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The blood-brain barrier (BBB) is a major obstacle preventing drugs from entering the central nervous system (CNS) from the periphery. Composed primarily of brain capillaries, the BBB regulates ion balance and nutrient transport while acting as a barrier against exogenous harmful substances. These capillaries are formed by brain microvascular endothelial cells, surrounded by pericytes and a 30-40nm thick basal lamina, and covered by astrocytic end-feet near neurons.
Although the BBB expresses several transporter proteins and receptors, these pathways are primarily designed for nutrient transport. Water-soluble substances can enter through paracellular pathways, while lipid-soluble substances can passively diffuse or be actively transported by transport proteins. A significant method for crossing the BBB is receptor-mediated transcytosis (RMT), where endogenous substances like iron/transferrin, insulin, and lipoproteins enter the brain. However, most small molecules and nearly all large molecules typically struggle to cross the BBB due to tight junctions and ABC transporter proteins.
Transferrin Receptor (TfR)
The transferrin receptor has two subtypes: TfR1 and TfR2. TfR1 is selectively highly expressed in brain capillary endothelial cells and facilitates transferrin (Tf) endocytosis and transcytosis. Known as CD71, TfR1 is a type II transmembrane glycoprotein formed by two 90 kDa subunits connected by disulfide bonds. TfR2 also binds circulating Tf, but its physiological role is to maintain iron levels rather than cellular iron uptake. Ligands for TfR, delivery systems like liposomes or nanoparticles, and receptor-specific antibodies can cross the BBB via this pathway.
For instance, radiolabeled EGF-conjugated anti-rat transferrin antibodies have been used for brain tumor imaging. Studies on bispecific antibodies targeting TfR and BACE1 (β-secretase-1) for Alzheimer's disease found that higher affinity to TfR led to more TfR entering lysosomes and being degraded. Therefore, optimal TfR affinity is crucial for effective delivery of antibodies to the brain, increasing the exposure of the target site.
Insulin Receptor (IR)
In addition to being highly expressed in the liver and intestines, the insulin receptor is also present in the BBB, serving as the main route for insulin to enter the brain. Similarly, other drugs or molecules can potentially enter the brain via this receptor, provided they can bind to it.
For example, radiolabeled peptide Aβ1-40 conjugated with an insulin receptor antibody increased brain peptide concentration in rhesus monkeys compared to unconjugated antibodies. Additionally, brain-derived neurotrophic factor (BDNF) conjugated with an insulin receptor antibody showed increased brain concentrations in rhesus monkeys. This approach successfully delivered α-L-iduronidase to the brain for treating mucopolysaccharidosis, a lysosomal storage disorder.
Low-Density Lipoprotein Receptor (LDLR)
LDLR, a multifunctional protein, is expressed in brain capillaries. LDL or other lipoproteins containing ApoB100 or ApoE can bind to LDLR, facilitating cellular uptake of lipids. This process, known as the LDL receptor pathway, allows large molecules to be transported across brain endothelial cells.
Recent studies have shown that cholesterol-conjugated siRNA targeting OAT3 mRNA, embedded in endogenous lipoproteins, successfully delivered siRNA to the brain in mice, providing a potential gene silencing approach for brain diseases.
Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1)
LRP1, similar in structure and function to LDLR, transports ligands across the BBB, including Aβ protein, tissue plasminogen activator, Apo-E2, and Apo-E3. LRP1 mediates Aβ protein efflux from the brain, making it a potential target for neurodegenerative disease treatment.
Leptin Receptor (LepR)
Leptin, a peptide hormone composed of 167 amino acids, regulates body weight by binding to leptin receptors in the arcuate nucleus and crossing the BBB via transcytosis. Damage or loss of leptin receptors can lead to obesity. Researchers have successfully delivered nanoparticles conjugated with key leptin sequence amino acids to the brain in rodents.
Receptor for Advanced Glycation Endproducts (RAGE)
RAGE, a 35 kDa immunoglobulin superfamily transmembrane receptor, is widely expressed in various cells, including endothelial cells, smooth muscle cells, and neurons. RAGE interacts with Aβ protein, mediating its transport across the BBB. Unlike LRP1, which facilitates Aβ protein efflux, RAGE transports Aβ from the periphery into the brain.
Scavenger Receptor (SR)
Discovered in macrophages, SR mediates the uptake and degradation of modified LDL. SR is expressed in brain microvascular endothelial cells, facilitating the absorption of polyanions like succinylated proteins. SR I and II are expressed in brain microvessels, with SR I mediating vitamin E uptake in pigs.
Conclusion
The BBB protects the brain by preventing harmful substances from entering, while allowing essential nutrients to pass through. Receptor-mediated transcytosis offers potential routes for biologics to enter the brain. By conjugating relevant receptors like transferrin or developing receptor-specific antibodies and peptides, researchers can exploit these pathways for drug delivery. While TfR and IR are the most studied receptors for CNS drug delivery, other receptors like LRP1, LRP2, LepR, RAGE, and SR also hold potential, albeit with more challenges.
Developing drugs for CNS diseases remains difficult, with few breakthroughs in treating conditions like Alzheimer's disease and gliomas. Receptor-mediated transcytosis is a promising strategy, and advancements in delivery technologies may pave the way for new treatments for CNS disorders.
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