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

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 ([email protected]) can raise LRP1 expression to surmount the low transcytosis of BBB. We demonstrate that [email protected] 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 [email protected] loaded with doxorubicin ([email protected]/DOX) observably lengthens median survival of mice bearing brain metastases. Due to the efficient BBB passing and brain metastasis targeting, [email protected]/DOX may serve as a potential approach for clinical management of brain metastases.