Systemic Brain Delivery of Antisense Oligonucleotides across the Blood–Brain Barrier with a Glucose‐Coated Polymeric Nanocarrier

Abstract

Current antisense oligonucleotide (ASO) therapies for the treatment of central nervous system (CNS) disorders are performed through invasive administration, thereby placing a major burden on patients. To alleviate this burden, we herein report systemic ASO delivery to the brain by crossing the blood–brain barrier using glycemic control as an external trigger. Glucose‐coated polymeric nanocarriers, which can be bound by glucose transporter‐1 expressed on the brain capillary endothelial cells, are designed for stable encapsulation of ASOs, with a particle size of about 45 nm and an adequate glucose‐ligand density. The optimized nanocarrier efficiently accumulates in the brain tissue 1 h after intravenous administration and exhibits significant knockdown of a target long non‐coding RNA in various brain regions, including the cerebral cortex and hippocampus. These results demonstrate that the glucose‐modified polymeric nanocarriers enable noninvasive ASO administration to the brain for the treatment of CNS disorders.

Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB

“…However, in the case of nanoparticles for delivering macromolecules such as proteins and nucleic acids, it appears to need to take advantage of transporter recycling instead of the usual transport pathway of GLUT1. There are reports on brain delivery via GLUT1 by utilizing recycling [ 56 , 57 ]. In these reports, not only the precisely controlled glucose density on the surface of the nanocarrier but also glycemic control as an external trigger showed a dramatically enhanced brain accumulation of the carrier (>6% injected dose/g of brain), resulting in significant knockdown of a target RNA in various brain regions by an antisense oligonucleotide that was encapsulated in the carrier.…”

“…In terms of drug delivery to the brain, a rational strategy is taking advantage of innate BBB functions such as BBB receptors/transporters that promote substance transfer into the brain [ 40 , 41 , 42 ]. Several nanoparticles (NPs) designed for receptor mediated transcytosis have been reported; transferrin (Tf) receptor [ 43 , 44 , 45 , 46 , 47 ], nicotinic receptor [ 48 , 49 , 50 ], low density lipoprotein receptor (LDLR) [ 51 , 52 , 53 , 54 , 55 ], glucose transporter (GLUT) [ 56 , 57 ]. Although the usefulness of those receptor mediated strategies have been demonstrated, we need to consider BBB functions and pathologies because there are differences in BBB structures between the normal brain and the diseased brain [ 58 , 59 , 60 ].…”

Poly(α-l-lysine)-based nanomaterials for versatile biomedical applications: Current advances and perspectives

“…PLLs can be readily functionalized with various targeting ligands, including folic acid [ 127 , 128 ], cRGD [ 129 ], CAGW peptide (Cys-Ala-Gly-Trp) [ 130 ], galactose [ 131 ], and glucose [ 132 ], to improve the selectivity and cellular internalization of the polyplex toward tumor cells or tissues or to enhance transport across the blood-brain barrier. Folic acid receptors are often overexpressed in tumor cells but are rarely found in healthy tissues, and folic acid is the most commonly used targeting ligand in tumor-targeting delivery systems.…”

“…Recently, Kataoka et al fabricated an antisense oligonucleotide-loaded, glucosylated poly-ion complex micelle from antisense oligonucleotides with a mixture of glucose-PEG-PLLs and PEG-PLLs. PIC micelles are capable of crossing the blood-brain barrier via the specific binding of glucose with glucose transporter-1 expressed on brain capillary endothelial cells, enabling noninvasive antisense oligonucleotide administration to brain parenchyma for treating central nervous system disorders [ 132 ]. Numata et al prepared a novel exogenous gene delivery carrier in the form of maleimide-conjugated tetra(ethylene glycol)- b -PLL (Mal-TEG-PLL) [ 133 ].…”

Immobilized Carbohydrates for Preparation of 3′‐Glycoconjugated Oligonucleotides

“…Bleomycin disaccharide and/or carbamoyl mannose show specificity to prostate cancer cells (Schroeder et al., 2014). Nanoparticles decorated with D ‐glucose are able to penetrate the blood brain barrier via the glucose transporter‐1 expressed on brain capillary endothelial cells (Min et al., 2020). However, affinities of these other sugar ligand‐receptor interactions may be too low to overcome the unfavorable delivery properties of an oligonucleotide payload.…”