期刊
JOURNAL OF CONTROLLED RELEASE
卷 303, 期 -, 页码 117-129出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2019.04.031
关键词
Blood-brain barrier; Brain metastases; LRP1 up-regulation; Nanoparticles; Statins
资金
- National Natural Science Foundation of China [81703428]
- Natural Science Foundation for Colleges and Universities in Jiangsu Province of China [17KJB350010]
Brain metastases present mostly multifocal, infiltrative and co-opting growth with the blood-brain barrier (BBB) remaining intact. The BBB, as the barrier of drug delivery to such lesions, is the major cause of the failure of systemic drug therapy and needs to be conquered. Angiopep-2 ligates the low density lipoprotein receptor related protein 1 (LRP1) on brain microvascular endothelial cells (BMECs) to drive transcytosis for BBB crossing. However, besides tight junction, low transcytosis is increasingly deemed to be a crucial factor in restricting BBB permeability. Herein, it is reported that statins-loaded Angiopep-2-anchored nanoparticles (S@A-NPs) can raise LRP1 expression to surmount the low transcytosis of BBB. We demonstrate that S@A-NPs can selectively heighten LRP1 expression on both BMECs and brain metastatic tumor cells, efficiently and self-promotingly penetrate through the BBB and target brain metastases through Angiopep-2 mediated endocytosis and statins induced LRP1 up-regulation. The systemic administration of S@A-NPs loaded with doxorubicin (S@A-NPs/DOX) observably lengthens median survival of mice bearing brain metastases. Due to the efficient BBB passing and brain metastasis targeting, S@A-NPs/DOX may serve as a potential approach for clinical management of brain metastases.
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