Strategies to optimize siRNA delivery to hepatocellular carcinoma cells

ABSTRACT

Introduction: hepatocellular carcinoma (hcc) is the predominant form of primary liver cancer and the second leading cause of cancer-associated mortality worldwide. available therapies for hcc have limited efficacy due to often late diagnosis and the general resistance of hcc to anti-cancer agents; therefore, the development of novel therapeutics is urgently required. small-interfering rna (sirna) molecules are short, double-stranded rnas that specifically recognize and bind the mrna of a target gene to inhibit gene expression. despite the great therapeutic potential of sirnas towards many human tumors including hcc, their use is limited by suboptimal delivery.

Areas covered: In this review, we outline the current data regarding the therapeutic potential of siRNAs in HCC and describe the development of effective siRNA delivery systems. We detail the key problems associated with siRNA delivery and discuss the possible solutions. Finally, we provide examples of the various siRNA delivery strategies that have been employed in animal models of HCC and in human patients enrolled in clinical trials.

Expert opinion: Despite the existing difficulties in siRNA delivery for HCC, the increasing scientific attention and breakthrough studies in this field is facilitating the design of novel and efficient technical solutions that may soon find practical applications.

KEYWORDS:

• siRNA
• hepatocellular carcinoma
• drug delivery
• polymers
• liposome

Article highlights

• Available therapies for hepatocellular carcinoma (HCC) have limited efficacy.

• Small interfering RNAs (siRNAs) have potential therapeutic value in HCC, but specific delivery of siRNAs to HCC lesions is a considerable challenge

• siRNAs are extremely labile in the biological environment and thus cannot be delivered as naked molecules

• Various siRNA delivery systems based on lipid nanoparticles, polymers or inorganic materials have been developed to target HCC

• Data from studies performed in animal models and the initiation of clinical trials are guiding the future of efficient siRNA-based treatment of HCC

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to thank Insight Editing London for their assistance in editing and proof-reading this manuscript.

Declaration of interest

The authors have no other 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 apart from those disclosed.

Writing assistance was utilized in the preparation of this manuscript and carried out by Insight Editing London

Additional information

Funding

This work was supported in part by the ‘Fondazione Cassa di Risparmio of Trieste’, the ‘Fondazione Benefica Kathleen Foreman Casali of Trieste’, the ‘Beneficentia Stiftung’ of Vaduz Liechtenstein, and the Italian Minister of Instruction, University and Research (MIUR), PRIN 2010-11, [20109PLMH2] and by FRA 2015, University of Trieste. G Forte was supported by the project no. LQ1605 (MEYS CR, NPU II).