Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China.
Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China.
Int J Biol Macromol. 2019 Oct 15;139:277-289. doi: 10.1016/j.ijbiomac.2019.07.220. Epub 2019 Aug 1.
It remains a crucial challenge to achieve efficient cellular uptake in tumor cells for nanoscale drug delivery systems. This work described that two multi-functional pullulan nanogels were prepared by co-polymerization between methacrylated pullulan (Pullulan-M) and different crosslink agents, an acid-labile ortho ester-modified pluronic (L61-MOE) or non-acid-sensitive methacrylated pluronic (L61-M). The prepared nanogels showed a regular spherical structure with the size about 200 nm measured by dynamic light scattering and transmission electron microscopy (TEM). Doxorubicin as a model drug was successfully encapsulated into nanogels. As expected, Pul-L61-MOE showed pH-dependent DOX release, and 25% of DOX was released at pH 7.4 while 84.48% of DOX was released at pH 5.0. In vitro cellular uptake and MTT results indicated that pH-sensitive nanogels (Pul-L61-MOE) displayed higher cellular internalization and cytotoxicity than acid-insensitive nanogels (Pul-L61-M) and free DOX. Flow cytometry assay suggested these nanogels remarkably increased intracellular reactive oxygen species (ROS) level and induced more cell apoptosis by the function of pluronic. Finally, in vivo antitumor results indicated that the multi-functional nanogels exhibit supreme antitumor efficiency, and the tumor growth inhibition (TGI) was 83.37%. Therefore, the pH-sensitive pullulan nanogels can be potential nano-carriers for drug delivery in tumor treatment.
对于纳米级药物递送系统，实现肿瘤细胞内的有效细胞摄取仍然是一个关键挑战。本工作描述了通过丙烯酰化普鲁兰（Pullulan-M）与不同交联剂共聚，制备了两种多功能普鲁兰纳米凝胶，一种是酸不稳定邻酯修饰的泊洛沙姆（L61-MOE），另一种是非酸敏感的丙烯酰化泊洛沙姆（L61-M）。通过动态光散射和透射电子显微镜（TEM）测量，所得纳米凝胶呈现出规则的球形结构，粒径约为 200nm。阿霉素作为模型药物成功包封于纳米凝胶中。正如预期的那样，Pul-L61-MOE 表现出 pH 依赖性 DOX 释放，在 pH 7.4 时释放了 25%的 DOX，而在 pH 5.0 时释放了 84.48%的 DOX。体外细胞摄取和 MTT 结果表明，pH 敏感纳米凝胶（Pul-L61-MOE）比酸不敏感纳米凝胶（Pul-L61-M）和游离 DOX 具有更高的细胞内化和细胞毒性。流式细胞术分析表明，这些纳米凝胶通过泊洛沙姆的功能显著增加了细胞内活性氧（ROS）水平，并诱导了更多的细胞凋亡。最后，体内抗肿瘤结果表明，多功能纳米凝胶表现出卓越的抗肿瘤效率，肿瘤生长抑制（TGI）为 83.37%。因此，pH 敏感的普鲁兰纳米凝胶可以作为肿瘤治疗中药物递送的潜在纳米载体。
