Skip to main content

Advertisement

SpringerLink
Log in

Glutathione-responsive nano-transporter-mediated siRNA delivery: silencing the mRNA expression of Ras

  • New Ideas in Cell Biology
  • Published:
Protoplasma Aims and scope Submit manuscript

Abstract

Gene therapy through antisense technology via intracellular delivery of a gene-silencing element is a promising approach to treat critical diseases like cancers. Ras acts as molecular switch, considered as one of the proto-oncogenes whose modification or mutation may promote tumor formation. The recent trends of nano-carrier-based drug delivery have gained superiority and proved to be 100 times more potent in drug delivery compared to standard therapies. The nano-based drug delivery has provided the basis of achieving successful target-specific drug delivery. Glutathione (GSH) is considered as one of the best and ubiquitous internal stimulus for swift destabilization of nano-transporters inside cells to accomplish proficient intracellular drug release. This concept has given a new hope to oncologists of modifying the existing drugs to be delivered to their desired destination. RNA interference is a primary tool in functional genomics to selectively silence messenger RNA (mRNA) expression, which can be exploited quickly to develop novel drugs against lethal disease target. Silencing of mRNA molecules using siRNA has also come of age to become one of the latest weapons developed in the concept of gene therapy. However, this strategy has severely failed to achieve target specificity especially to a tumor cell. In this context, we have proposed the incorporation of an antisense siRNA packed inside a GSH-responsive nano-transporter to be delivered specifically to a tumor cell against the sense mRNA of the Ras protein. It will limit the Ras-mediated activation of other proteins and transcription factors. Thus, it will knock down several differential gene expressions being regulated by Ras-activated pathways like enzyme-linked receptor kinase pathway. Henceforth, gene silencing technology through nano-drug delivery can be combined as a single weapon to terminate malignancy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Aigner A (2007) Applications of RNA interference: current state and prospects for siRNA based strategies in vivo. Appl Microbiol Biotechnol 76:9–21

    Article  PubMed  CAS  Google Scholar 

  • Akhtar S, Benter IF (2007) Nonviral delivery of synthetic siRNAs in vivo. J Clin Invest 117:3623–3632

    Article  PubMed  CAS  Google Scholar 

  • Akinc A, Zumbuehl A, Goldberg M, Leshchiner ES, Busini V et al (2008) A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat Biotechnol 26:561–569

    Article  PubMed  CAS  Google Scholar 

  • Arunachalam B, Phan UT, Geuze HJ, Cresswell P (2000) Enzymatic reduction of disulfide bonds in lysosomes: characterization of a gamma-interferoninducible lysosomal thiol reductase (GILT). Proc Natl Acad Sci USA 97:745–750

    Article  PubMed  CAS  Google Scholar 

  • Aubry S, Burlina F, Dupont E, Delaroche D, Joliot A, Lavielle S, Chassaing G, Sagan S (2009) Cell-surface thiols affect cell entry of disulfide-conjugated peptides. FASEB J 23:2956–2967

    Article  PubMed  CAS  Google Scholar 

  • Berger N, Sachse A, Bender J, Schubert R, Brandl M (2001) Filter extrusion of liposomes using different devices: comparison of liposome size, encapsulation efficiency, and process characteristics. Int J Pharm 223:55–68

    Article  PubMed  CAS  Google Scholar 

  • Bumcrot D, Manoharan M, Koteliansky V, Sah DW (2006) RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol 2:711–719

    Article  PubMed  CAS  Google Scholar 

  • Cheng R, Feng F, Meng F, Deng C, Feijen J, Zhong Z (2011) Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery. J Contr Release 152:2–12

    Article  CAS  Google Scholar 

  • Chono S, Li SD, Conwell CC, Huang L (2008) An efficient and low immunostimulatory nanoparticle formulation for systemic siRNA delivery to the tumor. J Control 131:64–69

    Article  CAS  Google Scholar 

  • Collins DS, Unanue ER, Harding CV (1991) Reduction of disulfide bonds within lysosomes is a key step in antigen processing. J Immunol 147:4054–4059

    PubMed  CAS  Google Scholar 

  • de Fougerolles AR (2008) Delivery vehicles for small interfering RNA in vivo. Hum Gene Ther 19:125–132

    Article  PubMed  Google Scholar 

  • de Fougerolles A, Vornlocher HP, Maraganore J, Lieberman J (2007) Interfering with disease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov 6:443–453

    Article  PubMed  Google Scholar 

  • Dubey PK, Mishra V, Jain S, Mahor S, Vyas SP (2004) Liposomes modified with cyclic RGD peptide for tumor targeting. J Drug Target 12:257–264

    Article  PubMed  CAS  Google Scholar 

  • Fattal E, Bochot A (2006) Ocular delivery of nucleic acids: antisense oligonucleotides, aptamers and siRNA. Adv Drug Deliv Rev 58:1203–1223

    Article  PubMed  CAS  Google Scholar 

  • Gao K, Huang L (2009) Non-viral methods for siRNA delivery. Mol Pharm 6:651–658

    Article  PubMed  CAS  Google Scholar 

  • Guo P (2005) RNA nanotechnology: engineering, assembly and applications in detection, gene delivery and therapy. J Nanosci Nanotechnol 5:1964–1982

    Article  PubMed  CAS  Google Scholar 

  • Han SE, Kang H, Shim GY, Suh MS et al (2008) Novel cationic cholesterol derivative-based liposomes for serum-enhanced delivery of siRNA. Int J Pharm 353:260–269

    PubMed  CAS  Google Scholar 

  • Higuchi Y, Kawakami S, Fumoto S, Yamashita F et al (2006) Effect of the particle size of galactosylated lipoplex on hepatocyte-selective gene transfection after intraportal administration. Biol Pharm Bull 29:1521–1523

    Article  PubMed  CAS  Google Scholar 

  • Kim B, Tang Q, Biswas PS, Xu J, Schiffelers RM et al (2004) Inhibition of ocular angiogenesis by siRNA targeting vascular endothelial growth factor pathway genes: therapeutic strategy for herpetic stromal keratitis. Am J Pathol 165:2177–2185

    Article  PubMed  CAS  Google Scholar 

  • Li SD, Huang L (2006) Targeted delivery of antisense oligodeoxynucleotide and small interference RNA into lung cancer cells. Mol Pharm 3:579–588

    Article  PubMed  CAS  Google Scholar 

  • Li YL, Zhu L, Liu ZZ, Cheng R, Meng FH, Cui JH, Ji SJ, Zhong Z (2009) Reversibly stabilized multifunctional dextran nanoparticles efficiently deliver doxorubicin into the nuclei of cancer cells. Angew Chem Int Ed 48:9914–9918

    Article  CAS  Google Scholar 

  • Lu PY, Xie FY, Woodle MC (2005) Modulation of angiogenesis with siRNA inhibitors for novel therapeutics. Trends Mol Med 11:104–113

    Article  PubMed  CAS  Google Scholar 

  • Meade BR, Dowdy SF (2008) Enhancing the cellular uptake of siRNA duplexes following noncovalent packaging with protein transduction domain peptides. Adv Drug Deliv Rev 60:530–536

    Article  PubMed  CAS  Google Scholar 

  • Meng FH, Zhong ZY, Feijen J (2009) Stimuli-responsive polymersomes for programmed drug delivery. Biomacromolecules 10:197–209

    Article  PubMed  CAS  Google Scholar 

  • Minakuchi Y, Takeshita F, Kosaka N, Sasaki H, Yamamoto Y et al (2004) Atelocollagen-mediated synthetic small interfering RNA delivery for effective gene silencing in vitro and in vivo. Nucleic Acids Res 32:e109

    Article  PubMed  Google Scholar 

  • Oh YK, Park TG (2009) siRNA delivery systems for cancer treatment. Adv Drug Deliv Rev 61:850–862

    Article  PubMed  CAS  Google Scholar 

  • Panyam J, Labhasetwar V (2003) Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev 55:329–347

    Article  PubMed  CAS  Google Scholar 

  • Park CW, Chen Z, Kren BT, Steer CJ (2004) Double-stranded siRNA targeted to the huntingtin gene does not induce DNA methylation. Biochem Biophys Res Commun 323:275–280

    Article  PubMed  CAS  Google Scholar 

  • Park KM, Kang HC, Cho JK, Chung IJ, Cho SH et al (2009) All-trans-retinoic acid (ATRA)-grafted polymeric gene carriers for nuclear translocation and cell growth control. Biomaterials 30:2642–2652

    Article  PubMed  CAS  Google Scholar 

  • Rijcken CJF, Soga O, Hennink WE, van Nostrum CF (2007) Triggered destabilisation of polymeric micelles and vesicles by changing polymers polarity: an attractive tool for drug delivery. J Control Release 120:131–148

    Article  PubMed  CAS  Google Scholar 

  • Schafer FQ, Buettner (2001) GR redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 30:1191–1212

    Article  PubMed  CAS  Google Scholar 

  • Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE (2001) Biodegradable polymeric nanoparticles as drug delivery devices. J Contr Release 70:1–20

    Article  CAS  Google Scholar 

  • Sorensen DR, Leirdal M, Sioud M (2003) Gene silencing by systemic delivery of synthetic siRNAs in adult mice. J Mol Biol 327:761–766

    Article  PubMed  CAS  Google Scholar 

  • Takei Y. et al (2004) A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res. 64:3365–3370

    Google Scholar 

  • Torchilin V (2009) Multifunctional and stimuli-sensitive pharmaceutical nanocarriers. Eur J Pharm Biopharm 71:431–444

    Article  PubMed  CAS  Google Scholar 

  • Vashist SK, Zheng D, Pastorin G, Al-Rubeaan K, Luong JHT, Sheu FS (2011) Delivery of drugs and biomolecules using carbon nanotubes. CARBON. 49:4077–4097

    Google Scholar 

  • Verma UN, Surabhi RM, Schmaltieg A, Becerra C, Gaynor RB (2003) Small interfering RNAs directed against beta-catenin inhibit the in vitro and in vivo growth of colon cancer cells. Clin. Cancer Res. 9:1291–1300

    Google Scholar 

  • Yang J, Chen H, Vlahov IR, Cheng JX, Low PS (2006) Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging. Proc Natl Acad Sci USA 103:13872–13877

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Wu YO, Xiao L, Li K, Chen LL, Sirois P (2007) Therapeutic potential of RNA interference against cellular targets of HIV infection. Mol. Biotechnol. 37:225–236.

    Google Scholar 

Download references

Acknowledgments

The authors thank the management of the VIT University for providing the facilities to carry out this study.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, 632014, Tamil Nadu, India

    C. George Priya Doss

  2. Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, 632014, Tamil Nadu, India

    S. Debottam & C. Debajyoti

Authors
  1. C. George Priya Doss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Debottam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Debajyoti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. George Priya Doss.

Additional information

Handling Editor: Damjana Drobne

Debottam S. and Debajyoti C. contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Doss, C.G.P., Debottam, S. & Debajyoti, C. Glutathione-responsive nano-transporter-mediated siRNA delivery: silencing the mRNA expression of Ras. Protoplasma 250, 787–792 (2013). https://doi.org/10.1007/s00709-012-0451-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00709-012-0451-1

Keywords

Search

Navigation