Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment

Abstract

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.

Prodrug Delivery Using Dual-Targeting Nanoparticles To Treat Breast Cancer Brain Metastases

“…Human brain-seeking breast cancer MDA-MB-231Br cells (231Br) were gifted by Dr. Patricia Steeg at the NCI and extensively used in our previously published papers. ,,− Both 231Br cells and bEND.3 cells (mouse BBB endothelial cells, ATCC) were grown in the complete DMEM medium with fetal bovine serum (10%), penicillin (100 units/mL), and streptomycin (100 μg/mL).…”

“…h DOX@NPs were assembled using poly­(lactic-co-glycolic acid)-poly­( ε -carbobenzoxy- l -lysine) as the starting material through a double-emulsion solvent evaporation technique. ,,− Typically, the internal aqueous phase (20 mg of h DOX dissolved in 0.2 mL of water) was added drop by drop into the organic phase under vortex (100 mg of starting material dissolved in 2 mL of ethyl acetate) and sonicated to form the water/oil emulsion. The water/oil emulsion was added drop by drop into the external aqueous phase under vortex (4 mL of 2.5% polyvinyl alcohol 403, Kuraray) and sonicated to form water/oil/water emulsion.…”

Angiopep-2-Modified Nanoparticles for Brain-Directed Delivery of Therapeutics: A Review

“…PLGA-PLL NPs co-carrying doxorubicin and lapatinib were modified with a MMP-1 sensitive fusion peptide containing HER2-targeting KAAYSL and LRP-1targeting Angiopep-2. MMP1-triggered cleavage removed Angiopep-2 for augmented accumulation in BCBMs-bearing brains [96]. NPs may also be engineered such that drug release is induced via an externally applied stimulus.…”

A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization

“…Another difficult challenge in glioma treatment is to overcome the BBB, which could be resolved with the advent of nano-based drug delivery system (NDDS) 33 , 34 , 35 , 36 . Polymer micelle is a commonly used nano-delivery system, which can enhance the water solubility of drugs, reduce the phagocytosis of the reticuloendothelial system and prolong drug circulation time 37 , 38 , 39 , 40 .…”