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The effect of chitosan complexes on biodistribution of siRNA

Year 2011, Volume: 1 Issue: 1, 1 - 7, 31.01.2014

Abstract

Objective: RNAi is a powerful tool for controlling cellular processes in the gene silencing and in the analysis of molecular mechanisms for many diseases including cancer. VEGF signaling is a potential therapeutic target for siRNA delivery in breast cancer. Although siRNA can be potential therapeutic agent for various diseases, intracellular delivery of siRNA is one of the major hurdles to turn siRNA into therapeutically active molecules. To date, numerous transfection methods or delivery systems have been developed. Among them, chitosan is potential gene carrier due to its characteristics such as biodegradability, biocompatibility, non immunogenic and toxicity. The purpose of this study was to investigate the biodistribution and tumor localization of chitosan/ VEGF siRNA complexes in breast cancer model of rat.
Method: In our study, we intravenously injected FITC labeled naked siRNA-VEGF (40 µg/rat) and chitosan/FITC labeled siRNAVEGF complexes (40 µg/rat) to breast tumor-bearing rats.
Results: While the biodistribution of chitosan/siVEGF complexes to the brain and heart appeared almost similar to that observed for naked siVEGF, the accumulation was slightly lower in the spleen, liver, lungs, muscle and higher in the kidney. In the breast tumor tissue, chitosan/FITC-labeled VEGF siRNA complexes were localized in the tumor 15 min post-injection but naked FITCsiVEGF did not localize in tumor tissue.
Conclusion: In this preliminary study, we revealed the promising potential of chitosan as VEGF siRNA delivery system for biodistribution. 

Key words: siRNA, VEGF, chitosan, biodistribution, breast cancer

References

  • Jeong JH, Kim SH, Lee M, Kim WJ, Park TG, Ko KS, Kim SW. Non- viral systemic delivery of Fas siRNA suppresses cyclophosphamide- induced diabetes in NOD mice. J Control Rel. 2010;143(1):88-94.
  • Shen HL, Xu W, Wu ZY, Zhou LL, Qin RJ, Tang HR. Vector-based RNAi approach to isoform-specific downregulation of vascular endothelial growth factor (VEGF)165 expression in human leukemia cells. Leukemia Res.2007;31:515-521.
  • Guo J, Bourre L, Soden DM, O’Sullivan GC, O’Driscoll C. Can non- viral technologies knockdown the barriers to siRNA delivery and achieve the next generation of cancer therapeutics? Biotechnol Adv. 2011;29(4):402-417.
  • Jiang HL, Xu CX, Kim YK, Arote R, Jere D, Lim HT, Cho MH, Cho CS. The suppression of lung tumorigenesis by aerosol-delivered folate- chitosan-graft-polyethylenimine/Akt1 shRNA complexes through the Akt signaling pathway.Biomaterials. 2009;30(29):5844-5852.
  • Wang J, Lu Z, Wientjes MG, Au JLS. Delivery of siRNA therapeutics: barriers and carriers. The AAPS Journal. 2010;12(4):492-503.
  • Akhtar S, Benter IF. Nonviral delivery of synthetic siRNAs in vivo. J Clin Invest. 2007;117(12):3623-3632.
  • Kawakami S, Hashida M. Targeted delivery systems of small interfering RNA by systemic administration. Drug Metab Pharmacokinet. 2007;22 (3):142-151.
  • Tahara K, H Yamamoto H, Hirashima N, Kawashima Y. Chitosan- modified poly(D,L-lactide-co-glycolide) nanospheres for improving siRNA delivery and gene-silencing effects. Eur J Pharm Biopharm. 2010;74(3):421-426.
  • Oh YK, Park TG. siRNA delivery systems for cancer treatment Adv Drug Del Rev. 2009;61:850-862.
  • Mao S, Sun W, Kissel T. Chitosan-based formulations for delivery of DNA and siRNA. Adv Drug Del Rev. 2010;62:12–27.
  • Gao S, Dagnaes-Hansen F, Nielsen EJB, Wengel J, Besenbacher F, Howard KA, Kjems J. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice. Mol Ther. 2009;17:1225-1233.
  • Şalva E, Kabasakal L, Eren F, Çakalağaoğlu F, Özkan N, Akbuğa J. Chitosan/short hairpin RNA complexes for VEGF suppression invasive breast carcinoma. Oligonucleotides. 2010;20(4):183-190.
  • Şalva E, Akbuğa J. In vitro silencing effect of chitosan nanoplexes containing siRNA expressing vector targeting VEGF in breast cancer cell lines. Die Pharmazie. 2010;65(12):896-903.
  • Şalva, E., Akbuğa, J. Comparison of silencing effect of chitosan/psiRNA complexes in different cell lines. Adv in Chitin Sci. 2009;XI:203-208.
  • Liska J, Galbavy S, Macejova D, Zlatos J, Brtko J. Histopathology of mammary tumours in female rats treated with 1-methyl-1- nitrosourea. Endocrine Reg. 2000;34(2):91-96.
  • Schiffelers RM, Mixson AJ, Ansari AM, Fensa MHAM, Tang Q, Zhou Q, Xu J, Molema G, Lu PY et. al. Transporting silence: Design of carriers for siRNA to angiogenic endothelium J Control Rel. 2005;109:5-14.
  • 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(2):167-175.
  • de Martimprey H, Vauthier C, Malvy C, Couvreur P. Polymer nanocarriers for the delivery of small fragments.Oligonucleotides and siRNA. Eur J Pharm Biopharm.2009;71:409-504.
  • Huh MS, Lee SY, Park S, Lee S, Chung H, Lee S, et al. Tumor-homing glycol chitosan/polyethylenimine nanoparticles for the systemic delivery of siRNA in tumor-bearing mice J Control Rel. 2010;144:134- 143.
  • David S, Pitard B, Benoît JB, Passirani C. Non-viral nanosystems for systemic siRNA delivery Pharmacol Res. 2010; 62:100-114.
  • Decuzzi P, Godin B, Tanaka T, Lee SY, Chiappini C, Liu X, Ferrari M. Size and shape effects in the biodistribution of intravascularly injected particles J Control Rel. 2010;141:320–327.
  • Kim WJ, Yockman JW, Jeong JH, Christensen LV, Lee M, Kim YH, Kim SW. Anti-angiogenic inhibition of tumor growth by systemic delivery of PEI-g-PEG-RGD/pCMV-sFlt-1 complexes in tumor-bearing mice. J Control Rel. 2006;114:381-388.
  • Merkel OM, Librizzi D, Pfestroff A, Schurrat T, et al. Stability of siRNA polyplexes from PEI and PEI-g-PEG under in vivo conditions: Effects on pharmacokinetics and biodistribution measured by Fluorescence Fluctuation Spectroscopy and SPECT imaging. J Control Rel. 2009;138:148-159.

siRNA’nın biyodağılımına kitozan komplekslerinin etkisi

Year 2011, Volume: 1 Issue: 1, 1 - 7, 31.01.2014

Abstract

Amaç: RNAi kanser dahil olmak üzere birçok hastalığın moleküler mekanizmasının analizinde ve gen susturulmasında hücresel proseslerin kontrolü için önemli bir araçtır. VEGF sinyali meme kanserinde siRNA taşınmasında önemli bir hedeftir. siRNA farklı hastalıklar için potansiyel bir ajan olmasına rağmen, siRNA’nın intrasellüler taşınması, terapötik olarak aktif bir moleküle dönüşmesindeki önemli engellerden biridir. Bugüne kadar birçok transfeksiyon yöntemi ve taşıyıcı sistem geliştirilmiştir. Bunlar arasında kitozan, biyouyumlu, biyoparçalanabilir olması, toksik ve immunojenik olmaması gibi özellikleri nedeniyle önemli bir gen taşıyıcısıdır. Bu çalışmanın amacı, meme kanserinde kitozan/VEGF-siRNA komplekslerinin tümör lokalizasyonunu ve biyodağılımını araştırmaktır.
Yöntem: Çalışmamızda meme tümörü taşıyan sıçanlara serbest FITC-işaretli siVEGF (40 µg/sıçan) ve kitozan/ FITC-işaretli siVEGF (40 µg/sıçan) kompleksleri intravenöz olarak enjekte edildi.
Bulgular: Kitozan/siVEGF komplekslerinin beyin ve kalbe biyodağılımı, serbest siVEGF ile hemen hemen benzerken, dalak, karaciğer, akciğer ve kasta biraz daha düşük ve böbrekte ise biraz daha yüksektir. Meme tümör dokusunda, kompleksler enjeksiyon sonrası 15 dakikada tümörde lokalize iken, serbest FITC-siVEGF tümör dokusunda lokalize değildir.
Sonuç: Bu ön çalışmada, biz biyodağılım için VEGF siRNA taşıyıcı sistem olarak kitozanın umut verici olduğunu gösterdik. 

Anahtar Kelimeler: siRNA, VEGF, kitozan, biyodağılım, meme kanseri

References

  • Jeong JH, Kim SH, Lee M, Kim WJ, Park TG, Ko KS, Kim SW. Non- viral systemic delivery of Fas siRNA suppresses cyclophosphamide- induced diabetes in NOD mice. J Control Rel. 2010;143(1):88-94.
  • Shen HL, Xu W, Wu ZY, Zhou LL, Qin RJ, Tang HR. Vector-based RNAi approach to isoform-specific downregulation of vascular endothelial growth factor (VEGF)165 expression in human leukemia cells. Leukemia Res.2007;31:515-521.
  • Guo J, Bourre L, Soden DM, O’Sullivan GC, O’Driscoll C. Can non- viral technologies knockdown the barriers to siRNA delivery and achieve the next generation of cancer therapeutics? Biotechnol Adv. 2011;29(4):402-417.
  • Jiang HL, Xu CX, Kim YK, Arote R, Jere D, Lim HT, Cho MH, Cho CS. The suppression of lung tumorigenesis by aerosol-delivered folate- chitosan-graft-polyethylenimine/Akt1 shRNA complexes through the Akt signaling pathway.Biomaterials. 2009;30(29):5844-5852.
  • Wang J, Lu Z, Wientjes MG, Au JLS. Delivery of siRNA therapeutics: barriers and carriers. The AAPS Journal. 2010;12(4):492-503.
  • Akhtar S, Benter IF. Nonviral delivery of synthetic siRNAs in vivo. J Clin Invest. 2007;117(12):3623-3632.
  • Kawakami S, Hashida M. Targeted delivery systems of small interfering RNA by systemic administration. Drug Metab Pharmacokinet. 2007;22 (3):142-151.
  • Tahara K, H Yamamoto H, Hirashima N, Kawashima Y. Chitosan- modified poly(D,L-lactide-co-glycolide) nanospheres for improving siRNA delivery and gene-silencing effects. Eur J Pharm Biopharm. 2010;74(3):421-426.
  • Oh YK, Park TG. siRNA delivery systems for cancer treatment Adv Drug Del Rev. 2009;61:850-862.
  • Mao S, Sun W, Kissel T. Chitosan-based formulations for delivery of DNA and siRNA. Adv Drug Del Rev. 2010;62:12–27.
  • Gao S, Dagnaes-Hansen F, Nielsen EJB, Wengel J, Besenbacher F, Howard KA, Kjems J. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice. Mol Ther. 2009;17:1225-1233.
  • Şalva E, Kabasakal L, Eren F, Çakalağaoğlu F, Özkan N, Akbuğa J. Chitosan/short hairpin RNA complexes for VEGF suppression invasive breast carcinoma. Oligonucleotides. 2010;20(4):183-190.
  • Şalva E, Akbuğa J. In vitro silencing effect of chitosan nanoplexes containing siRNA expressing vector targeting VEGF in breast cancer cell lines. Die Pharmazie. 2010;65(12):896-903.
  • Şalva, E., Akbuğa, J. Comparison of silencing effect of chitosan/psiRNA complexes in different cell lines. Adv in Chitin Sci. 2009;XI:203-208.
  • Liska J, Galbavy S, Macejova D, Zlatos J, Brtko J. Histopathology of mammary tumours in female rats treated with 1-methyl-1- nitrosourea. Endocrine Reg. 2000;34(2):91-96.
  • Schiffelers RM, Mixson AJ, Ansari AM, Fensa MHAM, Tang Q, Zhou Q, Xu J, Molema G, Lu PY et. al. Transporting silence: Design of carriers for siRNA to angiogenic endothelium J Control Rel. 2005;109:5-14.
  • 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(2):167-175.
  • de Martimprey H, Vauthier C, Malvy C, Couvreur P. Polymer nanocarriers for the delivery of small fragments.Oligonucleotides and siRNA. Eur J Pharm Biopharm.2009;71:409-504.
  • Huh MS, Lee SY, Park S, Lee S, Chung H, Lee S, et al. Tumor-homing glycol chitosan/polyethylenimine nanoparticles for the systemic delivery of siRNA in tumor-bearing mice J Control Rel. 2010;144:134- 143.
  • David S, Pitard B, Benoît JB, Passirani C. Non-viral nanosystems for systemic siRNA delivery Pharmacol Res. 2010; 62:100-114.
  • Decuzzi P, Godin B, Tanaka T, Lee SY, Chiappini C, Liu X, Ferrari M. Size and shape effects in the biodistribution of intravascularly injected particles J Control Rel. 2010;141:320–327.
  • Kim WJ, Yockman JW, Jeong JH, Christensen LV, Lee M, Kim YH, Kim SW. Anti-angiogenic inhibition of tumor growth by systemic delivery of PEI-g-PEG-RGD/pCMV-sFlt-1 complexes in tumor-bearing mice. J Control Rel. 2006;114:381-388.
  • Merkel OM, Librizzi D, Pfestroff A, Schurrat T, et al. Stability of siRNA polyplexes from PEI and PEI-g-PEG under in vivo conditions: Effects on pharmacokinetics and biodistribution measured by Fluorescence Fluctuation Spectroscopy and SPECT imaging. J Control Rel. 2009;138:148-159.
There are 23 citations in total.

Details

Primary Language Turkish
Journal Section Articles
Authors

Emine Şalva This is me

Naziye Özkan This is me

Levent Kabasakal This is me

Suna Özbaş Turan This is me

Jülide Akbuğa This is me

Publication Date January 31, 2014
Submission Date October 31, 2013
Published in Issue Year 2011 Volume: 1 Issue: 1

Cite

APA Şalva, E., Özkan, N., Kabasakal, L., Özbaş Turan, S., et al. (2014). siRNA’nın biyodağılımına kitozan komplekslerinin etkisi. Clinical and Experimental Health Sciences, 1(1), 1-7.
AMA Şalva E, Özkan N, Kabasakal L, Özbaş Turan S, Akbuğa J. siRNA’nın biyodağılımına kitozan komplekslerinin etkisi. Clinical and Experimental Health Sciences. January 2014;1(1):1-7.
Chicago Şalva, Emine, Naziye Özkan, Levent Kabasakal, Suna Özbaş Turan, and Jülide Akbuğa. “siRNA’nın biyodağılımına Kitozan Komplekslerinin Etkisi”. Clinical and Experimental Health Sciences 1, no. 1 (January 2014): 1-7.
EndNote Şalva E, Özkan N, Kabasakal L, Özbaş Turan S, Akbuğa J (January 1, 2014) siRNA’nın biyodağılımına kitozan komplekslerinin etkisi. Clinical and Experimental Health Sciences 1 1 1–7.
IEEE E. Şalva, N. Özkan, L. Kabasakal, S. Özbaş Turan, and J. Akbuğa, “siRNA’nın biyodağılımına kitozan komplekslerinin etkisi”, Clinical and Experimental Health Sciences, vol. 1, no. 1, pp. 1–7, 2014.
ISNAD Şalva, Emine et al. “siRNA’nın biyodağılımına Kitozan Komplekslerinin Etkisi”. Clinical and Experimental Health Sciences 1/1 (January 2014), 1-7.
JAMA Şalva E, Özkan N, Kabasakal L, Özbaş Turan S, Akbuğa J. siRNA’nın biyodağılımına kitozan komplekslerinin etkisi. Clinical and Experimental Health Sciences. 2014;1:1–7.
MLA Şalva, Emine et al. “siRNA’nın biyodağılımına Kitozan Komplekslerinin Etkisi”. Clinical and Experimental Health Sciences, vol. 1, no. 1, 2014, pp. 1-7.
Vancouver Şalva E, Özkan N, Kabasakal L, Özbaş Turan S, Akbuğa J. siRNA’nın biyodağılımına kitozan komplekslerinin etkisi. Clinical and Experimental Health Sciences. 2014;1(1):1-7.

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