Overcoming Mfsd2a-Mediated Low Transcytosis to Boost Nanoparticle Delivery to Brain for Chemotherapy of Brain Metastases.
Adv Healthc Mater
; 10(9): e2001997, 2021 05.
Article
em En
| MEDLINE
| ID: mdl-33738958
ABSTRACT
Microvessels of the blood-brain barrier (BBB) exclusively express the major facilitator superfamily domain-containing protein 2a (Mfsd2a), which is the key transporter for docosahexaenoic acid uptake into the brain. Mfsd2a suppresses caveolae-mediated transcytosis to regulate BBB transcellular permeability via controlling lipid composition of BBB endothelial cells. It is speculated that Mfsd2a can restrain BBB crossing efficiency and brain accumulation efficiency of brain-targeting drug delivery systems, which penetrate the BBB often through the receptor-mediated transcytosis pathway. Transcytosis across the BBB is a crucial bottleneck for targeted chemotherapy of brain metastases. To overcome this issue, a pair of priming nanoparticles (NPs) and following drug-loaded NPs are designed. Tunicamycin-(TM)-loaded transcytosis-targeting-peptide-(TTP)-decorated NPs (TM@TTP) are used to boost BBB transcytosis via inhibiting Mfsd2a. Doxorubicin (DOX)-loaded TTP and CD44-specific hyaluronic acid (HA)-comodified NPs (DOX@TTP-HA) are designed as following drug-loaded NPs. The brain accumulation efficacy of following DOX@TTP-HA with priming is 4.30-fold higher than that without priming through the enhanced transcytosis pathway rather than the tight junction opening. Effective BBB crossing and brain accumulation, selective tumor uptake, excellent antitumor efficacy, and low hepatotoxicity are achieved by TM@TTP and DOX@TTP-HA, suggesting this tactic as a significant therapeutic strategy against breast cancer brain metastases.
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MEDLINE
Assunto principal:
Neoplasias Encefálicas
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Simportadores
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Nanopartículas
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article