Cyclodextrins for Non-Viral Gene and siRNA Delivery

Aoife      M. O'Mahony; Martin      J. O'Neill; Bruno      M.D.C. Godinho; Raphael      Darcy; John      F. Cryan; Caitriona      M. O'Driscoll

Abstract

Considerable research is focused on the development of non-viral vectors for gene and RNA interference therapies, with significant advancements in this field over the past number of years. Cationic lipids and polymers have been extensively investigated for these purposes, but there still remains a need for alternative vectors. Cyclodextrins (CDs) are cyclic oligosaccharides derived from starch and are well characterised pharmaceutical excipients. They offer many advantages as potential non-viral vectors for gene and siRNA delivery, in particular the ease with which they can be chemically modified and their lack of toxicity. In recent years, there has been a surge in the number of publications concerning CDs in this field. In this paper, we will review the two main approaches to the use of CDs for gene and siRNA delivery. In the first instance, CDs are used as a scaffold, to which various chemical groups can be grafted, yielding monodisperse functionalised CDs which can self-assemble in the presence of oligonucleotides. CDs are particularly amenable to chemical modification and this approach enables specific and precise design of CD vectors for targeting to various cell and tissue types. In the second approach, CDs can be included as a component of a delivery system, for example, as part of a polymer backbone, appended to a dendrimeric vector, or in polyrotaxane systems. Here, the inclusion of CDs facilitates postmodification of the vector through the formation of inclusion complexes with adamantane and, in some instances, reduces toxicity of the vector. Lastly, we will consider the development of in vivo CD vectors for therapeutic use and other novel applications including siRNA delivery in neurons and the CNS.

Keywords: Click chemistry, cyclodextrins, genes, non-viral delivery, pre-clinical, siRNA.

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