Promising Use of Cyclodextrin-Based Non-Viral Vectors for Gene and Oligonucleotide Drugs

Abstract

Genes, short-hairpin RNA (shRNA), small-interfering RNA (siRNA), and decoy DNA can be principally used as tools for the treatment and prevention of many disorders, including but not limited to cancers, genetic disorders, and inherited diseases. This is accomplished by introducing exogenous nucleic acids into mammalian cells to modulate gene expression. However, direct use of such oligonucleotide drugs is hampered by several barriers, including their degradation by nucleases present in the blood and extracellular fluid, cell-membrane impermeability, and their retention in endosomes. To address this issue, the development of safe and effective delivery vectors has emerged as the main fundamental challenge for successful gene and oligonucleotide therapy. Due to the intrinsic risks associated with viral vectors, non-viral vectors have attracted increasing attention as gene and oligonucleotide carriers. We originally developed various cyclodextrin (CyD) conjugates with polyamidoamine (PAMAM) dendrimers as novel CyD-based polymers for the delivery of plasmid DNA, siRNA, shRNA, and decoy DNA. In this review, we describe the recent findings on PAMAM dendrimer conjugates using CyDs as carriers for gene, shRNA, siRNA, and decoy DNA delivery.

Cyclodextrins in the antiviral therapy

“…Reports on the gene and oligonucleotide drugs are summarized in the book chapter of Mohammed [14]. Nucleosides and nucleotides can generally form loose complexes with native CDs.…”

“…A DNA fragment can form a rotaxane-like molecular association with CDs which can be exploited in DNA sequencing [76,77] but less suitable for the entire DNA delivery. Amphiphilic CDs both as neutral and cationic versions have been found appropriate for antiviral oligonucleotide delivery [14,[78][79][80][81][82][83][84], but their complex synthesis and structure have placed them only onto the shelf of promise so far. It seems possible that cyclodextrin-containing macromolecules are suitable for intracellular delivery of shorter oligonucleotides or siRNAs, though the exploitation of these associations is currently in an experimental phase only [80,83,85].…”

“…d) destruction material for virus protein/lipid shell [10][11][12][13]. e) as multivalent antigen vector [14][15][16]. f) vaccine adjuvant [17][18][19][20][21][22].…”

Advances in the Design of (Nano)Formulations for Delivery of Antisense Oligonucleotides and Small Interfering RNA: Focus on the Central Nervous System

“…In the past decade, attention has been focused on the potential application of modified CD as gene delivery systems, − especially for treating brain diseases. − Modified amphiphilic β-cyclodextrins were used to deliver Huntingtin (HTT) targeted siRNAs to in vitro and in vivo models of Huntington disease. The formulation was stable in cerebrospinal fluid with limited toxicity.…”

Cyclodextrin-Based Nanoparticles for Delivery of Antisense Oligonucleotides Targeting Huntingtin

“…Different strategies have been developed to improve ASO stability, targeting, and delivery, including chemical modifications, bioconjugation to different moieties, and the use of delivery vehicles [ 9 ]. Among the delivery vehicles, cyclodextrins (CDs) are known as favorable natural nanocarriers for oligonucleotide therapy [ 10 , 11 , 12 , 13 ]. Cyclodextrins are non-toxic cyclic oligosaccharides constituted by six (α-CD), seven (β-CD), and eight (γ-CD) d -glucopyranosyl units.…”