RNA interference technology with emphasis on delivery vehicles—prospects and limitations

Figures & data

Figure 1. Mechanism of RNAi. siRNA is generated as Dicer cleaves dsRNA molecules. Incorporation of siRNAs into the RISC assembly, followed by unwinding of the double-stranded molecule due to helicase activity of RISC. Once the sense strand is removed, the antisense strand binds to targeted mRNA. RISC then cleaves mRNA that is then degraded by cellular nucleases.

Table I. Nanoparticles employed to deliver siRNA.

Vector	Proposed study	Outcome	Reference
Chitosan/TPP nanoparticles	In vitro gene silencing in CHOK1 and HEK293 cells	Chitosan/TPP nanoparticles are better vectors as compared to chitosan only.	Katas and Alpar, 2006
Chitosan/siRNA complexes	EGFP gene-silencing in human lung cancer cell line H1299 & murine macrophage	Development of an efficient siRNA nanocarrier that can be used for both in vitro and in vivo RNA interference protocols	Howard et al. 2006
Polyguluronate-coated chitosan/siRNA nanoparticles	Gene-silencing in HEK 293 T and HeLa cells	Efficient siRNA delivery	Lee et al. 2009
Chitosan/siRNA nanoparticles	FHL2 gene-silencing in SW40 & HeLa cells	FHL2 gene expression silenced by 69.6%	Ji et al. 2009
PEI/siRNA complexes	Subcutaneous administration of complexes to downregulate HER-2 expression in mice tumor models	siRNA downregulation & marked reduction in tumor growth	Urban-Klein et al. 2005
PEGylated PEI-RGD/siRNA self-assembling nanoparticles	siRNA delivery against VEGF R2 and tumor angiogenesis	Sequence-specific reduction of protein expression by siRNA	Schiffelers et al. 2004
PEI-alginate/siRNA nanoparticles	Deliver siRNA into COS-1 cells	80% suppression of GFP expression	Patnaik et al. 2006
Acylated PEI-PEG nanoparticles	Deliver siRNA into HEK 293 cells	85% inhibition of GFP expression	Nimesh and Chandra 2009
PEI nanoparticles to deliver siRNA against VEGF	Deliver siRNA against VEGF	Knockdown VEGF in pancreatic and prostate cancer models	Höbel et al. 2010
Cyclodextrin-containing polymers (CDP)	siRNA delivery targeted against the EWS-FLI1 gene	Significant inhibition of tumor growth	Hu-Lieskovan et al. 2005
Transferrin-targeted CDP nanoparticles	siRNA delivery to tumor cells	50% reduction of tumor luciferase activity	Bartlett et al. 2007
siRNA/CDP nanoparticles	Administration of siRNA to patients with solid cancers	Intracellular localization in melanoma patients	Davis et al. 2010
PEI modified with HA	siRNA delivery to B16F1, A549, HeLa, and Hep3B tumor cells	Survivin-specific siRNA resulted in significant reduction in the expression of mRNA	Han et al. 2009
Biodegradable poly(amido amine)s	siRNA against epidermal growth factor receptor (EGFR)	80% gene knockdown with low cytotoxicity	Vader et al. 2011
Biodegradable pHPMA-MPPM and TMC polymers	siRNA delivery to In H1299 cells	30–40% reduction in luciferase gene expression	Varkouhi et al. 2011
Triblock copolymer, of monomethoxy poly(ethylene glycol), poly(e-caprolactone) and poly(2-aminoethyl ethylene phosphate)	Delivery of siRNA to BT474 breast cancer cells	Efficient inhibition of tumor growth in a BT474 xenograft murine model	Mao et al. 2011

Katas H, Alpar HO. 2006. Development and characterisation of chitosan nanoparticles for siRNA delivery. J Control Release. 115:216–225.

 PubMed Web of Science ®Google Scholar

Howard KA, Rahbek UL, Liu XD, Damgaard CK, Glud SZ, Andersen MO, et al. 2006. RNA interference in vitro and in vivo using a chitosan/siRNA nanoparticle system. Mol Ther. 14:476–484.

 PubMed Web of Science ®Google Scholar

Lee DW, Yun KS, Ban HS, Choe W, Lee SK, Lee KY. 2009. Preparation and characterization of chitosan/polyguluronate nanoparticles for siRNA delivery. J Control Release. 139:146–152.

 PubMed Web of Science ®Google Scholar

Ji AM, Su D, Che O, Li WS, Sun L, Zhang ZY, et al. 2009. Functional gene silencing mediated by chitosan/siRNA nanocomplexes. Nanotechnology. 20:405103.

 PubMed Web of Science ®Google Scholar

Urban-Klein B, Werth S, Abuharbeid S, Czubayko F, Aigner A. 2005. RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo. Gene Ther. 12:461–466.

 PubMed Web of Science ®Google Scholar

Schiffelers RM, Ansari A, Xu J, Zhou Q, Tang Q, Storm G, et al. 2004. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res. 32:e149.

 PubMed Web of Science ®Google Scholar

Patnaik S, Aggarwal A, Nimesh S, Goel A, Ganguli M, Saini N, et al. 2006. PEI-alginate nanocomposites as efficient in vitro gene transfection agents. J Control Release. 114:398–409.

 PubMed Web of Science ®Google Scholar

Nimesh S, Chandra R. 2009. Polyethylenimine nanoparticles as an efficient in vitro siRNA delivery system. Eur J Pharm Biopharm. 73:43–49.

 PubMed Web of Science ®Google Scholar

Höbel S, Koburger I, John M, Czubayko F, Hadwiger P, Vornlocher HP, Aigner A. 2010. Polyethylenimine/small interfering RNA-mediated knockdown of vascular endothelial growth factor in vivo exerts anti-tumor effects synergistically with Bevacizumab. J Gene Med. 12:287–300.

 PubMed Web of Science ®Google Scholar

Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, Triche TJ. 2005. Sequence-Specific Knockdown of EWS-FLI1 by Targeted, Nonviral Delivery of Small Interfering RNA Inhibits Tumor Growth in a Murine Model of Metastatic Ewing's Sarcoma. Cancer Res. 65: 8984–8992.

 PubMed Web of Science ®Google Scholar

Bartlett DW, Su H, Hildebrandt IJ, Weber WA, Davis ME. 2007. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc Natl Acad Sci U S A. 104:15549–15554.

 PubMed Web of Science ®Google Scholar

Davis ME, Zuckerman JE, Choi CHJ, Seligson D, Tolcher A, Alabi CA, et al. 2010. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature. 464: 1067–1070.

 PubMed Web of Science ®Google Scholar

Han SE, Kang H, Shim GY, Kim SJ, Choi HG, Kim J, et al. 2009. Cationic derivatives of biocompatible hyaluronic acids for delivery of siRNA and antisense oligonucleotides. J Drug Target. 17:123–132.

 PubMed Web of Science ®Google Scholar

Vader P, Van Der Aa LJ, Engbersen JF, Storm G, Schiffelers RM. 2011. Disulfide-Based Poly(amido amine)s for siRNA Delivery: Effects of Structure on siRNA Complexation, Cellular Uptake, Gene Silencing and Toxicity. Pharm Res. 28:1013–1022.

 PubMed Web of Science ®Google Scholar

Varkouhi AK, Lammers T, Schiffelers RM, Van Steenbergen MJ, Hennink WE, Storm G. 2011. Gene silencing activity of siRNA polyplexes based on biodegradable polymers. Eur J Pharm Biopharm. 77:450–457.

 PubMed Web of Science ®Google Scholar

Mao CQ, Du JZ, Sun TM, Yao YD, Zhang PZ, Song EW, Wang J. 2011. A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy. Biomaterials. 32:3124–3133.

 PubMed Web of Science ®Google Scholar