr 9;9(20):11026-11037. doi: 10.1039/c9ra00834a.
Tumor targeting delivery of chemotherapeutic drugs by nanocarriers has been demonstrated to be a promising strategy for cancer therapy with improved therapeutic efficacy. In this work, we reported a novel type of active targeting micelle with pH-responsive drug release by using biodegradable poly(lactide)-poly(2-ethyl-2-oxazoline) di-block copolymers functionalized with spermine (SPM). SPM has been considered as a tumor binding ligand through its specific interaction with the polyamine transport system (PTS), a transmembrane protein overexpressed on various types of cancer cell, while its application in nano-drug delivery systems has rarely been explored. The micelles with spherical shape (∼110 nm) could load hydrophobic paclitaxel (PTX) with high capacity, and release the payload much faster at acidic pH (4.5-6.5) than at pH 7.4. This pH-responsive property assisted the rapid escape of drug from the endo/lysosome after internalization as demonstrated by confocal laser scanning microscopy images using coumarin-6 (Cou-6) as a fluorescent probe. With surface SPM modification, the micelles displayed much higher cellular uptake than SPM lacking micelles in various types of cancer cells, demonstrating tumor targeting ability. The uptake mechanism of SPM modified micelles was explored by flow cytometry, which suggested an energy-consuming sag vesicle-mediated endocytosis pathway. As expected, the micelles displayed significantly enhanced anti-cancer activity. This work demonstrates that SPM modified pH-sensitive micelles may be potential drug delivery vehicles for targeting and effective cancer therapy.
纳米载体对化疗药物的肿瘤靶向递送已被证明是一种具有改善治疗效果的癌症治疗的有前景的策略。在这项工作中，我们报道了一种新型的具有pH响应药物释放的主动靶向胶束，它使用了用精胺（SPM）功能化的可生物降解的聚（丙交酯）-聚（2-乙基-2-恶唑啉）二嵌段共聚物。SPM通过其与多胺转运系统（PTS）的特异性相互作用被认为是一种肿瘤结合配体，PTS是一种在各种类型癌细胞上过度表达的跨膜蛋白，而其在纳米药物递送系统中的应用很少被探索。具有球形形状（约110nm）的胶束可以高容量负载疏水性紫杉醇（PTX），并且在酸性pH（4.5-6.5）下比在pH 7.4时更快地释放负载物。这种pH响应特性有助于药物在被内化后从内体/溶酶体中快速逃逸，这通过使用香豆素-6（Cou-6）作为荧光探针的共聚焦激光扫描显微镜图像得到证明。通过表面SPM修饰，胶束在各种类型的癌细胞中显示出比缺乏SPM的胶束更高的细胞摄取，证明了肿瘤靶向能力。通过流式细胞术探索了SPM修饰胶束的摄取机制，这表明是一种耗能的凹陷囊泡介导的内吞途径。正如预期的那样，胶束显示出显著增强的抗癌活性。这项工作表明，SPM修饰的pH敏感胶束可能是用于靶向和有效癌症治疗的潜在药物递送载体。
