Highly efficacious and specific anti-glioma chemotherapy by tandem nanomicelles co-functionalized with brain tumor-targeting and cell-penetrating peptides
Yaqin Zhua,b, Yu Jianga, Fenghua Menga, Chao Denga, Ru Chenga, Jian Zhanga,*（张建）, Jan Feijena,b, **,Zhiyuan Zhonga, *（钟志远）
aBiomedical 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
bDepartment 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
Journal of Controlled Release 278 (2018) 1--8
Glioma is a highly challenging human malignancy as drugs typically exhibit a lowblood-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-penetratingpeptides, Angiopep-2 and TAT, enable a highly efficacious and specific anti-gliomachemotherapy. Interestingly, tandem nanomicelles with 20 mol% Angiopep-2 and 10 mol% TAT linkedvialong 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.