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New Core-Shell Nanoparticules for the Intravenous Delivery of siRNA to Experimental Thyroid Papillary Carcinoma

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Abstract

Purpose

Development of efficient in vivo delivery nanodevices remains a major challenge to achieve clinical application of siRNA. The present study refers to the conception of core-shell nanoparticles aiming to make possible intravenous administration of chemically unmodified siRNA oriented towards the junction oncogene of the papillary thyroid carcinoma.

Methods

Nanoparticles were prepared by redox radical emulsion polymerization of isobutylcyanoacrylate and isohexylcyanoacrylate with chitosan. The loading of the nanoparticles with siRNA was achieved by adsorption. The biological activity of the siRNA-loaded nanoparticles was assessed on mice bearing a papillary thyroid carcinoma after intratumoral and intravenous administration.

Results

Chitosan-coated nanoparticles with a diameter of 60 nm were obtained by adding 3% pluronic in the preparation medium. siRNA were associated with the nanoparticles by surface adsorption. In vivo, the antisense siRNA associated with the nanoparticles lead to a strong antitumoral activity. The tumor growth was almost stopped after intravenous injection of the antisense siRNA-loaded nanoparticles, while in all control experiments, the tumor size was increased by at least 10 times.

Conclusion

This work showed that poly(alkylcyanoacrylate) nanoparticles coated with chitosan are suitable carriers to achieve in vivo delivery of active siRNA to tumor including after systemic administration.

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REFERENCES

  1. Kalota A, Shetzline SE, Gewirtz AM. Progress in the development of nucleic acid therapeutics for cancer. Cancer Biol Ther. 2004;3:4–12.

    PubMed  CAS  Google Scholar 

  2. Meyer M, Wagner E. Recent developments in the application of plasmid DNA-based vectors and small interfering RNA therapeutics for cancer. Hum Gene Ther. 2006;17:1062–76.

    Article  PubMed  CAS  Google Scholar 

  3. Russ V, Wagner E. Cell and tissue targeting of nucleic acids for cancer gene therapy. Pharm Res. 2007;24:1047–57.

    Article  PubMed  CAS  Google Scholar 

  4. de Fougerolles AR. Delivery vehicles for small interfering RNA in vivo. Hum Gene Ther. 2008;19:125–32.

    Article  PubMed  CAS  Google Scholar 

  5. Shrivastava N, Srivastava A. RNA interference: an emerging generation of biologicals. Biotechnol J. 2008;3:339–53.

    Article  PubMed  CAS  Google Scholar 

  6. Hutvagner G, Simard MJ. Argonaute proteins: key players in RNA silencing. Nat Rev Mol Cell Biol. 2008;9:22–32.

    Article  PubMed  CAS  Google Scholar 

  7. Bertrand JR, Pottier M, Vekris A, Opolon P, Maksimenko A, Malvy C. Comparison of antisense oligonucleotides and siRNA in cell culture and in vivo. Biochem Biophys Res Commun. 2002;296:1000–4.

    Article  PubMed  CAS  Google Scholar 

  8. Downward J. RNA interference. BMJ. 2004;328:1245–8.

    Article  PubMed  CAS  Google Scholar 

  9. Nguyen T, Menocal EM, Harborth J, Fruehauf JH. RNAi therapeutics: an update on delivery. Curr Opin Mol Ther. 2008;10:158–67.

    PubMed  CAS  Google Scholar 

  10. Pirollo KF, Chang EH. Targeted delivery of small interfering RNA: approaching effective cancer therapies. Cancer Res. 2008;68:1247–50.

    Article  PubMed  CAS  Google Scholar 

  11. Fattal E, Barratt G. Nanotechnologies and controlled release systems for the delivery of antisense oligonucleotides and small interfering RNA. Br J Pharmacol. 2009;157:179–94.

    Article  PubMed  CAS  Google Scholar 

  12. de Wolf HK, Snel CJ, Verbaan FJ, Schiffelers RM, Hennink WE, Storm G. Effect of cationic carriers on the pharmacokinetics and tumor localization of nucleic acids after intravenous administration. Int J Pharm. 2007;331:167–75.

    Article  PubMed  CAS  Google Scholar 

  13. Garbuzenko OB, Saad M, Betigeri S, Zhang M, Vetcher AA, Soldatenkov VA, et al. Intratracheal versus intravenous liposomal delivery of siRNA, antisense oligonucleotides and anticancer drug. Pharm Res. 2009;26:382–94.

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Howard KA. Delivery of RNA interference therapeutics using polycation-based nanoparticles. Adv Drug Deliv Rev. 2009;61:710–20.

    Article  PubMed  CAS  Google Scholar 

  16. Bouclier C, Moine L, Hillaireau H, Marsaud V, Connault E, Opolon P, et al. Physicochemical characteristics and preliminary in vivo biological evaluation of nanocapsules loaded with siRNA targeting estrogen receptor alpha. Biomacromolecules. 2008;9:2881–90.

    Article  PubMed  CAS  Google Scholar 

  17. Bartlett DW, Davis ME. Impact of tumor-specific targeting and dosing schedule on tumor growth inhibition after intravenous administration of siRNA-containing nanoparticles. Biotechnol Bioeng. 2008;99:975–85.

    Article  PubMed  CAS  Google Scholar 

  18. Maksimenko A, Polard V, Villemeur M, Elhamess H, Couvreur P, Bertrand JR, et al. In vivo potentialities of EWS-Fli-1 targeted antisense oligonucleotides-nanospheres complexes. Ann NY Acad Sci. 2005;1058:52–61.

    Article  PubMed  CAS  Google Scholar 

  19. De Martimprey H, Vauthier C, Malvy C, Couvreur P. Polymer nanocarriers for the delivery of small fragments of nucleic acids: oligonucleotides and siRNA. Eur J Pharm Biopharm. 2009;71:490–504.

    Article  PubMed  CAS  Google Scholar 

  20. Wang XL, Xu R, Wu X, Gillespie D, Jensen R, Lu ZR. Targeted systemic delivery of a therapeutic siRNA with a multifunctional carrier controls tumor proliferation in mice. Mol Pharm. 2009;6:738–46.

    Article  PubMed  CAS  Google Scholar 

  21. Toub N, Bertrand JR, Tamaddon A, Elhamess H, Hillaireau H, Maksimenko A, et al. Efficacy of siRNA nanocapsules targeted against the EWS-Fli1 oncogene in Ewing sarcoma. Pharm Res. 2006;23:892–900.

    Article  PubMed  CAS  Google Scholar 

  22. Elhamess H, Bertrand JR, Maccario J, Maksimenko A, Malvy C. Antitumor vectorized oligonucleotides in a model of ewing sarcoma: unexpected role of nanoparticles. Oligonucleotides. 2009;19:255–64.

    Article  PubMed  CAS  Google Scholar 

  23. de Martimprey H, Bertrand JR, Fusco A, Santoro M, Couvreur P, Vauthier C, et al. siRNA nanoformulation against the ret/PTC1 junction oncogene is efficient in an in vivo model of papillary thyroid carcinoma. Nucleic Acids Res. 2008;36(1):e2. doi:10.1093/nar/gkm1094.

    Article  PubMed  CAS  Google Scholar 

  24. Bertholon I, Lesieur S, Labarre D, Besnard M, Vauthier C. Characterization of dextran-poly(isobutylcyanoacrylate) copolymers obtained by redox radical and anionic emulsion polymerization. Macromolecules. 2006;39:3559–67.

    Article  CAS  Google Scholar 

  25. Bertholon I, Vauthier C, Labarre D. Complement activation by core-shell poly(isobutylcyanoacrylate)-polysaccharide nanoparticles: influences of surface morphology, length, and type of polysaccharide. Pharm Res. 2006;23:1313–23.

    Article  PubMed  CAS  Google Scholar 

  26. Vonarbourg A, Passirani C, Saulnier P, Benoit JP. Parameters influencing the stealthiness of colloidal drug delivery systems. Biomaterials. 2006;27:4356–73.

    Article  PubMed  CAS  Google Scholar 

  27. Passirani C, Barratt G, Devissaguet JP, Labarre D. Long-circulating nanoparticles bearing heparin or dextran covalently bound to poly(methyl methacrylate). Pharm Res. 1998;15:1046–50.

    Article  PubMed  CAS  Google Scholar 

  28. Decuzzi P, Pasqualini R, Arap W, Ferrari M. Intravascular delivery of particulate systems: does geometry really matter? Pharm Res. 2009;26:235–43.

    Article  PubMed  CAS  Google Scholar 

  29. Bravo-Osuna I, Ponchel G, Vauthier C. Tuning of shell and core characteristics of chitosan-decorated acrylic nanoparticles. Eur J Pharm Sci. 2007;30:143–54.

    Article  PubMed  CAS  Google Scholar 

  30. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Meth. 1983;65:55–63.

    Article  CAS  Google Scholar 

  31. Vauthier C, Schmidt C, Couvreur P. Measurement of the density of polymeric nanoparticulate drug carriers made of poly(alkylcyanoacrylate) and poly(lactic acid) derivatives. J Nanoparticle Res. 1999;1:411–8.

    Article  CAS  Google Scholar 

  32. Kim IY, Yoo MK, Kim BC, Kim SK, Lee HC, Cho CS. Preparation of semi-interpenetrating polymer networks composed of chitosan and poloxamer. Int J Biol Macromol. 2006;38:51–8.

    Article  PubMed  CAS  Google Scholar 

  33. Chauvierre C, Leclerc L, Labarre D, Appel M, Marden MC, Couvreur P, et al. Enhancing the tolerance of poly(alkylcyanoacrylate) nanoparticles with surface modular design. Int J Pharm. 2007;338:327–32.

    Article  PubMed  CAS  Google Scholar 

  34. Nemati F, Dubernet C, Colin de Verdière A, Poupon MF, Treupel-Acar L, Puisieux F, et al. Some parameters influencing cytotoxicity of free doxorubicin loaded nanoparticles in sensitive and multidrug resistant leucemic murine cells: incubation time, number of nanoparticles per cell. Int J Pharm. 1994;102:55–62.

    Article  CAS  Google Scholar 

  35. Mailänder V, Landfester K. Interaction of nanoparticles with cells. Biomacromolecules. 2009;10:2379–400.

    Article  PubMed  CAS  Google Scholar 

  36. Iyer AK, Khaled G, Fang J, Maeda H. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today. 2006;11:812–8.

    Article  PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENT

We would thank Jeril Degrouard and Danielle Jaillard for the TEM analysis at the CCME Orsay and Bassim Al-Sakere (MD) for his help in animal experimentation. The “Budget Qualité Recherches” of the University of Paris Sud-11 is gratefully acknowledged for the funding of this project as is Henkel Biomedical (Dublin, Ireland) for the gift of isobutylcyanoacrylate and isohexylcyanoacrylate. Henri de Martimprey was supported by a fellowship from the French Ministère de la Recherche et de la Technologie and the French Association pour la Recherche sur le Cancer (ARC).

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Authors and Affiliations

  1. Université de Paris-Sud-11, UMR CNRS 8612, 5 rue J.B. Clément, 92296, Châtenay-Malabry, France

    Henri de Martimprey, Patrick Couvreur & Christine Vauthier

  2. Institut Gustave Roussy, UMR CNRS 8121, 39 rue Camille Desmoulins, 94805, Villejuif, France

    Henri de Martimprey, Jean-Rémi Bertrand & Claude Malvy

Authors
  1. Henri de Martimprey
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  2. Jean-Rémi Bertrand
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  3. Claude Malvy
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  4. Patrick Couvreur
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  5. Christine Vauthier
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Correspondence to Christine Vauthier.

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de Martimprey, H., Bertrand, JR., Malvy, C. et al. New Core-Shell Nanoparticules for the Intravenous Delivery of siRNA to Experimental Thyroid Papillary Carcinoma. Pharm Res 27, 498–509 (2010). https://doi.org/10.1007/s11095-009-0043-8

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  • DOI: https://doi.org/10.1007/s11095-009-0043-8

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