Smart Strategies for Therapeutic Agent Delivery into Brain across the Blood–Brain Barrier Using Receptor-Mediated Transcytosis

Abstract

Discriminatory drug delivery into target cells is essential to effectively elicit the drug activity and to avoid off-target side effects; however, transporting drugs across the cell membrane is difficult due to factors such as molecular size, hydrophilicity, intercellular adhesiveness, and efflux transporters, particularly, in the brain capillary endothelial cells. Drug delivery into the brain is blocked by the blood-brain barrier (BBB). Thus, developing drugs for the central nervous system (CNS) diseases remains a challenge. The approach based on receptor-mediated transcytosis (RMT) can overcome this impassable problem at the BBB. Well-designed molecules for RMT form conjugates with the ligand and drugs via linkers or nanoparticles. Cell penetrating peptides (CPPs), receptor-targeting peptides, and monoclonal antibodies (mAbs) are often used as ligands. The binding of ligand to the receptor on the endothelial cell surface induces endocytosis. Existing exosomes comprising the conjugates move in the cytoplasm and fuse with the opposite plasma membrane to release them. Subsequently, the transcytosed conjugate-loaded drugs or released drugs from the conjugates elicit activity in the brain. As receptors, transferrin receptor (TfR), low-density lipoprotein receptor (LDLR), and insulin receptor (InsR) have been used to intendedly induce transcytosis. Presently, several clinical trials on CNS drugs for Alzheimer's and Parkinson disease are hindered due to poor drug distribution into the brain. Therefore, this strategy based on RMT is a promising method for CNS drugs to be transported into the brain. In this review, I introduce the practicality and possibility of drug delivery into brain across the BBB using RMT.

Shortcut Approaches to Substance Delivery into the Brain Based on Intranasal Administration Using Nanodelivery Strategies for Insulin

“…Although hydrophobic low-molecular-weight compounds can penetrate the apical and successively basolateral membrane through passive diffusion or transporter-mediated transportation, middle-and large-molecular-weight compounds cannot easily penetrate the cell membrane. Alternatively, such large substances are transported across the cell through transcytosis [4]. (i) In fact, protein ligands such as insulin, transferrin, and apolipoproteinE (ApoE) could enter the cells through receptor-mediated endocytosis, are contained in endosomes, and then leave the cells through exocytosis on the opposite side.…”

“…From the point of such structural features, it is relatively hard, though not impossible, for the insulin to cross the membrane through passive diffusion or direct translocation even together with CPPs such as TAT, due to insulin size and non-N-methylated hydrophilicity. It is known that at the BBB, insulin is transported into capillary endothelial cells based on receptor-mediated endocytosis due to insulin receptor (InsR) and subsequently exocytosed to the brain [4]. Endocytosed InsRs are indeed recycled into the plasma membrane, but it is thought that at the surface of the olfactory epithelium, InsRs are probably not expressed at a high level compared to other tissues, as it does not directly lie next to the bloodstream, while InsRs are highly expressed in the olfactory bulb [29].…”

“…Similarly, RMT using arbitrary ligands with cargos could be a direct approach to bypass tight junction-based boundary at the BBB [3]. Similarly, RMT using arbitrary ligands with cargos could be a direct approach to bypass tight junction-based physical boundaries at the BBB [4]. In general, substances could be classified as low-molecular-weight compounds (< approximately 500 Da), high-molecularweight compounds (> approximately 3000 Da), and middle-molecular-weight compounds (approximately 500-3000 Da).…”

“…Furthermore, nanoparticles based on nanodelivery strategies have been extraordinarily used for membrane permeation. I have already described carrier-mediated transport methods based on tissue-specifically expressed transporters using arbitrary substratecargo conjugates [3], molecular cross-membrane internalization into the cells using cell-penetrating peptides (CPPs) [7], specific delivery into cancer cells based on receptor-mediated endocytosis [8], and RMT-based brain-targeted delivery across the BBB using arbitrary ligand-cargo conjugates [4]. A constantly growing number of new results allows us to gain a broader view and a more in-depth understanding of the cross-membrane drug delivery.…”

Delivery of Orally Administered Digestible Antibodies Using Nanoparticles

“…Drug delivery systems are highly important in solving barrier problems, such as transmembrane transportation in drug discovery and development. I have described a transporter-conscious drug design for crossing the cell membrane based on carrier-mediated transport [ 5 ], delivery of substances into cells across the membrane using cell-penetrating peptides through endocytosis or direct translocation [ 6 ], drug internalization into cancer cells that express specific proteins to avoid off-target side effects in cancer therapy [ 7 ], substance delivery into the brain across the blood–brain barrier (BBB) based on transcytosis [ 8 ], and intranasal conjugated substance delivery into the brain using insulin as a carrier [ 9 ]. Despite these approaches, problems in drug delivery persist.…”