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Selective gene delivery to cancer cells secreting matrix metalloproteinases using a gelatin/polyethylenimine/DNA complex

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Abstract

We developed a gene delivery strategy targeting metastatic tumors by exploiting the specific matrix metalloproteinases (MMPs) secreting properties of metastatic tumor cells. A ternary polyplex has been formed by coating polyethylenimine/DNA (PD) complex with an excessive amount of negatively charged gelatin B (GPDB). We show that GPD-B’s gene delivery activity could be targeted to cancer cells via the MMP-mediated proteolytic process, while GPD-A, made from positively charged gelatin A, was not successful in exhibiting such activity. The 1,10-Phenanthroline, an MMP2 inhibitor, abrogated the MMP-dependent transfection activity of GPD-B. GPD-B carried much less positive surface charges than PD, and thus exhibited significantly reduced interactions with erythrocytes. However, MMP2 elevated the positiveness in GPDB’s surface charge and, thus, its interaction with erythrocytes. These results suggest that the anionic gelatin coating may confer improved stabilities on GPD-B in the surrounding medium, while MMP2-mediated disintegration of the gelatin coat enhances the gene delivery to metastatic cancer cells via increasing the likelihood of local chargemediated interactions between the polyplex and cancer cell membrane.

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References

  1. Boussif, O., F. Lezoualc’h, M. A. Zanta, M. D. Mergny, D. Scherman, B. Demeneix, and J. P. Behr (1995) A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: Polyethylenimine. Proc. Natl Acad. Sci.USA 92: 7297–7301.

    Article  CAS  Google Scholar 

  2. Fasbender, A., J. Zabner, M. Chillon, T. O. Moninger, A. P. Puga, B. L. Davidson, and M. J. Welsh (1997) Complexes of adenovirus with polycationic polymers and cationic lipids increase the efficiency of gene transfer in vitro and in vivo. J. Biol. Chem. 272: 6479–6489.

    Article  CAS  Google Scholar 

  3. Lampela, P., P. Soininen, A. Urtti, P. T. Mannisto, and A. Raasmaja (2004) Synergism in gene delivery by small PEIs and three different nonviral vectors. Int. J. Pharm. 270: 175–184.

    Article  CAS  Google Scholar 

  4. Emi, N. and Y. Yoshikawa (1996) Synthetic vectors for gene transfection. Nippon Rinsho. 54: 1997–2002.

    CAS  Google Scholar 

  5. Peng, K. W., F. J. Morling, F. L. Cosset, G. Murphy, and S. J. Russell (1997) A gene delivery system activatable by diseaseassociated matrix metalloproteinases. Hum Gene Ther. 8: 729–738.

    Article  CAS  Google Scholar 

  6. Kirkham, L. A., A. R. Bateman, A. A. Melcher, R. G. Vile, and A. K. Fielding (2002) Lack of specificity of cell-surface protease targeting of a cytotoxic hyperfusogenic gibbon ape leukaemia virus envelope glycoprotein. J Gene Med. 4: 592–600.

    Article  CAS  Google Scholar 

  7. Hatakeyama, H., H. Akita, K. Kogure, M. Oishi, Y. Nagasaki, Y. Kihira, M. Ueno, H. Kobayashi, H. Kikuchi, and H. Harashima (2007) Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid. Gene Ther. 14: 68–77.

    Article  CAS  Google Scholar 

  8. Nishikawa, M. and L. Huang (2001) Nonviral vectors in the new millennium: Delivery barriers in gene transfer. Hum Gene Ther. 12: 861–870.

    Article  CAS  Google Scholar 

  9. Dincer, S., M. Turk, and E. Piskin (2005) Intelligent polymers as non viral vectors. Gene Ther. 12Suppl 1: 139–145.

    Article  Google Scholar 

  10. Herbst, R. S. and D. M. Shin (2002) Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: A new paradigm for cancer therapy. Cancer 94: 1593–1611.

    Article  CAS  Google Scholar 

  11. Min, S. H., D. C. Lee, M. J. Lim, H. S. Park, D. M. Kim, C. W. Cho, Y. Yoon do, and Y. I. Yeom (2006) A composite gene delivery system consisting of polyethylenimine and an amphipathic peptide KALA. J. Gene Med. 8: 1425–1434.

    Article  CAS  Google Scholar 

  12. Ogris, M., S. Brunner, S. Schuller, R. Kircheis, and E. Wagner (1999) PEGylated DNA/transferrin-PEI complexes: Reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery. Gene Ther. 6: 595–605.

    Article  CAS  Google Scholar 

  13. Hotary, K., E. Allen, A. Punturieri, I. Yana, and S. J. Weiss (2000) Regulation of cell invasion and morphogenesis in a threedimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. J. Cell Biol. 149: 1309–1323.

    Article  CAS  Google Scholar 

  14. Nomura, H., H. Sato, M. Seiki, M. Mai, and Y. Okada (1995) Expression of membrane-type matrix metalloproteinase in human gastric carcinomas. Cancer Res. 55: 3263–3266.

    CAS  Google Scholar 

  15. Afzal, S., N. Lalani el, W. D. Foulkes, B. Boyce, S. Tickle, M. R. Cardillo, T. Baker, M. Pignatelli, and G. W. Stamp (1996) Matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression and synthetic matrix metalloproteinase-2 inhibitor binding in ovarian carcinomas and tumor cell lines. Lab Invest. 74: 406–421.

    CAS  Google Scholar 

  16. Sato, H., T. Takino, Y. Okada, J. Cao, A. Shinagawa, E. Yamamoto, and M. Seiki (1994) A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370: 61–65.

    Article  CAS  Google Scholar 

  17. Truong-Le, V. L., J. T. August, and K. W. Leong (1998) Controlled gene delivery by DNA-gelatin nanospheres. Hum Gene Ther. 9: 1709–1717.

    Article  CAS  Google Scholar 

  18. Truong-Le, V. L., S. M. Walsh, E. Schweibert, H. Q. Mao, W. B. Guggino, J. T. August, and K. W. Leong (1999) Gene transfer by DNA-gelatin nanospheres. Arch Biochem. Biophys. 361: 47–56.

    Article  CAS  Google Scholar 

  19. Leong, K. W., H. Q. Mao, V. L. Truong-Le, K. Roy, S. M. Walsh, and J. T. August (1998) DNA-polycation nanospheres as nonviral gene delivery vehicles. J. Control Rel. 53: 183–193.

    Article  CAS  Google Scholar 

  20. Kaul, G. and M. Amiji (2005) Cellular interactions and in vitro DNA transfection studies with poly(ethylene glycol)-modified gelatin nanoparticles. J. Pharm Sci. 94: 184–198.

    Article  CAS  Google Scholar 

  21. Ossevoort, M. A., M. C. Feltkamp, K. J. van Veen, C. J. Melief, and W. M. Kast (1995) Dendritic cells as carriers for a cytotoxic T-lymphocyte epitope-based peptide vaccine in protection against a human papillomavirus type 16-induced tumor. J. Immunother Emphasis Tumor Immunol. 18: 86–94.

    Article  CAS  Google Scholar 

  22. Fleischmajer, R., K. Kuroda, R. Hazan, R. E. Gordon, M. G. Lebwohl, A. N. Sapadin, F. Unda, N. Iehara, and Y. Yamada (2000) Basement membrane alterations in psoriasis are accompanied by epidermal overexpression of MMP-2 and its inhibitor TIMP-2. J. Invest Dermatol. 115: 771–777.

    Article  CAS  Google Scholar 

  23. Kim, E. M., H. J. Jeong, I. K. Park, C. S. Cho, H. S. Bom, and C. G. Kim (2004) Monitoring the effect of PEGylation on polyethylenimine in vivo using nuclear imaging technique. Nucl. Med. Biol. 31: 781–784.

    Article  CAS  Google Scholar 

  24. Jiang, G., S. H. Min, E. J. Oh, and S. K. Hahn (2007) DNA/PEI/alginate polyplex as an efficient in vivo gene delivery system. Biotechnol. Bioproc. Eng. 12: 684–689.

    Article  CAS  Google Scholar 

  25. Jiang, G., S. H. Min, M. N. Kim, D. C. Lee, M. J. Lim, and Y. I. Yeom (2006) Alginate/PEI/DNA polyplexes: A new gene delivery system. Yao Xue Xue Bao. 41: 439–445.

    CAS  Google Scholar 

  26. Boussif, O., M. A. Zanta, and J. P. Behr (1996) Optimized galenics improve in vitro gene transfer with cationic molecules up to 1000-fold. Gene Ther. 3: 1074–1080.

    CAS  Google Scholar 

  27. Oupicky, D., M. Ogris, K. A. Howard, P. R. Dash, K. Ulbrich, and L. W. Seymour (2002) Importance of lateral and steric stabilization of polyelectrolyte gene delivery vectors for extended systemic circulation. Mol. Ther. 5: 463–472.

    Article  CAS  Google Scholar 

  28. Trubetskoy, V. S., S. C. Wong, V. Subbotin, V. G. Budker, A. Loomis, J. E. Hagstrom, and J. A. Wolff (2003) Recharging cationic DNA complexes with highly charged polyanions for in vitro and in vivo gene delivery. Gene Ther. 10: 261–271.

    Article  CAS  Google Scholar 

  29. Kyriakides, T. R., C. Y. Cheung, N. Murthy, P. Bornstein, P. S. Stayton, and A. S. Hoffman (2002) pH-sensitive polymers that enhance intracellular drug delivery in vivo. J. Control Release 78: 295–303.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea

    Jiang Ge, Sang-Hyun Min, Dong Min Kim, Dong Chul Lee, Kyung Chan Park & Young Il Yeom

  2. Bioengineering College, Dalian University, Dalian, 116-622, China

    Jiang Ge

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  1. Jiang Ge
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  2. Sang-Hyun Min
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  3. Dong Min Kim
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  4. Dong Chul Lee
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  5. Kyung Chan Park
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  6. Young Il Yeom
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Correspondence to Young Il Yeom.

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Ge, J., Min, SH., Kim, D.M. et al. Selective gene delivery to cancer cells secreting matrix metalloproteinases using a gelatin/polyethylenimine/DNA complex. Biotechnol Bioproc E 17, 160–167 (2012). https://doi.org/10.1007/s12257-011-0423-x

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  • DOI: https://doi.org/10.1007/s12257-011-0423-x

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