LRP1-upregulated nanoparticles for efficiently conquering the blood-brain barrier and targetedly suppressing multifocal and infiltrative brain metastases.

Abstract

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.

• Authors: Qian Guo, Qiuning Zhu, Tongtong Miao, Jing Tao, Xiufeng Ju, Zhenglong Sun, Hui Li, Guoqiang Xu, Huabing Chen, Liang Han
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 303 Pg. 117-129 (06 10 2019) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 31026546 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Angiopep-2
• Antibiotics, Antineoplastic
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Low Density Lipoprotein Receptor-Related Protein-1
• Lrp1 protein, mouse
• Peptides
• Doxorubicin
• Simvastatin

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage)
• Blood-Brain Barrier (metabolism)
• Brain Neoplasms (drug therapy, metabolism, secondary)
• Cell Line
• Doxorubicin (administration & dosage)
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (administration & dosage)
• Low Density Lipoprotein Receptor-Related Protein-1 (metabolism)
• Mice, Inbred BALB C
• Mice, Inbred ICR
• Mice, Nude
• Nanoparticles (administration & dosage)
• Peptides (administration & dosage)
• Simvastatin (administration & dosage)