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The effect of the histological properties of tumors on transfection efficiency of electrically assisted gene delivery to solid tumors in mice

Gene Therapy volume 14, pages 1261–1269 (2007)Cite this article

Abstract

Uniform DNA distribution in tumors is a prerequisite step for high transfection efficiency in solid tumors. To improve the transfection efficiency of electrically assisted gene delivery to solid tumors in vivo, we explored how tumor histological properties affected transfection efficiency. In four different tumor types (B16F1, EAT, SA-1 and LPB), proteoglycan and collagen content was morphometrically analyzed, and cell size and cell density were determined in paraffin-embedded tumor sections under a transmission microscope. To demonstrate the influence of the histological properties of solid tumors on electrically assisted gene delivery, the correlation between histological properties and transfection efficiency with regard to the time interval between DNA injection and electroporation was determined. Our data demonstrate that soft tumors with larger spherical cells, low proteoglycan and collagen content, and low cell density are more effectively transfected (B16F1 and EAT) than rigid tumors with high proteoglycan and collagen content, small spindle-shaped cells and high cell density (LPB and SA-1). Furthermore, an optimal time interval for increased transfection exists only in soft tumors, this being in the range of 5–15 min. Therefore, knowledge about the histology of tumors is important in planning electrogene therapy with respect to the time interval between DNA injection and electroporation.

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References

  1. Nishikawa M, Huang L . Non-viral vectors in the new millennium: delivery barriers in gene transfer. Hum Gene Ther 2001; 12: 861–870.

    Article  CAS  Google Scholar 

  2. Cemazar M, Golzio M, Sersa G, Rols MP, Teissie J . Electrically-assisted nucleic acids delivery to tissues in vivo: where do we stand? Curr Pharm Des 2006; 12: 3817–3825.

    Article  CAS  Google Scholar 

  3. Heller LC, Heller R . In vivo electroporation for gene therapy. Hum Gene Ther 2006; 17: 890–897.

    Article  CAS  Google Scholar 

  4. Cemazar M, Grosel A, Glavac D, Kotnik V, Skobrne M, Kranjc S et al. Effects of electrogenetherapy with p53wt combined with cisplatin on curvival of human tumor cell lines with different p53 status. DNA Cell Biol 2003; 22: 765–775.

    Article  CAS  Google Scholar 

  5. Haupt S, Haupt Y . Manipulation of the tumor suppressor p53 for potentiating cancer therapy. Semin Cancer Biol 2004; 14: 244–252.

    Article  CAS  Google Scholar 

  6. Bettan M, Ivanov MA, Mir LM, Boissiere F, Delaere P, Scherman D . Efficient DNA electrotransfer into tumors. Bioelectrochemistry 2000; 52: 83–90.

    Article  CAS  Google Scholar 

  7. Cemazar M, Sersa G, Wilson J, Tozer GM, Hart SL, Grosel A et al. Effective gene transfer to solid tumors using different non-viral gene delivery techniques: electroporation, liposomes, and integrin-targeted vector. Cancer Gene Ther 2002; 9: 399–406.

    Article  CAS  Google Scholar 

  8. Heller L, Jaroszeski MJ, Coppola D, Pottinger C, Gilbert R, Heller R . Electrically mediated plasmid DNA delivery to hepatocellular carcinomas in vivo. Gene Therapy 2000; 7: 826–829.

    Article  CAS  Google Scholar 

  9. Rols MP, Delteil C, Golzio M, Dumond P, Cros S, Teissie J . In vivo electrically mediated protein and gene transfer in murine melanoma. Nat Biotechnol 1998; 16: 168–171.

    Article  CAS  Google Scholar 

  10. Wells JM, Li LH, Sen A, Jahreis GP, Hui SW . Electroporation-enhanced gene delivery in mammary tumors. Gene Therapy 2000; 7: 541–547.

    Article  CAS  Google Scholar 

  11. Cichon T, Jamrozy L, Glogowska J, Missol-Kolka E, Szala S . Electrotransfer of gene encoding endostatin into normal and neoplastic mouse tissues: inhibition of primary tumor growth and metastatic spread. Cancer Gene Ther 2002; 9: 771–777.

    Article  CAS  Google Scholar 

  12. Collins CG, Tangney M, Larkin JO, Casey G, Whelan MC, Cashman J et al. Local gene therapy of solid tumors with GM-CSF and B7-1 eradicates both treated and distal tumors. Cancer Gene Ther 2006; 13: 1061–1071.

    Article  CAS  Google Scholar 

  13. Grosel A, Sersa G, Kranjc S, Cemazar M . Electrogene therapy with p53 of murine sarcomas alone or combined with electrochemotherapy using cisplatin. DNA Cell Biol 2006; 25: 674–683.

    Article  CAS  Google Scholar 

  14. Lucas ML, Heller L, Coppola D, Heller R . IL-12 plasmid delivery by in vivo electroporation for the successful treatment of established subcutaneous B16.F10 melanoma. Mol Ther 2002; 5: 668–675.

    Article  CAS  Google Scholar 

  15. Tamura T, Nishi T, Goto T, Takeshima H, Ushio Y, Sakata T . Combination of IL-12 and IL-18 of electro-gene therapy synergistically inhibits tumor growth. Anticancer Res 2003; 23: 1173–1179.

    CAS  PubMed  Google Scholar 

  16. Gehl J . Electroporation: theory and methods, perspectives for drug delivery, gene therapy and research. Acta Physiol Scand 2003; 177: 437–447.

    Article  CAS  Google Scholar 

  17. Li S . Electroporation gene therapy: new developments in vivo and in vitro. Curr Gene Ther 2004; 4: 309–316.

    Article  CAS  Google Scholar 

  18. Somiari S, Glasspool-Malone J, Drabick JJ, Gilbert RA, Heller R, Jaroszeski MJ et al. Theory and in vivo application of electroporative gene delivery. Mol Ther 2000; 2: 178–187.

    Article  CAS  Google Scholar 

  19. Smrekar B, Wightman L, Wolschek MF, Lichtenberger C, Ruzicka R, Ogris M et al. Tissue-dependent factors affect gene delivery to tumors in vivo. Gene Therapy 2003; 10: 1079–1088.

    Article  CAS  Google Scholar 

  20. Zaharoff DA, Barr RC, Li CY, Yuan F . Electromobility of plasmid DNA in tumor tissues during electric field-mediated gene delivery. Gene Therapy 2002; 9: 1286–1290.

    Article  CAS  Google Scholar 

  21. Canatella PJ, Black MM, Bonnichsen DM, McKenna C, Prausnitz MR . Tissue electroporation: quantification and analysis of heterogeneous transport in multicellular environments. Biophys J 2004; 86: 3260–3268.

    Article  CAS  Google Scholar 

  22. Baumgartner G . The impact of extracellular matrix on chemoresistance of solid tumors – experimental and clinical results of hyaluronidase as additive to cytostatic chemotherapy. Cancer Lett 1998; 131: 1–2.

    Article  CAS  Google Scholar 

  23. Davis AJ, Tannock IF . Tumor physiology and resistance to chemotherapy: repopulation and drug penetration. Cancer Treat Res 2002; 112: 1–26.

    Article  CAS  Google Scholar 

  24. Tannock IF, Lee CM, Tunggal JK, Cowan DS, Egorin MJ . Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy. Clin Cancer Res 2002; 8: 878–884.

    CAS  PubMed  Google Scholar 

  25. Grantab R, Sivananthan S, Tannock IF . The penetration of anticancer drugs through tumor tissue as a function of cellular adhesion and packing density of tumor cells. Cancer Res 2006; 66: 1033–1039.

    Article  CAS  Google Scholar 

  26. Minchinton AI, Tannock IF . Drug penetration in solid tumours. Nat Rev Cancer 2006; 6: 583–592.

    Article  CAS  Google Scholar 

  27. Netti PA, Hamberg LM, Babich JW, Kierstead D, Graham W, Hunter GJ et al. Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules. Proc Natl Acad Sci USA 1999; 96: 3137–3142.

    Article  CAS  Google Scholar 

  28. Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK . Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res 2000; 60: 2497–2503.

    CAS  PubMed  Google Scholar 

  29. Pluen A, Boucher Y, Ramanujan S, McKee TD, Gohongi T, Tomaso E et al. Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs subcutaneous tumors. Proc Natl Acad Sci USA 2001; 98: 4628–4633.

    Article  CAS  Google Scholar 

  30. Alexandrakis G, Brown EB, Tong RT, McKee TD, Campbell RB, Boucher Y et al. Two-photon fluorescence correlation microscopy reveals the two-phase nature of transport in tumors. Nat Med 2004; 10: 203–207.

    Article  CAS  Google Scholar 

  31. Valic B, Golzio M, Pavlin M, Schatz A, Faurie C, Gabriel B et al. Effect of electric field induced transmembrane potential on spheroidal cells: theory and experiment. Eur Biophys J 2003; 32: 519–528.

    Article  Google Scholar 

  32. Susil R, Semrov D, Miklavcic D . Electric field-induced transmembrane potential depends on cell density and organization. Electro- and Magnetobiology 1998; 17: 391–399.

    Article  Google Scholar 

  33. Cemazar M, Pavlin D, Kranjc S, Grosel A, Mesojednik S, Sersa G . Sequence and time dependence of transfection efficiency of electrically-assisted gene delivery to tumors in mice. Curr Drug Deliv 2006; 3: 77–81.

    Article  CAS  Google Scholar 

  34. Mir LM, Bureau MF, Gehl J, Rangara R, Rouy D, Caillaud JM et al. High-efficiency gene transfer into skeletal muscle mediated by electric pulses. Proc Natl Acad Sci USA 1999; 96: 4262–4267.

    Article  CAS  Google Scholar 

  35. Gimsa J, Wachner D . Analytical description of the transmembrane voltage induced on arbitrarily oriented ellipsoidal and cylindrical cells. Biophys J 2001; 81: 1888–1896.

    Article  CAS  Google Scholar 

  36. Sixou S, Teissie J . Specific electropermeabilization of leucocytes in a blood sample and application to large volumes of cells. Biochim Biophys Acta 1990; 1028: 154–160.

    Article  CAS  Google Scholar 

  37. Andre FM, Cournil-Henrionnet C, Vernerey D, Opolon P, Mir LM . Variability of naked DNA expression after direct local injection: the influence of the injection speed. Gene Therapy 2006; 13: 1619–1627.

    Article  CAS  Google Scholar 

  38. Hanahan D, Weinberg RA . The hallmarks of cancer. Cell 2000; 100: 57–70.

    Article  CAS  Google Scholar 

  39. Golzio M, Rols MP, Teissie J . In vitro and in vivo electric field-mediated permeabilization, gene transfer, and expression. Methods 2004; 33: 126–135.

    Article  CAS  Google Scholar 

  40. Prud'homme GJ, Glinka Y, Khan AS, Draghia-Akli R . Electroporation-enhanced non-viral gene transfer for the prevention or treatment of immunological, endocrine and neoplastic diseases. Curr Gene Ther 2006; 6: 243–273.

    Article  CAS  Google Scholar 

  41. Cemazar M, Wilson I, Dachs GU, Tozer GM, Sersa G . Direct visualization of electroporation-assisted in vivo gene delivery to tumors using intravital microscopy - spatial and time dependent distribution. BMC Cancer 2004; 4: 81.

    Article  Google Scholar 

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Acknowledgements

The authors acknowledge financial support from the state budget of the Slovenian Research Agency (program No. P3-0003; project No. J3-7044). Grateful acknowledgement is also extended to Mira Lavric for her help with experiments.

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Authors and Affiliations

  1. Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, Ljubljana, Slovenia

    S Mesojednik, G Sersa, S Kranjc, A Grosel, G Tevz & M Cemazar

  2. University of Ljubljana, Veterinary Faculty, Cesta v Mestni log 47, Ljubljana, Slovenia

    D Pavlin

  3. University of Ljubljana, Medical Faculty, Korytkova 2, Ljubljana, Slovenia

    A Coer

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  1. S Mesojednik
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Correspondence to M Cemazar.

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Mesojednik, S., Pavlin, D., Sersa, G. et al. The effect of the histological properties of tumors on transfection efficiency of electrically assisted gene delivery to solid tumors in mice. Gene Ther 14, 1261–1269 (2007). https://doi.org/10.1038/sj.gt.3302989

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