Skip to main content
SpringerLink
Log in
Book cover

RNA Interference from Biology to Therapeutics pp 143–160Cite as

Lipidoids: A Combinatorial Approach to siRNA Delivery

  • Chapter
  • First Online:

Part of the book series: Advances in Delivery Science and Technology ((ADST))

Abstract

The safe and effective delivery of siRNA remains the principal challenge to the realization of its clinical potential. The present collection of delivery materials and their diversity remains limited, in part due to their slow, multistep syntheses. This chapter will describe a class of lipid-like delivery molecules, termed “lipidoids,” as carriers for RNAi therapeutics. Specifically, the chapter will address the rationale underlying the combinatorial approach; the synthetic chemical methods employed; the screening assay utilized; the structure–activity relationships determined; the formulation considerations learned; several applications of the platform; and the evolution of the strategy to generate next-generation libraries.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Fire A et al (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669):806–811

    Article  PubMed  CAS  Google Scholar 

  2. Berns K et al (2004) A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 428(6981):431–437

    Article  PubMed  CAS  Google Scholar 

  3. Kittler R et al (2004) An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division. Nature 432(7020):1036–1040

    Article  PubMed  CAS  Google Scholar 

  4. Paddison PJ et al (2004) A resource for large-scale RNA-interference-based screens in mammals. Nature 428(6981):427–431

    Article  PubMed  CAS  Google Scholar 

  5. Bumcrot D et al (2006) RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol 2(12):711–719

    Article  PubMed  CAS  Google Scholar 

  6. McCaffrey AP et al (2002) Gene expression: RNA interference in adult mice. Nature 418(6893):38–39

    Article  PubMed  CAS  Google Scholar 

  7. McCaffrey AP et al (2003) Inhibition of hepatitis B virus in mice by RNA interference. Nat Biotechnol 21(6):639–644

    Article  PubMed  CAS  Google Scholar 

  8. Soutschek J et al (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432(7014):173–178

    Article  PubMed  CAS  Google Scholar 

  9. Zimmermann TS et al (2006) RNAi-mediated gene silencing in non-human primates. Nature 441(7089):111–114

    Article  PubMed  CAS  Google Scholar 

  10. Grimm D et al (2006) Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441(7092):537–541

    Article  PubMed  CAS  Google Scholar 

  11. John M et al (2007) Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway. Nature 449(7163):745–747

    Article  PubMed  CAS  Google Scholar 

  12. Whitehead KA, Langer R, Anderson DG (2009) Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 8(2):129–138

    Article  PubMed  CAS  Google Scholar 

  13. Schroeder A et al (2010) Lipid-based nanotherapeutics for siRNA delivery. J Intern Med 267(1):9–21

    Article  PubMed  CAS  Google Scholar 

  14. Heyes J et al (2005) Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. J Control Release 107(2):276–287

    Article  PubMed  CAS  Google Scholar 

  15. Semple SC et al (2010) Rational design of cationic lipids for siRNA delivery. Nat Biotechnol 28(2):172–176

    Article  PubMed  CAS  Google Scholar 

  16. Lynn DM et al (2001) Accelerated discovery of synthetic transfection vectors: parallel synthesis and screening of a degradable polymer library. J Am Chem Soc 123(33):8155–8156

    Article  PubMed  CAS  Google Scholar 

  17. Goldberg M (2008) Screening, synthesis, and applications of “lipidoids”: a novel class of molecules developed for the delivery of RNAi therapeutics, in biological chemistry. Massachusetts Institute of Technology, Cambridge

    Google Scholar 

  18. Akinc A et al (2008) A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat Biotechnol 26(5):561–569

    Article  PubMed  CAS  Google Scholar 

  19. Behr JP et al (1989) Efficient gene transfer into mammalian primary endocrine cells with lipopolyamine-coated DNA. Proc Natl Acad Sci USA 86(18):6982–6986

    Article  PubMed  CAS  Google Scholar 

  20. Boussif O et al (1995) A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci USA 92(16):7297–7301

    Article  PubMed  CAS  Google Scholar 

  21. Sonawane ND, Szoka FC, Verkman AS (2003) Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J Biol Chem 278(45): 44826–44831

    Article  PubMed  CAS  Google Scholar 

  22. Medina-Kauwe LK, Xie J, Hamm-Alvarez S (2005) Intracellular trafficking of nonviral vectors. Gene Ther 12(24):1734–1751

    Article  PubMed  CAS  Google Scholar 

  23. Wolff JA, Rozema DB (2007) Breaking the bonds: non-viral vectors become chemically dynamic. Mol Ther 16(1):8–15

    Article  PubMed  Google Scholar 

  24. Wattiaux R et al (2000) Endosomes, lysosomes: their implication in gene transfer. Adv Drug Deliv Rev 41(2):201–208

    Article  PubMed  CAS  Google Scholar 

  25. Miller AD (1998) Cationic liposomes for gene therapy. Angew Chem Int Ed 37(13–14): 1768–1785

    Article  Google Scholar 

  26. Maurer N et al (1999) Lipid-based systems for the intracellular delivery of genetic drugs. Mol Membr Biol 16(1):129–140

    Article  PubMed  CAS  Google Scholar 

  27. Shmueli RB, Anderson DG, Green JJ (2010) Electrostatic surface modifications to improve gene delivery. Expert Opin Drug Deliv 7(4):535–550

    Article  PubMed  CAS  Google Scholar 

  28. Kedmi R, Ben-Arie N, Peer D (2010) The systemic toxicity of positively charged lipid nanoparticles and the role of toll-like receptor 4 in immune activation. Biomaterials 31(26): 6867–6875

    Article  PubMed  CAS  Google Scholar 

  29. Wheeler JJ et al (1999) Stabilized plasmid-lipid particles: construction and characterization. Gene Ther 6(2):271–281

    Article  PubMed  CAS  Google Scholar 

  30. Wisse E et al (2008) The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer. Gene Ther 15(17):1193–1199

    Article  PubMed  CAS  Google Scholar 

  31. Akinc A et al (2009) Development of lipidoid-siRNA formulations for systemic delivery to the liver. Mol Ther 17(5):872–879

    Article  PubMed  CAS  Google Scholar 

  32. Adlakha-Hutcheon G et al (1999) Controlled destabilization of a liposomal drug delivery system enhances mitoxantrone antitumor activity. Nat Biotechnol 17(8):775–779

    Article  PubMed  CAS  Google Scholar 

  33. Webb MS et al (1998) Comparison of different hydrophobic anchors conjugated to poly(ethylene glycol): effects on the pharmacokinetics of liposomal vincristine. Biochim Biophys Acta 1372(2):272–282

    Article  PubMed  CAS  Google Scholar 

  34. Svensson RU et al (2008) Assessing siRNA pharmacodynamics in a luciferase-expressing mouse. Mol Ther 16(12):1995–2001

    Article  PubMed  CAS  Google Scholar 

  35. Sioud M (2008) Does the understanding of immune activation by RNA predict the design of safe siRNAs? Front Biosci 13:4379–4392

    Article  PubMed  CAS  Google Scholar 

  36. Eberle F et al (2008) Modifications in small interfering RNA that separate immunostimulation from RNA interference. J Immunol 180(5):3229–3237

    PubMed  CAS  Google Scholar 

  37. Zhang HY et al (2006) RNA interference with chemically modified siRNA. Curr Top Med Chem 6(9):893–900

    Article  PubMed  CAS  Google Scholar 

  38. Morrissey DV et al (2005) Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 23(8):1002–1007

    Article  PubMed  CAS  Google Scholar 

  39. Judge AD et al (2006) Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther 13(3):494–505

    Article  PubMed  CAS  Google Scholar 

  40. Schlee M, Hornung V, Hartmann G (2006) siRNA and isRNA: two edges of one sword. Mol Ther 14(4):463–470

    Article  PubMed  CAS  Google Scholar 

  41. Nguyen DN et al (2009) Drug delivery-mediated control of RNA immunostimulation. Mol Ther 17(9):1555–1562

    Article  PubMed  CAS  Google Scholar 

  42. Frank-Kamenetsky M et al (2008) Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci USA 105(33):11915–11920

    Article  PubMed  CAS  Google Scholar 

  43. Epiphanio S et al (2008) Heme oxygenase-1 is an anti-inflammatory host factor that promotes murine plasmodium liver infection. Cell Host Microbe 3(5):331–338

    Article  PubMed  CAS  Google Scholar 

  44. Huang Y-H et al (2009) Claudin-3 gene silencing with siRNA suppresses ovarian tumor growth and metastasis. Proc Natl Acad Sci USA 106(9):3426–3430

    Article  PubMed  CAS  Google Scholar 

  45. Goldberg MS et al (2011) Nanoparticle-mediated delivery of siRNA targeting Parp1 extends survival of mice bearing tumors derived from Brca1-deficient ovarian cancer cells. Proc Natl Acad Sci USA 108(2):745–750

    Article  PubMed  CAS  Google Scholar 

  46. Armstrong DK et al (2006) Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354(1):34–43

    Article  PubMed  CAS  Google Scholar 

  47. O’Donovan PJ, Livingston DM (2010) BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. Carcinogenesis 31(6):961–967

    Article  PubMed  Google Scholar 

  48. Mahon KP et al (2010) Combinatorial approach to determine functional group effects on lipidoid-mediated siRNA delivery. Bioconjug Chem 21(8):1448–1454

    Article  PubMed  CAS  Google Scholar 

  49. Love KT et al (2010) Lipid-like materials for low-dose, in vivo gene silencing. Proc Natl Acad Sci USA 107(5):1864–1869

    Article  PubMed  CAS  Google Scholar 

  50. Whitehead KA, et al. (2011) Synergistic silencing: combinations of lipid-like materials for efficacious siRNA delivery. Mol Ther

    Google Scholar 

  51. Kolb HC, Finn MG, Sharpless KB (2001) Click chemistry: diverse chemical function from a few good reactions. Angew Chem Int Ed 40(11):2004–2021

    Article  CAS  Google Scholar 

  52. Saxon E, Armstrong JI, Bertozzi CR (2000) A “traceless” staudinger ligation for the chemoselective synthesis of amide bonds. Org Lett 2(14):2141–2143

    Article  PubMed  CAS  Google Scholar 

  53. Dassie JP et al (2009) Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors. Nat Biotechnol 27(9):839–846

    Article  PubMed  CAS  Google Scholar 

  54. Neff CP et al (2011) An aptamer-siRNA chimera suppresses HIV-1 viral loads and protects from helper CD4+ T cell decline in humanized mice. Sci Transl Med 3(66):66ra6

    Article  PubMed  Google Scholar 

  55. Wheeler LA et al (2011) Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras. J Clin Invest 121(6):2401–2412

    Article  PubMed  CAS  Google Scholar 

  56. Davis ME et al (2010) Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464(7291):1067–1070

    Article  PubMed  CAS  Google Scholar 

  57. Bartlett DW et al (2007) Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc Natl Acad Sci USA 104(39):15549–15554

    Article  PubMed  CAS  Google Scholar 

  58. Sharp PA, Langer R (2011) Promoting convergence in biomedical science. Science 333(6042):527

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA

    Michael Goldberg

Authors
  1. Michael Goldberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Goldberg .

Editor information

Editors and Affiliations

  1. Interdisciplinary Nanoscience Center, Aarhus University, Ny Munkegade 118, Aarhus, 8000 AA, Denmark

    Kenneth A. Howard

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Controlled Release Society

About this chapter

Cite this chapter

Goldberg, M. (2013). Lipidoids: A Combinatorial Approach to siRNA Delivery. In: Howard, K. (eds) RNA Interference from Biology to Therapeutics. Advances in Delivery Science and Technology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-4744-3_7

Download citation

Publish with us

Policies and ethics

Search

Navigation