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A nonviral carrier for targeted gene delivery to tumor cells

Cancer Gene Therapy volume 11, pages 156–164 (2004)Cite this article

Abstract

In this study, we developed a nonviral, cationic, targeted DNA–carrier system by coupling SAINT/DOPE lipids to monoclonal antibodies. The two monoclonal antibodies used were both tumor specific, that is, MOC31 recognizes the epithelial glycoprotein EGP-2 present in carcinomas and Herceptin recognizes the HER-2/neu protein in breast and ovarian cancers. Coupling was performed under nonreducing conditions by covalent attachment. The coupling procedure appeared to be reproducible and the binding capacity of the antibody was not affected by linking them to the cationic lipid. Binding and transfection efficiency was assayed with target cells and nontarget cells. SAINT/DOPE lipoplexes as such appeared to be an effective transfection reagent for various cell lines. After coupling SAINT/DOPE to the monoclonal antibodies or F(ab)2 fragments, it was shown that the targeted MoAb-SAINT/DOPE lipoplexes preferably bound to target cells, compared to binding to the nontarget cells, especially for the Herceptin-SAINT/DOPE lipoplexes. More importantly, transfection of the target cells could also be improved with these targeted lipoplexes. In conclusion, we have shown that by using monoclonal antibody-coupled SAINT/DOPE lipoplexes cells targeted gene delivery can be achieved, and also a higher number of transfected target cells was seen.

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References

  1. Venter JC, Adams MD, Myers EW, et al., The sequence of the human genome. Science. 1995;291:1304–1351.

    Article  Google Scholar 

  2. Miller AD . Retrovirus packaging cells. Human Gene Ther. 1990;1(1):5–14.

    Article  CAS  Google Scholar 

  3. Mah C, Byrne BJ, Flotte TR . Virus-based gene delivery systems. Clin Pharmacokinet. 2002;41:901–911.

    Article  CAS  Google Scholar 

  4. Schiedner G, Morral N, Parks RJ, et al. Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet. 1998;18:180–183.

    Article  CAS  Google Scholar 

  5. Carter PJ, Samulski RJ . Adeno-associated viral vectors as gene delivery vehicles. Int J Mol Med. 2000;6:17–27.

    CAS  PubMed  Google Scholar 

  6. Kay MA, Manno CS, Ragni MV . Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet. 2000;24:257–261.

    Article  CAS  Google Scholar 

  7. Cristiano RJ . Protein/DNA polyplexes for gene therapy. Surg Oncol Clin N Am. 2002;11:697–716.

    Article  Google Scholar 

  8. Dunlap DD, Maggi AS, Marco R, Monaco L . Nanoscopic structure of DNA condensed for gene delivery. Nucl Acid Res. 1997;25:3095–3101.

    Article  CAS  Google Scholar 

  9. Ferkol T, Perales JC, Eckman, E, et al. Gene transfer into the airway epithelium of animals by targeting the polymeric immunogobulin receptor. J Clin Invest. 1995;95:493–502.

    Article  CAS  Google Scholar 

  10. Nishikawa M, Yamauchi M, Morimoto K, Ishida E, et al. Hepatocyte-targeted in vivo gene expression by intravenous injection of plasmid DNA complexed with synthetic multi-functional gene delivery system. Gene therapy. 2000;7:548–555.

    Article  CAS  Google Scholar 

  11. Kircheis R, Kichler A, Wallner G, et al. Coupling of cell-binding ligands to polyethylenimine for targeted gene delivery. Gene Therapy. 1997;4:409–418.

    Article  CAS  Google Scholar 

  12. Li S, Rizzo MA, Bhattacharaya S, Huang L . Characterization of cationic lipid-protamine-DNA (LPD) complexes for intravenous gene delivery. Gene Therapy. 1998;5:930–937.

    Article  CAS  Google Scholar 

  13. Felgner PL, Gadek TR, Holm M, Roman R, et al. Lipofection: a highly efficient, lipid mediated DNA transfection procedure. Proc Natl Acad Sci USA. 1987;84:7413–7417.

    Article  CAS  Google Scholar 

  14. Smyth Templeton N, Lasic DD, Frederik PM, et al. Improved DNA: liposome complexes for increased systemic delivery and gene expression. Nat Biotechnol. 1997;15:647–652.

    Article  Google Scholar 

  15. Liu Y, Thor A, Shtivelman E, et al. Systemic gene delivery expands the repertoire of effective antiangiogenic agents. J Biol Chem. 1999;274:13338–13344.

    Article  CAS  Google Scholar 

  16. Vd Woude I, Wagenaar A, Meekel AP, et al. Novel pyridinium surfactants for efficient, nontoxic in vitro gene delivery. Proc Natl Acad Sci. 1997;94:1160–1165.

    Article  Google Scholar 

  17. Audouy S, Molema G, de Leij L, Hoekstra D . Serum as a modulator of lipoplex-mediated gene transfection: dependance of amphiphile, cell type and complex stability. J Gene Med. 2000;2:465–476.

    Article  CAS  Google Scholar 

  18. Zuhorn IS, Oberle V, Visser W, Engberts JBFN, Bakowsky U, Hoekstra D . The phase behavior of cationic amphiphiles and their mixtures with helper lipid influences lipoplex shape, DNA translocation, and transfection efficiency. Biophys J. 2002;83(4):2096–2108.

    Article  CAS  Google Scholar 

  19. Li S, Tan Y, Viroonchatapan E, et al. Targeted gene delivery to pulmonary endothelium by anti-PECAM antibody. Am J Physiol Lung Cell Mol Phys. 2000;278:504–511.

    Article  Google Scholar 

  20. Spragg DD, Alford DR, Greferath R, et al. Immunotargeting of liposomes to activated vascular endothelial cells: a strategy for site-selective delivery in the cardiovascular system. Proc Natl Acad Sci USA. 1997;94:8795–8800.

    Article  CAS  Google Scholar 

  21. Mastrobattista E, Kapel RHG, Eggenhuisen MH, et al. Lipid-coated polyplexes for targeted gene delivery to ovarian carcinoma cells. Cancer Gene Ther. 2001;8(6):405–413.

    Article  CAS  Google Scholar 

  22. Xu L, Tang W-H, Huang C-C, et al. Systemic p53 gene therapy of cancer with immunolipoplexes targeted by anti-transferrin receptor scFv. Mol Med. 2001;7(10):723–734.

    Article  CAS  Google Scholar 

  23. Balzar M, Winter MJ, de Boer CJ, Litvinov S . The biology of the 17-1A antigen (Ep-CAM). J Mol Med. 1999;77:699–712.

    Article  CAS  Google Scholar 

  24. Herlyn M, Steplewski Z, Herlyn D, Koprowski H . Colorectal carcinoma-specific antigen: detection by means of monoclonal antibodies. Proc Natl Acad Sci USA. 1979;76:1438–1452.

    Article  CAS  Google Scholar 

  25. Semba K, Kamata N, Toyoshima K, Yamamoto T . A v-erbB-related protooncogene, c-erbB2, is distinct from the c-erb-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma. Proc Natl Acad Sci USA. 1985;82:6497.

    Article  CAS  Google Scholar 

  26. Carter P, Presta L, Gorman C, et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA. 1992;89:4285–4290.

    Article  CAS  Google Scholar 

  27. Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA . Nonclinical studies addressing the mechanism of action of Trastuzumab (Herceptin). Seminars in Oncol. 1999;26(4):60–70.

    CAS  Google Scholar 

  28. Mariani M, Camagna M, Tarditi L, Seccamini E . A new anzymatic method to obtain high yield F(ab)2 suitable for clinical use from mouse IgG1. Mol Immunol. 1991;28(1/2):69–77.

    Article  CAS  Google Scholar 

  29. De Jonge MW, Kosterink JGW, Bin YY, et al. Radioimmunodetection of human small cell lung carcinoma xenografts in the nude rat using 111 in-labelled monoclonal antibody MOC31. Eur J Cancer. 1993;29A(13):1885–1890.

    Article  CAS  Google Scholar 

  30. Ross PC, Hui HW . Lipoplex size is a major determinant of in vitro lipofection efficiency. Gene Therapy. 1999;6:651–659.

    Article  CAS  Google Scholar 

  31. Audouy S, Hoekstra D, de Leij L, Hospers G, Molema G . Behaviour of SAINT lipoplexes after intravenous administration: safety and biodistribution in mice. Thesis, Cationic liposomes as DNA delivery system. 2002; Chapter 5, p. 87–101.

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Acknowledgements

This research was supported by a STIGON grant from the Netherlands Organization for Scientific Research (ZON-MW). We thank Dr JAAM Kamps (Dept of Cell Biology, section Liposome Research, Groningen University Institute for Drug Exploration) for particle size measurements.

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Authors and Affiliations

  1. Department of PLG/Medical Biology, Academic Hospital Groningen, PO Box 30.001, Groningen, 9700 RB, The Netherlands

    Jacoba van Zanten, Berber Doornbos-van der Meer & Lou de Leij

  2. Department of Membrane Cell Biology, PO Box 196, Groningen, 9700 AD, The Netherlands

    Sandrine Audouy

  3. Department of Pharmacokinetics and Drug Delivery, PO Box 196, Groningen, 9700 AD, The Netherlands

    Robbert Jan Kok

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  1. Jacoba van Zanten
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  2. Berber Doornbos-van der Meer
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Correspondence to Jacoba van Zanten.

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Zanten, J., Meer, Bv., Audouy, S. et al. A nonviral carrier for targeted gene delivery to tumor cells. Cancer Gene Ther 11, 156–164 (2004). https://doi.org/10.1038/sj.cgt.7700668

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