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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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.
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.
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.
Emi, N. and Y. Yoshikawa (1996) Synthetic vectors for gene transfection. Nippon Rinsho. 54: 1997–2002.
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.
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.
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.
Nishikawa, M. and L. Huang (2001) Nonviral vectors in the new millennium: Delivery barriers in gene transfer. Hum Gene Ther. 12: 861–870.
Dincer, S., M. Turk, and E. Piskin (2005) Intelligent polymers as non viral vectors. Gene Ther. 12Suppl 1: 139–145.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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