title: Blood-brain barrier-penetrating amphiphilic polymer nanoparticles deliver docetaxel for the treatment of brain metastases of triple negative breast cancer.
abstract: 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 AUC0-24hin tumor-bearing brain by 5-fold compared to the clinically used DTX formulation Taxotere®.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®, without inducing histological changes in the major organs.
authors.affiliation: Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: He
authors.affiliation: Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Cai
authors.affiliation: Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Lucy
authors.initials: L
authors.lastname: Lin
authors.affiliation: Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Azhar Z
authors.initials: AZ
authors.lastname: Abbasi
authors.affiliation: Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Henderson
authors.affiliation: Departments of Medical Biophysics and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Andrew Michael
authors.initials: AM
authors.lastname: Rauth
authors.affiliation: Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada. Electronic address: xywu@phm.utoronto.ca.
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D016513:Mice, SCID; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism*; D011108:Polymers / Q000378:metabolism; D013501:Surface-Active Agents / Q000737:chemistry / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011108:Polymers; D013501:Surface-Active Agents; D043823:Taxoids; D000077143:Docetaxel
keywords: Amphiphilic polymer nanoparticles; Blood-brain barrier; Brain metastases; Chemotherapy; Docetaxel delivery; Triple-negative breast cancer