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  • Review Article
  • Published:

RNA interference in the clinic: challenges and future directions

Nature Reviews Cancer volume 11, pages 59–67 (2011)Cite this article

Subjects

Key Points

  • Many cancer targets are difficult to block with conventional therapies. Although RNA interference (RNAi) as a therapeutic approach is appealing, many challenges to delivery must be overcome.

  • Nanoparticles hold promise for the safe and effective intracellular delivery of RNAi-based molecules.

  • Physiological barriers and systemic toxicity of nanoparticle-based carrier systems create multiple challenges to bringing RNAi-based therapeutics to the clinic.

  • Nanoparticles can be used to help avoid immune-mediated responses to systemic RNAi-based therapy.

  • Solutions to improving tumour specificity and the ability to monitor and control short-term and long-term RNAi-based therapies are crucial next steps before clinical use.

  • As the technology for delivery improves, so we will also need to improve our understanding of the heterogeneity of RNAi processing in different cancer types.

  • Various resistance mechanisms to RNAi-based therapies must be anticipated.

Abstract

Inherent difficulties with blocking many desirable targets using conventional approaches have prompted many to consider using RNA interference (RNAi) as a therapeutic approach. Although exploitation of RNAi has immense potential as a cancer therapeutic, many physiological obstacles stand in the way of successful and efficient delivery. This Review explores current challenges to the development of synthetic RNAi-based therapies and considers new approaches to circumvent biological barriers, to avoid intolerable side effects and to achieve controlled and sustained release.

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Figure 1: Mechanism of RNAi following intracellular dsRNA delivery.
Figure 2: Overcoming the biological barriers of RNAi delivery.

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Acknowledgements

Portions of this work were supported by the NIH (CA110793, CA109298, P50 CA083639, P50 CA098258, CA128797, RC2GM092599 and U54 CA151668), the Ovarian Cancer Research Fund, Inc. (Program Project Development Grant), the DOD (OC073399, W81XWH-10-1-0158 and BC085265), the Zarrow Foundation, the Laura and John Arnold Foundation and the Betty Anne Asche Murray Distinguished Professorship.

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Authors and Affiliations

  1. Division of Cancer Medicine, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, 77030, Texas, USA

    Chad V. Pecot & Gabriel Lopez-Berestein

  2. Center for RNA Interference and Non-Coding RNA,U.T. M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, 77030, Texas, USA

    George A. Calin, Robert L. Coleman, Gabriel Lopez-Berestein & Anil K. Sood

  3. Department of Experimental Therapeutics, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, 77030, Texas, USA

    George A. Calin & Gabriel Lopez-Berestein

  4. Department of Gynecologic Oncology, U.T. M.D. Anderson Cancer Center, 1155 Herman Pressler, Unit 1362, Houston, 77030, Texas, USA

    Robert L. Coleman & Anil K. Sood

  5. Department of Cancer Biology, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 173, Houston, 77030, Texas, USA

    Gabriel Lopez-Berestein & Anil K. Sood

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Glossary

RNA interference

(RNAi). Refers to the mechanism of potent and specific gene-silencing caused by double-stranded RNA (dsRNA) produced by endogenous (miRNA) or exogenous (siRNA) sources.

Opsonins

Plasma proteins that act as binding enhancers for phagocytosis.

Reticuloendothelial system

(RES). System composed of scavenging monocytes and macrophages located in the reticular connective tissue (notably the liver, spleen, lung and marrow).

Enhanced permeability and retention

(EPR). The property by which certain sizes of molecules tend to accumulate and remain in tumour tissue more than in normal tissues.

Endocytosis

The active uptake of molecules into a cell by clathrin-dependent and clathrin-independent receptor-mediated endocytosis, pinocytosis and phagocytosis.

Fusogenic lipids

Lipoplexes (containing cationic lipids and nucleic acids) that adopt an inverted hexagonal phase and fuse with anionic membranes resulting in endosomal release.

Fusogenic peptides

Peptides that have cell penetrating properties (such as being highly hydrophobic), which cause cell membrane destabilization and intra-cytoplasmic release.

pH-sensitive lipoplexes

Liposomes that hydrolyse and trigger release of contents owing to subtle drops in pH, such as with endosomal fusion, allowing for endosomal escape.

pH-sensitive polyplexes

Polyplexes (cationic polymer complexed with nucleic acid) that act as proton 'sponges', preventing acidification after endosomal fusion and allowing influx of counter ions, osmotic swelling and endosome rupture.

Aptamer

A DNA or RNA oligonucleotide sequence with a high-affinity binding for specific proteins.

Logic-embedded vector

Vehicles that work in a time-sequential manner to cross biological barriers.

Mesoporous silicon

A biodegradable and biocompatible material made from non-oxidized silicon.

Polyethylene glycol

(PEG). A synthetic polymer that is non-toxic, non-immunogenic and highly water soluble.

Quantum dots

Colloidal semiconductor nanocrystals with optical and electronic properties superior to conventional organic fluorophores that can be used for imaging purposes.

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Pecot, C., Calin, G., Coleman, R. et al. RNA interference in the clinic: challenges and future directions. Nat Rev Cancer 11, 59–67 (2011). https://doi.org/10.1038/nrc2966

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