Hyaluronan-based delivery of therapeutic oligonucleotides for treatment of human diseases

ABSTRACT

Introduction: Oligonucleotide therapeutics such as antisense oligonucleotides and siRNA requires chemical modifications and nano-sized carriers to circumvent stability problems in vivo, to reach target tissues, and to overcome tissue and cellular barriers. Hyaluronic acid (HA), already utilized in drug delivery and tissue engineering, possess properties that are useful to solve these problems and achieve full potential of oligonucleotide therapeutics.

Areas covered: Complexes of oligonucleotide therapeutics with HA are discussed in terms of interactions providing the complexes formation and genes targeted by the therapeutics to cure diseases such as cancer, atherosclerosis, liver cirrhosis, and inflammation. The achieved therapeutic effects are rationalized as consequences of biodistribution, cell internalization and endosomal escape provided by HA.

Expert opinion: Design of electrostatic, coordination, and hydrophobic interactions as well as covalent conjugation between oligonucleotide drugs, HA macromolecules and intermediate ligands are crucial for carrier–cargo association and dissociation under different conditions to impart oligonucleotides stability in vivo, their accumulation in diseased organs, cellular uptake, and dissociation in cytoplasm intact. These are the delivery factors that provides eventual complex formation of oligonucleotide therapeutics with their mRNA, microRNA, or protein targets. Elucidation of the impact of structural parameters of oligonucleotide/HA complexes on their therapeutic effect in vivo is important for the future rational design of the delivery agents.

KEYWORDS:

• Hyaluronan
• siRNA
• antisense oligonucleotide
• drug delivery complexes
• gene regulation
• biodistribution
• cell uptake
• endosomal escape

Article highlights

• Oligonucleotide (ON) therapeutics such as antisense oligonucleotides and siRNA can regulate translation of genes associated with diseases by acting on mRNA by Watson-Crick base pairing. In order to reach their targets in vivo, ON drugs should be delivered by carrier agents.

• Hyaluronic acid (HA), a native polysaccharide component of extracellular matrix, can be useful as a delivery carrier for ON therapeutics owing to its biocompatibility, biodegradability, binding to specific tissues and transport of its cargos into cells by HA receptors-mediated endocytosis.

• ON/HA drug delivery systems can be devised by chemical modification of HA with cationic polymers, metal chelating ligands, lipophilic or chemoselective groups to establish electrostatic, coordination, hydrophobic and covalent linkages between the otherwise repelling each other anionic ON and HA components. These interactions are also used for HA coating of other known ON carriers including liposomes and inorganic nanoparticles.

• Association of ON therapeutics with HA provides stability of ONs against nucleases, their longer circulation after systemic administration in vivo, and accumulation in tumors, liver, atherosclerotic tissues and inflammation sites. Owing to the overexpression of HA receptors on the cell surface and the related transfection of the ON/HA complexes, downregulation of the targeted mRNAs can be achieved with the efficiency higher than that obtained with classical transfection agents.

• In accordance with the mRNA regulation and other targets (such as microRNA and transcription factors) binding, inhibition of solid tumor growth, reduction of liver fibrosis and disappearance of atherosclerosis lesions was achieved in mice in the course of localized or systemic treatment with the corresponding ON/HA complexes.

• Based on the results obtained with the ON/HA complexes, it is promising to expand their use to other areas of drug delivery such as, for example, tissue engineering.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Swedish Research Council (Grant No. 2017-04651).