Overcoming Mfsd2a‐Mediated Low Transcytosis to Boost Nanoparticle Delivery to Brain for Chemotherapy of Brain Metastases

Abstract

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.

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.…”

“…h DOX was further loaded into transcytosis-targeting peptide (TTP) and hyaluronic acid co-functionalized poly­(lactic-co-glycolic acid)-poly­( ε -carbobenzoxy- l -lysine) nanoparticles ( h DOX@NPs), to specifically treat brain metastases from breast cancer. BBB penetration of NPs can be efficiently enhanced through TTP functionalization and TTP-mediated binding with the heparin sulfate proteoglycans at the BBB. − TTP-functionalized NPs were found to penetrate through the BBB via caveolae-mediated endocytosis and the subsequent transcytosis directed pathway. , Hyaluronic acid can mediate special binding with highly expressed CD44 on breast cancer cells and subsequent internalization via CD44-mediated endocytosis. ,− NPs without ligand functionalization ( h DOX@Basic) and with either hyaluronic acid ( h DOX@Basic-H) or TTP functionalization ( h DOX@Basic-T) were used as controls. We assessed h DOX cleavage, DNA intercalation, cellular uptake, cytotoxicity, brain accumulation, and therapeutic efficacy in a mouse model of brain metastases from breast cancer.…”

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 .…”

Targeting Antibacterial Effect and Promoting of Skin Wound Healing After Infected with Methicillin-Resistant Staphylococcus aureus for the Novel Polyvinyl Alcohol Nanoparticles

“…Recent reports have identified nanomedicine as an ideal approach to improve the efficiency and wound treatment. 3 Nanoparticles are ultrafine particles between 1–1000 nm in diameter, 8 that have many advantageous properties related to trauma therapy, including being biodegradable, exhibiting controlled drug release, enough drug delivery efficacy, 10 have healing properties, penetrated blood-brain barrier 11 and their ability to be used as an extracellular matrix material. 3 Many studies have shown that nanoparticles can improve antibacterial and wound-healing activities.…”