Biomedical Polymers Laboratory, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China; Department of Polymer Chemistry and Biomaterials, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands.
Biomedical Polymers Laboratory, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China.
J Control Release. 2018 May 28;278:1-8. doi: 10.1016/j.jconrel.2018.03.025. Epub 2018 Mar 27.
Glioma is a highly challenging human malignancy as drugs typically exhibit a low blood-brain barrier (BBB) permeability as well as poor glioma selectivity and penetration. Here, we report that tandem nanomicelles co-functionalized with brain tumor-targeting and cell-penetrating peptides, Angiopep-2 and TAT, enable a highly efficacious and specific anti-glioma chemotherapy. Interestingly, tandem nanomicelles with 20 mol% Angiopep-2 and 10 mol% TAT linked via long and short poly(ethylene glycol)s, respectively, while maintaining a high glioma cell selectivity display markedly enhanced BBB permeation, glioma accumulation and penetration, and glioma cell uptake. We further show that docetaxel-loaded tandem nanomicelles have a long blood circulation time in mice and significantly better inhibit orthotopic U87MG human glioma than the corresponding Angiopep-2 single peptide-functionalized control, leading to an improved survival rate with little adverse effects. These tandem nanomicelles uniquely combining brain tumor-targeting and cell-penetrating functions provide a novel and effective strategy for targeted glioma therapy.
脑胶质瘤是一种极具挑战性的人类恶性肿瘤，因为药物通常表现出较低的血脑屏障（BBB）通透性，以及较差的脑胶质瘤选择性和穿透性。在这里，我们报告了串联纳米胶束共功能化脑肿瘤靶向和细胞穿透肽，即血管生成肽-2 和 TAT，可实现高效和特异的抗脑胶质瘤化疗。有趣的是，通过长和短聚乙二醇分别连接 20 mol%血管生成肽-2 和 10 mol% TAT 的串联纳米胶束，同时保持对神经胶质瘤细胞的高选择性，显示出明显增强的 BBB 渗透、脑胶质瘤积累和穿透以及脑胶质瘤细胞摄取。我们进一步表明，多西紫杉醇负载的串联纳米胶束在小鼠体内具有较长的血液循环时间，并且比相应的血管生成肽-2 单肽功能化对照物更能显著抑制原位 U87MG 人神经胶质瘤，从而提高存活率，且副作用小。这些串联纳米胶束独特地结合了脑肿瘤靶向和细胞穿透功能，为靶向脑胶质瘤治疗提供了一种新的有效策略。
