Apolipoprotein E Peptide-Directed Chimeric Polymersomes Mediate an Ultrahigh-Efficiency Targeted Protein Therapy for Glioblastoma

被引:158
作者
Jiang, Yu
Zhang, Jian [1 ]
Meng, Fenghua
Zhong, Zhiyuan [1 ]
机构
[1] Soochow Univ, Biomed Polymers Lab, Coll Chem Chem Engn & Mat Sci, Suzhou 215123, Peoples R China
基金
中国国家自然科学基金;
关键词
brain tumor; blood-brain barrier; protein delivery; nanomedicines; targeted therapy; BLOOD-BRAIN-BARRIER; DENSITY-LIPOPROTEIN RECEPTOR; LYSOSOMAL-ENZYME; DRUG-DELIVERY; NANOPARTICLES; ANGIOPEP-2; LIPOSOMES; THERAPEUTICS; PACLITAXEL; CONJUGATE;
D O I
10.1021/acsnano.8b05265
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The inability to cross the blood-brain barrier (BBB) prevents nearly all chemotherapeutics and biotherapeutics from the effective treatment of brain tumors, rendering few improvements in patient survival rates to date. Here, we report that apolipoprotein E peptide [ApoE, (LRKLRICRLL)(2)C] specifically binds to low-density lipoprotein receptor members (LDLRs) and mediates superb BBB crossing and highly efficient glioblastoma (GBM)-targeted protein therapy in vivo. The in vitro BBB model studies reveal that ApoE induces 2.2-fold better penetration of the immortalized mouse brain endothelial cell line (bEnd.3) monolayer for chimeric polymersomes (CP) compared to Angiopep-2, the best-known BBB-crossing peptide used in clinical trials for GBM therapy. ApoE-installed CP (ApoE-CP) carrying saporin (SAP) displays a highly specific and potent antitumor effect toward U-87 MG cells with a low half-maximum inhibitory concentration of 14.2 nM SAP. Notably, ApoE-CP shows efficient BBB crossing as well as accumulation and penetration in orthotopic U-87 MG glioblastoma. The systemic administration of SAP-loaded ApoE-CP causes complete growth inhibition of orthotopic U-87 MG GBM without eliciting any observable adverse effects, affording markedly improved survival benefits. ApoE peptide provides an ultrahigh-efficiency targeting strategy for GBM therapy.
引用
收藏
页码:11070 / 11079
页数:10
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