Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Nanoparticle delivery of anti-metastatic NM23-H1 gene improves chemotherapy in a mouse tumor model

Cancer Gene Therapy volume 16, pages 423–429 (2009)Cite this article

Abstract

Gene therapy provides a promising approach for cancer treatment. Earlier studies suggested that poly-L-lysine-modified iron oxide nanoparticles (IONP-PLL) might be a promising gene delivery system that can transfect DNA efficiently in vitro and in vivo. In this study we used IONP-PLL as gene carriers to deliver the NM23-H1 gene, the first suppressor gene of cancer metastasis, to tumor cells in vivo. The intravenous injection of IONP-PLL carrying NM23-H1-GFP plasmid DNA significantly extended the survival time of an experimental pulmonary metastasis mouse model. In the IONP-PLL/NM23-H1-GFP-treated group, metastasis was clearly suppressed compared with the group treated with free NM23-H1-GFP plasmid. Furthermore, this gene therapy combined with cyclophosphamide treatment resulted in longer survival times and greater suppression of metastasis growth. In conclusion, treatment with IONP-PLL nanoparticles incorporating the NM23-H1gene is an efficient gene therapy method, and it is even more effective in combination with chemotherapy. This approach appears to be a promising strategy for treatment of metastatic tumors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Gardlík R, Pálffy R, Hodosy J, Lukács J, Turna J, Celec P . Vectors and delivery systems in gene therapy. Med Sci Monit 2005; 11: 110–121.

    Google Scholar 

  2. Wu Q, Moyana T, Xiang J . Cancer gene therapy by adenovirus-mediated gene transfer. Curr Gene Ther 2001; 1: 101–122.

    Article  CAS  Google Scholar 

  3. Lundstrom K . Latest development in viral vectors for gene therapy. Trends Biotechnol 2003; 21: 117–122.

    Article  CAS  Google Scholar 

  4. Lundstrom K, Boulikas T . Viral and non-viral vectors in gene therapy: technology development and clinical trials. Technol Cancer Res Treat 2003; 2: 471–486.

    Article  CAS  Google Scholar 

  5. Merdan T, Kopecek J, Kissel T . Prospects for cationic polymers in gene and oligonucleotide therapy against cancer. Adv Drug Deliv Rev 2002; 54: 715–758.

    Article  CAS  Google Scholar 

  6. Matsuura M, Yamazaki Y, Suqiyama M, Kondo M, Ori H, Nango M et al. Polycation liposome-mediated gene transfer in vivo. Biochim Biophys Acta 2003; 1612: 136–143.

    Article  CAS  Google Scholar 

  7. Kushibikil T, Matsumoto K, Nakamura T, Tabata Y . Suppression of tumor metastasis by NK4 plasmid DNA released from cationized gelatin. Gene Therapy 2004; 11: 1205–1214.

    Article  Google Scholar 

  8. Ogris M . Non-viral cancer gene therapy—what is best? Drug Discovery Today 2003; 8: 63.

    Article  Google Scholar 

  9. Gasco MR, Gasco P . Nanovector. Nanomedicine 2007; 2: 955–960.

    Article  Google Scholar 

  10. Ferrari M . Nanovector therapeutics. Curr Opin Chem Biol 2005; 9: 343–346.

    Article  CAS  Google Scholar 

  11. Li Z, Zhu SG, Gan K, Zhang Q, Zeng Z, Zhou Y et al. Poly-L-lysine-modified silica nanoparticles: a potential oral gene delivery system. J Nanoscience and Nanotechnology 2005; 5: 1199–1203.

    Article  CAS  Google Scholar 

  12. Ferrari M . Cancer nanotechnology: opportunities and challenges. Nat rev Cancer 2005; 5: 161–171.

    Article  CAS  Google Scholar 

  13. Duncan R . The dawning era of polymer therapeutics. Nat Rev Drug Discov 2003; 2: 347–360.

    Article  CAS  Google Scholar 

  14. Santhakumaran LM, Thomas T, Thomas TJ . Enhanced cellular uptake of triplex-forming oligonucleotide by nanoparticle formation in the presence of polypropylenimine dendrimers. Nucleic Acids Res 2004; 32: 2102–2112.

    Article  CAS  Google Scholar 

  15. Zhu SG, Lu HB, Xiang JJ, Tang K, Zhang BC, Zhou M, et al. A novel nonviral nanoparticle gene vector: poly-L-lysine silica nanoparticles. Chin Sci Bull 2002; 47: 654–657.

    Article  CAS  Google Scholar 

  16. Zhu SG, Xiang JJ, Li XL, Shen SR, Lu HB, Zhou J et al. Poly(L-lysine)-modified silica nanoparticles for delivery of antisence oligonucleotides. Biotechnol Appl Biochem 2004; 39: 179–187.

    Article  CAS  Google Scholar 

  17. Xiang JJ, Zhu SG, Lu HB, Ruan JM, Zhang BC, Li J et al. Use of Magnetic iron oxide nanoparticles as gene carrier. Chinese Journal of cancer 2001; 10: 1009–1014.

    Google Scholar 

  18. Xiang JJ, Tang JQ, Zhu SG, Nie XM, Lu HB, Shen SR et al. IONP-PLL: a novel non-viral vector for efficient gene delivery. J Gene Medicine 2003; 5: 803–817.

    Article  CAS  Google Scholar 

  19. Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA et al. Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 1988; 80: 200–204.

    Article  CAS  Google Scholar 

  20. Sgouros J, Galani E, Gonos E, Moutsatsou P, Belechri M, Skarlos D et al. Correlation of NM23-H1 gene expression with clinical outcome in patients with advanced breast cancer. In Vivo 2007; 21: 519–522.

    CAS  PubMed  Google Scholar 

  21. Horak CE, Mendoza A, Vega-Valle E, Albaugh M, Graff-Cherry C, McDermott WG et al. NM23-H1 suppresses metastasis by inhibiting expression of the lysophosphatidic acid receptor EDG2. Cancer Res 2007; 67: 11751–11759.

    Article  CAS  Google Scholar 

  22. Boissan M, Wendum D, Arnaud-Dabernat S, Munier A, Debray M, Lascu I et al. Increased lung metastasis in transgenic NM23-Null/SV40 mice with hepatocellular carcinoma. J Natl Cancer Inst 2005; 97: 836–845.

    Article  CAS  Google Scholar 

  23. Che G, Chen J, Liu L, Wang Y, Li L, Qin Y et al. Transfection of NM23-H1 increased expression of beta-Catenin, E-Cadherin and TIMP-1 and decreased the expression of MMP-2, CD44v6 and VEGF and inhibited the metastatic potential of human non-small cell lung cancer cell line L9981. Neoplasma 2006; 53: 530–537.

    CAS  PubMed  Google Scholar 

  24. Prowatke I, Devens F, Benner A, Gröne EF, Mertens D, Gröne HJ et al. Expression analysis of imbalanced genes in prostate carcinoma using tissue microarrays. Br J Cancer 2007; 96: 82–88.

    Article  CAS  Google Scholar 

  25. Ferenc T, Lewinski A, Lange D, Niewiadomska H, Sygut J, Sporny S et al. Analysis of NM23-H1 protein immunoreactivity in follicular thyroid tumors. Pol J Pathol 2004; 55: 149–153.

    CAS  PubMed  Google Scholar 

  26. Leone A, Seeger RC, Hong CM, Hu YY, Arboleda MJ, Brodeur GM et al. Evidence for Nm23 RNA overexpression, DNA amplification and mutation in aggressive childhood neuroblastomas. Oncogene 1993; 8: 855–865.

    CAS  PubMed  Google Scholar 

  27. Pavelic K, Kapitanovic S, Radosevic S, Bura M, Seiwerth S, Paveliæ LJ et al. Increased activity of NM23-H1 gene in squamous cell carcinoma of the head and neck is associated with advanced disease and poor prognosis. Mol Med 2000; 78: 111–118.

    Article  CAS  Google Scholar 

  28. Fishbach M, Settleman J . Specific biochemical inactivation of oncogenic ras proteins by nucleoside diphosphate kinase. Cancer Res 2003; 63: 4089–4094.

    Google Scholar 

  29. Engel M, Veron M, Theisinger B, Lacombe ML, Seib T, Dooley S et al. A novel serine/threonine-specific protein phosphotransferase activity of Nm23/nucleoside-diphosphate kinase. Eur J Biochem 1995; 234: 200–207.

    Article  CAS  Google Scholar 

  30. Lombardi D, Mileo AM . Protein interactions provide new insight into Nm23/nucleoside diphosphate kinase functions. J Bioenerg Biomembr 2003; 5: 67–71.

    Article  Google Scholar 

  31. Giehl K . Oncogenic Ras in tumour progression and metastasis. Biol Chem 2005; 386: 193–205.

    CAS  PubMed  Google Scholar 

  32. Salerno M, Palmieri D, Bouadis A, Halverson D, Steeg PS . NM23-H1 metastasis suppressor expression level influences the binding properties, stability, and function of the kinase suppressor of Ras1 (KSR1) Erk scaffold in breast carcinoma cells. Mol Cell Biol 2005; 25: 1379–1388.

    Article  CAS  Google Scholar 

  33. Hartsough MT, Morrison DK, Salerno M, Palmieri D, Quatas T, Mair M et al. NM23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway. J Biol Chem 2002; 277: 32389–32399.

    Article  CAS  Google Scholar 

  34. Jung HY, Seong HA, Ha HJ . NM23-H1 tumor suppressor and its interacting partner STRAP activate p53 function. J Biol Cem 2007; 282: 35293–35307.

    CAS  Google Scholar 

  35. Xiang JJ, Nie XM, Tang JQ, Wang YJ, Li Z, Gan K et al. In vitro gene transfection by magnetic iron oxide nanoparticles and the effect of magnetic field on the efficiency of transfection. Zhonghua Zhong Liu Za Zhi 2004; 26: 71–74.

    PubMed  Google Scholar 

  36. Lee H, Lee E, Kim do K, Jang NK, Jeong YY, Jon S . Antibiofouling polymer-coated superparamagnetic iron oxide nanoparticles as potential magnetic resonance contrast agents for in vivo cancer imaging. J Am Chem Soc 2006; 128: 7383–7389.

    Article  CAS  Google Scholar 

  37. Hanessian S, Grzyb JA, Cengelli F, Juillerat-Jeanneret L . Synthesis of chemically functionalized superparamagnetic nanoparticles as delivery vectors for chemotherapeutic drugs. Bioorg Med Chem 2008; 16: 2921–2931.

    Article  CAS  Google Scholar 

  38. Pan BF, Cui DX, Sheng Y, Ozkan C, Gao F, He R et al. Dendrimer-modified magnetic nanoparticles enhance efficiency of gene delivery system. Cancer Res 2007; 67: 8156–8163.

    Article  CAS  Google Scholar 

  39. Safarik I, Safarikova M . Magnetic techniques for the isolation and purification of proteins and peptides. Biomagn Res Technol 2004; 2: 7.

    Article  Google Scholar 

  40. Chemla YR, Grossman HL, Poon Y, McDermott R, Stevens R, Alper MD et al. Ultrasensitive magnetic biosensor for homogeneous immunoassay. Proc Natl Acad Sci USA 2000; 97: 14268–14272.

    Article  CAS  Google Scholar 

  41. Kim DH, Lee SH, Kim KN, Kim KM, Chim IB, Lee YK . Cytotoxicity of ferrite particles by MTT and agar diffusion methods for hyperthermic application. J Magn Magn Mater 2005; 293: 287–292.

    Article  CAS  Google Scholar 

  42. Hirsch LR, Stafford RJ, Bankson JA, Sershen SR, Rivera B, Price RE et al. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc Natl Acad Sci USA 2003; 100: 13549–13554.

    Article  CAS  Google Scholar 

  43. Gao L, Zhuang J, Nie L, Zhang J, Zhang Y, Gu N et al. Intrinsic peroxidase-like activity of ferromagnetic nanoparticles. Nat Nanotechnol 2007; 2: 577–583.

    Article  CAS  Google Scholar 

  44. Morishita N, Nakagami H, Morishita R, Takeda S, Mishima F, Terazono B et al. Magnetic nanoparticles with surface modification enhanced gene delivery of HVJ-E vector. Biochem Biophys Res Commun 2005; 334: 1121–1126.

    Article  CAS  Google Scholar 

  45. Gupta AK, Naregalkar RR, Vaidya VD, Gupta M . Recent advances on surface engineering of magnetic iron oxide nanoparticles and their biomedical applications. Nanomedicine 2007; 2: 23–39.

    Article  CAS  Google Scholar 

  46. Sonabend AM, Velicu S, Ulasov IV, Han Y, Tyler B, Brem H et al. A safety and efficacy study of local delivery of interleukin-12 transgene by PPC polymer in a model of experimental glioma. Anticancer Drugs 2008; 19: 133–142.

    Article  CAS  Google Scholar 

  47. He C, He P, Zhu YS . Expression of NM23-H1-GFP fusion protein in human lung cancer cells and its effect on in vitro invasive potential of tumor cells. Chin J Biochem Mol Biol 2000; 16: 51–56.

    CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the State Key Science Research Program of China (2006CB910502, 2006CB910504), The 111 project (111-2-12), The National ‘863’ High Technology Program of China (2007AA02Z170).

Author information

Authors and Affiliations

  1. Cancer Research Institute, Central South University, 110# Xiang-Ya Road, Changsha, Hunan, 410078, The People's Republic of China

    Z Li, J Xiang, W Zhang, M Wu, X Li & G Li

  2. The Second Affiliated Hospital of Xiang Ya School of Medicine, Central South University, Changsha, Hunan, 410078, The People's Republic of China

    S Fan

Authors
  1. Z Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. X Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Z., Xiang, J., Zhang, W. et al. Nanoparticle delivery of anti-metastatic NM23-H1 gene improves chemotherapy in a mouse tumor model. Cancer Gene Ther 16, 423–429 (2009). https://doi.org/10.1038/cgt.2008.97

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2008.97

Keywords

This article is cited by

Search

Advanced search

Quick links