Intracellular transport and regulation of transcytosis across the blood–brain barrier

Abstract

The blood–brain barrier is a dynamic multicellular interface that regulates the transport of molecules between the blood circulation and the brain parenchyma. Proteins and peptides required for brain homeostasis cross the blood–brain barrier via transcellular transport, but the mechanisms that control this pathway are not well characterized. Here, we highlight recent studies on intracellular transport and transcytosis across the blood–brain barrier. Endothelial cells at the blood–brain barrier possess an intricate endosomal network that allows sorting to diverse cellular destinations. Internalization from the plasma membrane, endosomal sorting, and exocytosis all contribute to the regulation of transcytosis. Transmembrane receptors and blood-borne proteins utilize different pathways and mechanisms for transport across brain endothelial cells. Alterations to intracellular transport in brain endothelial cells during diseases of the central nervous system contribute to blood–brain barrier disruption and disease progression. Harnessing the intracellular sorting mechanisms at the blood–brain barrier can help improve delivery of biotherapeutics to the brain.

Potential therapeutic target for aging and age-related neurodegenerative diseases: the role of acid sphingomyelinase

“…Lipid transport and lipid mediators, including ASM, regulate the assembly of caveolae, which are involved in transcytosis across the BBB, at plasma membranes in brain ECs 52,53 . Caveolae are submicroscopic vesicles that are associated with the plasma membrane and consist of caveolin-1 (Cav-1) membrane proteins and cytoplasmic cavin proteins [54][55][56] .…”

Tailoring Iron Oxide Nanoparticles for Efficient Cellular Internalization and Endosomal Escape

“…Nanoparticle delivery to the brain has gathered special interest for the diagnosis and treatment of neurodegenerative diseases, cancer and other brain-derived pathologies. However, unlike the endothelial barriers between the blood and other tissues, transport across the BBB is much more regulated and poses an additional constraint for targeting neural tissues [ 231 ]. Although disease conditions are known to increase BBB permeability, diagnostic and therapeutic strategies are ideally performed at early stages before BBB disruption [ 231 ].…”

“…However, unlike the endothelial barriers between the blood and other tissues, transport across the BBB is much more regulated and poses an additional constraint for targeting neural tissues [ 231 ]. Although disease conditions are known to increase BBB permeability, diagnostic and therapeutic strategies are ideally performed at early stages before BBB disruption [ 231 ]. Therefore, nanoparticles should be able to cross healthy barriers.…”

“…Hybrid ION/UCNP systems have been widely applied in cancer therapy, MRI and diagnosis, gene therapy, and drug delivery [ 308 ]. In general, the most prevalent host matrices for iron oxide core-shell nanoparticles include Y 2 O 3 , Y 2 O 2 S, LaF 3 , BaYF 5 , NaYF 4 , and NaGdF 4 , which have been doped with Yb 3+ /Tm 3+ and Yb 3+ /Er 3+ ions [ 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , …”

Immunotoxin Screening System: A Rapid and Direct Approach to Obtain Functional Antibodies with Internalization Capacities

“…In addition to development of cancer therapeutics, at the preclinical level, another intriguing concept is delivery of drugs across the blood brain barrier (BBB) into the brain by using ILPs. The BBB, where cell membrane proteins involved in receptor-mediated transcytosis, such as transferrin receptor and insulin receptor are expressed, is a selective barrier between systemic blood circulation and brain parenchyma [ 105 , 106 , 107 , 108 ]. Recently, Johnsen et al reported that intravenous injection of OX26 (a mouse anti-rat CD71/transferrin receptor monoclonal antibody)-conjugated and oxaliplatin-encapsulated liposome resulted in higher concentration of platinum in the rat brain parenchyma compared to the control ILP [ 109 ].…”