Blood-Brain Barrier Transport of Transferrin-Receptor Targeted Nanoparticles

Abstract

The blood-brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes need attachment of a targeting molecule, as BECs unfortunately are virtually incapable of uptake of non-targeted liposomes from the circulation. Experiments of independent research groups have qualified antibodies targeting the transferrin receptor as superior for targeted delivery of nanoparticles to BECs. Functionalization of nanoparticles via conjugation with anti-transferrin receptor antibodies leads to nanoparticle uptake by endothelial cells of both brain capillaries and post-capillary venules. Reducing the density of transferrin receptor-targeted antibodies conjugated to liposomes limits uptake in BECs. Opposing the transport of nanoparticles conjugated to high-affine anti-transferrin receptor antibodies, lowering the affinity of the targeting antibodies or implementing monovalent antibodies increase uptake by BECs and allows for further transport across the BBB. The novel demonstration of transport of targeted liposomes in post-capillary venules from blood to the brain is interesting and clearly warrants further mechanistic pursuit. The recent evidence for passing targeted nanoparticles through the BBB shows great promise for future drug delivery of biologics to the brain.

Preserved blood-brain barrier and neurovascular coupling in female 5xFAD model of Alzheimer’s disease

“…Recent advances allowed monitoring of AMT at unprecedented details in vivo, i.e., at different categories of cerebral microvessels and at the level of single transport vesicles in the living brain (Mathiesen Janiurek et al, 2019;Kucharz et al, 2021;Thomsen et al, 2022). Here, using 2 PM, we found that AMT was unchanged in 5xFAD mice compared to the WT, regardless of the vessel type.…”

Exploring Chinese herbal medicine for ischemic stroke: insights into microglia and signaling pathways

“…Tf has been extensively researched as a potential probe for drug delivery targeting, due to its ability to target drugs to the blood and cerebrospinal fluid barriers. The transferrin receptor (TfR) has long been a widely studied therapeutic target, as it is highly expressed in nerve cells and cerebrovascular epithelial cells (THOMSEN et al, 2022). Utilizing endogenous ligands Tf or antibodies against Tf Frontiers in Pharmacology frontiersin.org enables drug targeting through TfR-mediated cellular uptake, effectively facilitating drug accumulation in the brain (BIEN-LY et al, 2015).…”

Nucleic acid-based therapeutics for the treatment of central nervous system disorders

“…Receptor-mediated transport is another possible mechanism, in which an NBT is conjugated with a ligand specific to a receptor present in brain endothelial cells. One method by which receptormediated transport is exploited for drug delivery to the brain is targeting the transferrin receptor (Tfr1) abundant on brain endothelial cells (Thomsen et al, 2022).…”