Blood-brain barrier-penetrating amphiphilic polymer nanoparticles deliver docetaxel for the treatment of brain metastases of triple negative breast cancer

被引：80

作者：

He, Chunsheng ^{[1
]}

Cai, Ping ^{[1
]}

Li, Jason ^{[1
]}

Zhang, Tian ^{[1
]}

Lin, Lucy ^{[1
]}

Abbasi, Azhar Z. ^{[1
]}

Henderson, Jeffrey T. ^{[1
]}

Rauth, Andrew Michael ^{[2
,3
]}

Wu, Xiao Yu ^{[1
]}

机构：

[1] Univ Toronto, Leslie Dan Fac Pharm, Adv Pharmaceut & Drug Delivery Lab, Toronto, ON M5S 3M2, Canada

[2] Univ Toronto, Fac Med, Dept Med Biophys, Toronto, ON M5G 2M9, Canada

[3] Univ Toronto, Fac Med, Dept Radiat Oncol, Toronto, ON M5G 2M9, Canada

来源：

JOURNAL OF CONTROLLED RELEASE | 2017年 / 246卷

基金：

加拿大健康研究院; 加拿大自然科学与工程研究理事会;

关键词：

Blood-brain barrier; Amphiphilic polymer nanoparticles; Brain metastases; Triple-negative breast cancer; Docetaxel delivery; Chemotherapy; CENTRAL-NERVOUS-SYSTEM; RECURRENT MALIGNANT GLIOMA; DRUG-DELIVERY; IN-VIVO; TARGETING DELIVERY; PHASE-II; CELLS; DOXORUBICIN; TRANSPORT; THERAPEUTICS;

D O I：

10.1016/j.jconrel.2016.12.019

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Brain metastasis is a fatal disease with limited treatment options and very short survival. Although systemic chemotherapy has some effect on peripheral metastases of breast cancer, it is ineffective in treating brain metastasis due largely to the blood-brain barrier (BBB). Here we developed a BBB-penetrating amphiphilic polymer-lipid nanoparticle (NP) system that efficiently delivered anti-mitotic drug docetaxel (DTX) for the treatment of brain metastasis of triple negative breast cancer (TNBC). We evaluated the biodistribution, brain accumulation, pharmacokinetics and efficacy of DTX-NP in a mouse model of brain metastasis of TNBC. Confocal fluorescence microscopy revealed extravasation of dye-loaded NPs from intact brain microvessels in healthy mice. DTX-NP also extravasated from brain microvessels and accumulated in micrometastasis lesions in the brain. Intravenously injected DTX-NPs increased the blood circulation time of DTX by 5.5-fold and the AUC(0-24) (h) in tumor-bearing brain by 5-fold compared to the clinically used DTX formulation Taxotere (R). The kinetics of NPs in the brain, determined by ex vivo fluorescence imaging, showed synchronization with DTX kinetics in the brain measured by LC-MS/MS. This result confirmed successful delivery of DTX by the NPs into the brain and suggested that ex vivo fluorescence imaging of NP could be an effective and quick means for probing drug disposition in the brain. Treatment with the DTX-NP formulation delayed tumor growth by 11-fold and prolonged median survival of tumor bearing mice by 94% compared to an equivalent dose of Taxotere (R), without inducing histological changes in the major organs. (C) 2016 Elsevier B.V. All rights reserved.

引用

页码：98 / 109

页数：12

共 67 条

[1] Therapeutic Efficacy of a Novel Nanosomal Docetaxel Lipid Suspension Compared With Taxotere in Locally Advanced or Metastatic Breast Cancer Patients [J].