Efficient siRNA Delivery with Non-viral Polymeric Vehicles

Sequence-specific gene silencing using small interfering RNA (siRNA) provides a potent and specific method for gene expression, thus is now being evaluated in clinical trials as a novel therapeutic strategy. As a results, there has been a significant surge of interest in the application of siRNA in therapeutics as a means of silencing the specific gene function. However, for siRNA technology to be valuable and effective, the development of efficient siRNA delivery strategy is essential for improving biological activities such as stability, cellular uptake, sequence-specificity, devoid of nonspecific knockdown and toxic side effects. Accordingly, a number of delivery systems, both viral and nonviral, have been reported and some of them successfully used for the introduction of siRNA into cells both in vitro and in vivo. Here, we discuss the current understanding of synthetic siRNA delivery mechanism and strategies of siRNA delivery by non-viral polymeric vehicles which are currently used in vitro and in vivo.

[1]  Stephen P. Fox,et al.  Sustained Polymeric Delivery of Gene Silencing Antisense ODNs, siRNA, DNAzymes and Ribozymes: In Vitro and In Vivo Studies , 2004, Journal of drug targeting.

[2]  H. Blau,et al.  Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies , 2005, Nature Cell Biology.

[3]  David R Corey,et al.  Chemical modification: the key to clinical application of RNA interference? , 2007, The Journal of clinical investigation.

[4]  D. Scherman,et al.  A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[5]  T. Bártfai,et al.  Cellular translocation of proteins by transportan , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  T. Park,et al.  Local and systemic delivery of VEGF siRNA using polyelectrolyte complex micelles for effective treatment of cancer. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[7]  L. Gold,et al.  High affinity ligands from in vitro selection: complex targets. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[8]  M. Breunig,et al.  Mechanistic investigation of poly(ethylene imine)-based siRNA delivery: disulfide bonds boost intracellular release of the cargo. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[9]  P. Low,et al.  Endocytosis of folate-protein conjugates: ultrastructural localization in KB cells. , 1993, Journal of cell science.

[10]  T. Park,et al.  Target-specific gene silencing by siRNA plasmid DNA complexed with folate-modified poly(ethylenimine). , 2005 .

[11]  S. Futaki,et al.  Possible Existence of Common Internalization Mechanisms among Arginine-rich Peptides* , 2002, The Journal of Biological Chemistry.

[12]  Kenneth A Howard,et al.  RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  Judy Lieberman,et al.  Interfering with disease: a progress report on siRNA-based therapeutics , 2007, Nature Reviews Drug Discovery.

[14]  R. Griffey,et al.  Fully 2'-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA. , 2005, Journal of medicinal chemistry.

[15]  T. Park,et al.  Comparative evaluation of target-specific GFP gene silencing efficiencies for antisense ODN, synthetic siRNA, and siRNA plasmid complexed with PEI-PEG-FOL conjugate. , 2006, Bioconjugate chemistry.

[16]  M. Hashida,et al.  Cell-specific delivery of genes with glycosylated carriers. , 2001, Advanced drug delivery reviews.

[17]  T. Meade,et al.  Transfection of folate-polylysine DNA complexes: evidence for lysosomal delivery. , 1995, Bioconjugate chemistry.

[18]  A. Aigner Delivery Systems for the Direct Application of siRNAs to Induce RNA Interference (RNAi) In Vivo , 2006, Journal of biomedicine & biotechnology.

[19]  Y. Bae,et al.  Polymeric gene carriers. , 2002, Critical reviews in eukaryotic gene expression.

[20]  J. Ross,et al.  Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications , 1994, Cancer.

[21]  Mark E. Davis,et al.  Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA , 2007, Proceedings of the National Academy of Sciences.

[22]  S. W. Kim,et al.  Soluble Flt-1 gene delivery using PEI-g-PEG-RGD conjugate for anti-angiogenesis. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[23]  L. Gold,et al.  A tenascin-C aptamer identified by tumor cell SELEX: Systematic evolution of ligands by exponential enrichment , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  D. Cheresh,et al.  Requirement of vascular integrin alpha v beta 3 for angiogenesis. , 1994, Science.

[25]  A. Prochiantz,et al.  The third helix of the Antennapedia homeodomain translocates through biological membranes. , 1994, The Journal of biological chemistry.

[26]  Ann Logan,et al.  A versatile reducible polycation-based system for efficient delivery of a broad range of nucleic acids , 2005, Nucleic acids research.

[27]  D. Bull,et al.  Water-soluble lipopolymer as an efficient carrier for gene delivery to myocardium , 2003, Gene Therapy.

[28]  P. D. Cook,et al.  Uniformly modified 2'-deoxy-2'-fluoro phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets. , 1993, Journal of medicinal chemistry.

[29]  P. Aisen,et al.  Transferrin receptor 1. , 2004, The international journal of biochemistry & cell biology.

[30]  H. Schluesener,et al.  Systematic Evolution of a DNA Aptamer Binding to Rat Brain Tumor Microvessels , 2001, The Journal of Biological Chemistry.

[31]  V. Torchilin,et al.  TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Amy C Richards Grayson,et al.  Biophysical and Structural Characterization of Polyethylenimine-Mediated siRNA Delivery in Vitro , 2006, Pharmaceutical Research.

[33]  Y. Li,et al.  Characterization of commercially available and synthesized polyethylenimines for gene delivery. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[34]  Mark E. Davis,et al.  Impact of tumor‐specific targeting and dosing schedule on tumor growth inhibition after intravenous administration of siRNA‐containing nanoparticles , 2008, Biotechnology and bioengineering.

[35]  P. Low,et al.  Delivery of antisense oligodeoxyribonucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  M. Behlke Progress towards in Vivo Use of siRNAs , 2006, Molecular Therapy.

[37]  M. Eccles,et al.  Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells , 2004, FEBS letters.

[38]  Anastasia Khvorova,et al.  Functional siRNAs and miRNAs Exhibit Strand Bias , 2003, Cell.

[39]  S. W. Kim,et al.  A new synthesis of galactose-poly(ethylene glycol)-polyethylenimine for gene delivery to hepatocytes. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[40]  D. Fischer,et al.  A Novel Non-Viral Vector for DNA Delivery Based on Low Molecular Weight, Branched Polyethylenimine: Effect of Molecular Weight on Transfection Efficiency and Cytotoxicity , 1999, Pharmaceutical Research.

[41]  Kazunori Kataoka,et al.  Lactosylated poly(ethylene glycol)-siRNA conjugate through acid-labile beta-thiopropionate linkage to construct pH-sensitive polyion complex micelles achieving enhanced gene silencing in hepatoma cells. , 2005, Journal of the American Chemical Society.

[42]  Yong Wang,et al.  Cell type–specific delivery of siRNAs with aptamer-siRNA chimeras , 2006, Nature Biotechnology.

[43]  Simon W. Jones,et al.  Characterisation of cell‐penetrating peptide‐mediated peptide delivery , 2005, British journal of pharmacology.

[44]  P. Opolon,et al.  Intravenous delivery of anti-RhoA small interfering RNA loaded in nanoparticles of chitosan in mice: safety and efficacy in xenografted aggressive breast cancer. , 2006, Human gene therapy.

[45]  R. Surabhi,et al.  Small interfering RNAs directed against beta-catenin inhibit the in vitro and in vivo growth of colon cancer cells. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[46]  T. Rana,et al.  Visualizing a correlation between siRNA localization, cellular uptake, and RNAi in living cells. , 2004, Chemistry & biology.

[47]  B. Hicke,et al.  Escort aptamers: a delivery service for diagnosis and therapy. , 2000, The Journal of clinical investigation.

[48]  C. Ahn,et al.  Biodegradable poly(ethylenimine) for plasmid DNA delivery. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[49]  Judy Lieberman,et al.  Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors , 2005, Nature Biotechnology.

[50]  Eric Vives,et al.  Cell-penetrating Peptides , 2003, The Journal of Biological Chemistry.

[51]  R. Juliano,et al.  Tat-Conjugated PAMAM Dendrimers as Delivery Agents for Antisense and siRNA Oligonucleotides , 2005, Pharmaceutical Research.

[52]  L. Greene,et al.  Highly Efficient Small Interfering RNA Delivery to Primary Mammalian Neurons Induces MicroRNA-Like Effects before mRNA Degradation , 2004, The Journal of Neuroscience.

[53]  T. Rana,et al.  siRNA function in RNAi: a chemical modification analysis. , 2003, RNA.

[54]  S. W. Kim,et al.  Polyethylene Glycol-Conjugated Copolymers for Plasmid DNA Delivery , 2004, Pharmaceutical Research.

[55]  Rosie Yu,et al.  Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis , 2000, Nature Biotechnology.

[56]  Matthias John,et al.  Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs , 2004, Nature.

[57]  John J. Rossi,et al.  Strategies for silencing human disease using RNA interference , 2007, Nature Reviews Genetics.

[58]  S. Futaki,et al.  Arginine-rich Peptides , 2001, The Journal of Biological Chemistry.

[59]  Priscille Brodin,et al.  A Truncated HIV-1 Tat Protein Basic Domain Rapidly Translocates through the Plasma Membrane and Accumulates in the Cell Nucleus* , 1997, The Journal of Biological Chemistry.

[60]  M. Hughes,et al.  The cellular delivery of antisense oligonucleotides and ribozymes. , 2001, Drug discovery today.

[61]  D. Bull,et al.  Hypoxia-inducible VEGF gene delivery to ischemic myocardium using water-soluble lipopolymer , 2003, Gene Therapy.

[62]  S. W. Kim,et al.  Cholesteryl oligoarginine delivering vascular endothelial growth factor siRNA effectively inhibits tumor growth in colon adenocarcinoma. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[63]  Qing Ge,et al.  Full deacylation of polyethylenimine dramatically boosts its gene delivery efficiency and specificity to mouse lung. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[64]  S. Kawakami,et al.  Targeted delivery systems of small interfering RNA by systemic administration. , 2007, Drug metabolism and pharmacokinetics.

[65]  P. Marschall,et al.  Transfer of YACs up to 2.3 Mb intact into human cells with polyethylenimine , 1999, Gene Therapy.

[66]  P. Whittaker,et al.  RNA interference: From gene silencing to gene-specific therapeutics , 2005, Pharmacology & Therapeutics.

[67]  A. Reynolds,et al.  Rational siRNA design for RNA interference , 2004, Nature Biotechnology.

[68]  Andrew D. Ellington,et al.  Aptamer mediated siRNA delivery , 2006, Nucleic acids research.

[69]  S. W. Kim,et al.  Efficient siRNA delivery using water soluble lipopolymer for anti-angiogenic gene therapy. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[70]  S. W. Kim,et al.  Lactose-poly(ethylene glycol)-grafted poly-L-lysine as hepatoma cell-tapgeted gene carrier. , 1998, Bioconjugate chemistry.

[71]  S. W. Kim,et al.  Anti-angiogenic inhibition of tumor growth by systemic delivery of PEI-g-PEG-RGD/pCMV-sFlt-1 complexes in tumor-bearing mice. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[72]  T. Bettinger,et al.  Size reduction of galactosylated PEI/DNA complexes improves lectin-mediated gene transfer into hepatocytes. , 1999, Bioconjugate chemistry.

[73]  Matthias John,et al.  RNAi-mediated gene silencing in non-human primates , 2006, Nature.

[74]  Kyung Chul Cho,et al.  Target-specific gene silencing by siRNA plasmid DNA complexed with folate-modified poly(ethylenimine). , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[75]  S. W. Kim,et al.  Water-soluble lipopolymer for gene delivery. , 2001, Bioconjugate chemistry.

[76]  J. Whitton,et al.  Full-length proteins attached to the HIV tat protein transduction domain are neither transduced between cells, nor exhibit enhanced immunogenicity , 2002, Gene Therapy.

[77]  Simon W. Jones,et al.  RNA targeting with peptide conjugates of oligonucleotides, siRNA and PNA. , 2007, Blood cells, molecules & diseases.

[78]  A. Aigner,et al.  RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo , 2005, Gene Therapy.

[79]  P. Saggau,et al.  Poly(ethylenimine)-mediated transfection: a new paradigm for gene delivery. , 2000, Journal of biomedical materials research.

[80]  S. Agrawal,et al.  Biodistribution and metabolism of a mixed backbone oligonucleotide (GEM 231) following single and multiple dose administration in mice. , 2000, Antisense & nucleic acid drug development.

[81]  T. Du,et al.  Asymmetry in the Assembly of the RNAi Enzyme Complex , 2003, Cell.

[82]  A. Arnold,et al.  Specific β1-adrenergic receptor silencing with small interfering RNA lowers high blood pressure and improves cardiac function in myocardial ischemia , 2007, Journal of hypertension.

[83]  L. Lim,et al.  Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing. , 2006, RNA.

[84]  J. Feijen,et al.  Reducible poly(amido ethylenimine) directed to enhance RNA interference. , 2007, Biomaterials.

[85]  Mark E. Davis,et al.  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. , 2005, Cancer research.

[86]  M. Amarzguioui,et al.  Tolerance for mutations and chemical modifications in a siRNA. , 2003, Nucleic acids research.

[87]  J. Double,et al.  The delivery of antisense therapeutics. , 2000, Advanced drug delivery reviews.

[88]  D. Fischer,et al.  Low-molecular-weight polyethylenimine as a non-viral vector for DNA delivery: comparison of physicochemical properties, transfection efficiency and in vivo distribution with high-molecular-weight polyethylenimine. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[89]  J. Northrop,et al.  Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[90]  M. Manoharan,et al.  RNAi therapeutics: a potential new class of pharmaceutical drugs , 2006, Nature chemical biology.

[91]  David A. Cheresh,et al.  Detection of tumor angiogenesis in vivo by αvβ3-targeted magnetic resonance imaging , 1998, Nature Medicine.

[92]  David R Corey,et al.  RNA interference in mammalian cells by chemically-modified RNA. , 2003, Biochemistry.

[93]  S. W. Kim,et al.  Tumor regression by repeated intratumoral delivery of water soluble lipopolymers/p2CMVmIL-12 complexes. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[94]  Stephen P. Fox,et al.  The Design and Exogenous Delivery of siRNA for Post-transcriptional Gene Silencing , 2004, Journal of drug targeting.

[95]  E. Wagner,et al.  Simple modifications of branched PEI lead to highly efficient siRNA carriers with low toxicity. , 2008, Bioconjugate chemistry.

[96]  R. Schiffelers,et al.  Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. , 2004, Nucleic acids research.