School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Eur J Pharm Biopharm. 2020 Jul;152:85-94. doi: 10.1016/j.ejpb.2020.05.001. Epub 2020 May 5.
We previously developed a nose-to-brain delivery system using poly(ethylene glycol)-polycaprolactone block polymeric micelles modified by a cell-penetrating peptide, Tat (PEG-PCL-Tat). This system showed excellent delivery of the anti-cancer drug camptothecin to the brain and improved therapeutic efficacy in a brain tumor model. However, improvements are necessary to selectively deliver drugs to tumor sites once they enter the brain, and avoid toxic side effects to normal brain tissue. In this study, to develop tumor-selective novel polymeric micelles, mixed micelles consisting of Tat-conjugated polymer micelles and stearoyl-modified bombesin (Bom/PEG-PCL-Tat) were designed. The GRPR selectivity, cellular uptake, and cytotoxicity in C6 glioma cells as well as the intracerebral drug distribution and therapeutic efficacy of Bom/PEG-PCL-Tat mixed micelles after intranasal administration in C6 glioma orthotropic grafted rats were evaluated. Selective cellular uptake and marked cytotoxic effects against GRPR-expressing C6 glioma cells were observed, as well as C6 tumor tissue-specific accumulation in vivo. Rats treated with camptothecin subsequent to a brain tumor graft survived longer when the drug was delivered by Bom/PEG-PCL-Tat mixed micelles than by PEG-PCL-Tat micelles.
我们之前开发了一种使用穿透肽 Tat（PEG-PCL-Tat）修饰的聚乙二醇-聚己内酯嵌段聚合物胶束的鼻内递药系统。该系统显示出了将抗癌药物喜树碱递送到大脑中的优异效果，并在脑肿瘤模型中提高了治疗效果。然而，有必要进行改进，以便在药物进入大脑后选择性地将药物递送到肿瘤部位，并避免对正常脑组织产生毒性副作用。在这项研究中，为了开发肿瘤选择性的新型聚合物胶束，设计了由 Tat 修饰的聚合物胶束和硬脂酰化的脑肠肽（Bom/PEG-PCL-Tat）组成的混合胶束。评估了 Bom/PEG-PCL-Tat 混合胶束在 C6 神经胶质瘤细胞中的 GRPR 选择性、细胞摄取和细胞毒性，以及在 C6 神经胶质瘤原位移植大鼠经鼻给药后的脑内药物分布和治疗效果。观察到了对表达 GRPR 的 C6 神经胶质瘤细胞的选择性细胞摄取和明显的细胞毒性作用，以及体内 C6 肿瘤组织的特异性蓄积。在脑肿瘤移植后，用 Bom/PEG-PCL-Tat 混合胶束递送喜树碱的大鼠比用 PEG-PCL-Tat 胶束递送的大鼠存活时间更长。
