A Historical Review of Brain Drug Delivery

Abstract

The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a drug for syphilis, salvarsan, did not enter the brain, due to the presence of a blood–brain barrier (BBB). Owing to restricted transport across the BBB, FDA-approved drugs for the CNS have been generally limited to lipid-soluble small molecules. Drugs that do not cross the BBB can be re-engineered for transport on endogenous BBB carrier-mediated transport and receptor-mediated transport systems, which were identified during the 1970s–1980s. By the 1990s, a multitude of brain drug delivery technologies emerged, including trans-cranial delivery, CSF delivery, BBB disruption, lipid carriers, prodrugs, stem cells, exosomes, nanoparticles, gene therapy, and biologics. The advantages and limitations of each of these brain drug delivery technologies are critically reviewed.

Selection of single domain anti-transferrin receptor antibodies for blood-brain barrier transcytosis using a neurotensin based assay and histological assessment of target engagement in a mouse model of Alzheimer’s related amyloid-beta pathology

“…Using RMT to transport payload across the BBB has limitations, such as downregulating the targeted receptors and competition with natural ligands which may affect the receptors’ normal physiological functions [ 79 , 88 , 89 ]. For example, Couch et al, found that anti-TfR antibodies could cause a reduction of reticulocyte count and acute clinical signs [ 88 ].…”

Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses

“…The treatment of CNS manifestations in MPSs has been a critical but unmet need. However, a BBB-crossing technology based on the physiological mechanism of receptor-mediated transcytosis has been pioneered by Pardridge and colleagues [ 100 , 101 , 102 , 103 , 104 ] and paved the way for addressing this research gap. Recently, pabinafusp alfa, a BBB-penetrating fusion protein consisting of an anti-human transferrin receptor (TfR) antibody and IDS, was approved in Japan for the treatment of patients with all, including neuronopathic, forms of MPS II [ 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ].…”

Blood-Brain Barrier Transport of Transferrin-Receptor Targeted Nanoparticles

“…The BBB proper consists of endothelial cells connected by tight junctions. The blood-CSF barrier is formed by choroid plexus epithelial cells also connected by tight junctions, but opposed to the BBB, the capillaries of the blood-CSF barrier are leaky, meaning that solutes of the plasma diffuse into the extracellular space of the choroid plexus where the epithelial cells selectively transport molecules to the CSF [2,3,14] From a quantitative drug delivery perspective, passaging across the BBB is by far the most important as the brain microvasculature has a surface area thousand-fold higher than that of the choroid plexus. This allow drugs to enter the entire brain while transport across the blood-CSF barrier is restricted to the ventricular system [2,3,15].…”

“…This includes entry via the paracellular space between the endothelial cells where tight junctions limit diffusion from blood to brain [1,2,9]. To enable nutrient uptake while preventing the influx of unwanted substances, the BECs express nutrient transporters for, e.g., amino-and fatty acids, monosaccharides, vitamins, and essential ions and metals [1][2][3][4]. In contrast, the transport of large molecules of the plasma, like albumin and IgG, is diminutive, e.g., intravenous injection of non-immune IgG in the adult rat is limited to as little as 0.03 % of the injected dose, which can be superseded more than ten-fold by injecting anti-rat transferrin receptortargeted IgG (OX26) [16].…”