No abstract

Brain metastases are one of the most difficult malignancies to treat owing to their location and mostly multifocal and infiltrative growth. Chemotherapy, which is often effective against tumors outside the brain, offers some hope for brain metastases. However, the efficacy of systemic drug delivery to brain metastases is extremely limited due largely to the blood–brain tumor barrier (BTB). Herein, it is reported that minoxidil‐loaded hyaluronic acid–tethered nanoparticles (M@H‐NPs) can efficiently and specially surmount the BTB through both transcellular and paracellular pathways and target brain metastases through coordination of hyaluronic acid with CD44 target. The transcellular endocytosis, paracellular claudin‐5 expression, and BTB crossing are evaluated to confirm that the developed M@H‐NPs can be endued with minoxidil's ability to boost transcytosis and downregulate tight junction protein in BTB endothelial cells at brain metastases for promoted BTB penetration. M@H‐NPs selectively deliver doxorubicin (DOX) to brain metastatic lesions, while sparing normal brain cells from harm. Treatment with M@H‐NPs/DOX significantly prolongs median survival of mice bearing brain metastases. Due to the fruitful BTB penetration and brain metastasis homing, and improved therapeutic outcome, the minoxidil‐based systemic drug delivery strategy may serve as a potential approach for clinical management of brain metastases.

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.

Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.

The blood-brain barrier (BBB) severely blocks the intracranial accumulation of most systemic drugs. Inspired by the contribution of the bacterial outer membrane to Escherichia coli K1 (EC-K1) binding to and invasion of BBB endothelial cells in bacterial meningitis, utilization of the BBB invasion ability of the EC-K1 outer membrane for brain-targeted drug delivery and construction of a biomimetic self-assembled nanoparticle with a surface featuring a lipopolysaccharide-free EC-K1 outer membrane are proposed. BBB penetration of biomimetic nanoparticles is demonstrated to occur through the transcellular vesicle transport pathway, which is at least partially dependent on internalization, endosomal escape, and transcytosis mediated by the interactions between outer membrane protein A and gp96 on BBB endothelial cells. This biomimetic nanoengineering strategy endows the loaded drugs with prolonged circulation, intracranial interstitial distribution, and extremely high biocompatibility. Based on the critical roles of gp96 in cancer biology, this strategy reveals enormous potential for delivering therapeutics to treat gp96-overexpressing intracranial malignancies.