Annals of Biomedical Engineering

, Volume 42, Issue 1, pp 193–204 | Cite as

Membrane-Targeting Approaches for Enhanced Cancer Cell Destruction with Irreversible Electroporation

Article

Abstract

Irreversible electroporation (IRE) is a promising technology to treat local malignant cancer using short, high-voltage electric pulses. Unfortunately, in vivo studies show that IRE suffers from an inability to destroy large volumes of cancer tissue without introduction of cytotoxic agents and/or increasing the applied electrical dose to dangerous levels. This research will address this limitation by leveraging membrane-targeting mechanisms that increase lethal membrane permeabilization. Methods that directly modify membrane properties or change the pulse delivery timing are proposed that do not rely on cytotoxic agents. This work shows that significant enhancement (67–75% more cell destruction in vitro and >100% treatment volume increase in vivo) can be achieved using membrane-targeting approaches for IRE cancer destruction. The methods introduced are surfactants (i.e., DMSO) and pulse timing which are low cost, non-toxic, and easy to be incorporated into existing clinical use. Moreover, when needed, these methods can also be combined with electrochemotherapy to further enhance IRE treatment efficacy.

Keywords

Irreversible electroporation Cancer treatment Adjuvant DMSO Pulse timing Membrane permeabilization 

Notes

Acknowledgments

This study was supported by Ethicon Endo-Surgery Inc. We thank Peter Shires for helpful discussions. JCB was supported by a McKnight Distinguished Professorship and the Carl and Janet Kuhrmeyer Chair of Mechanical Engineering from the University of Minnesota.

Supplementary material

10439_2013_882_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 18 kb)

References

  1. 1.
    Al-Sakere, B., F. André, C. Bernat, E. Connault, P. Opolon, R. V. Davalos, B. Rubinsky, and L. M. Mir. Tumor ablation with irreversible electroporation. PLoS ONE 2(11):e1135, 2007.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Au, J. T., T. P. Kingham, K. Jun, D. Haddad, S. Gholami, K. Mojica, S. Monette, P. Ezell, and Y. Fong. Irreversible electroporation ablation of the liver can be detected with ultrasound B-mode and elastography. Surgery 153(6):787–793, 2013.PubMedCrossRefGoogle Scholar
  3. 3.
    Bao, N., T. T. Le, J.-X. Cheng, and C. Lu. Microfluidic electroporation of tumor and blood cells: observation of nucleus expansion and implications on selective analysis and purging of circulating tumor cells. Integr. Biol. (Camb.) 2(2–3):113–120, 2010.CrossRefGoogle Scholar
  4. 4.
    Cheng, D. K. L., L. Tung, and E. A. Sobie. Nonuniform responses of transmembrane potential during electric field stimulation of single cardiac cells. Am. J. Physiol. Heart Circ. Physiol. 277(1):H351–H362, 1999.Google Scholar
  5. 5.
    Davalos, R. V., I. L. M. Mir, and B. Rubinsky. Tissue ablation with irreversible electroporation. Ann. Biomed. Eng. 33(2):223–231, 2005.PubMedCrossRefGoogle Scholar
  6. 6.
    Davalos, R. V., B. Rubinsky, and L. M. Mir. Theoretical analysis of the thermal effects during in vivo tissue electroporation. Bioelectrochemistry 61(1–2):99–107, 2003.PubMedCrossRefGoogle Scholar
  7. 7.
    Deodhar, A., T. Dickfeld, G. W. Single, W. C. Hamilton, R. H. Thornton, C. T. Sofocleous, M. Maybody, M. Gónen, B. Rubinsky, and S. B. Solomon. Irreversible electroporation near the heart: ventricular arrhythmias can be prevented with ECG synchronization. AJR Am. J. Roentgenol. 196(3):W330–W335, 2011.PubMedCrossRefGoogle Scholar
  8. 8.
    Deodhar, A., S. Monette, G. W. Single, Jr., W. C. Hamilton, Jr., R. Thornton, M. Maybody, J. A. Coleman, and S. B. Solomon. Renal tissue ablation with irreversible electroporation: preliminary results in a porcine model. Urology 77(3):754–760, 2011.PubMedCrossRefGoogle Scholar
  9. 9.
    Devireddy, R. V. Statistical thermodynamics of biomembranes. Cryobiology 60(1):80–90, 2010.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Edd, J. F., L. Horowitz, R. V. Davalos, L. M. Mir, and B. Rubinsky. In vivo results of a new focal tissue ablation technique: irreversible electroporation. IEEE Trans. Biomed. Eng. 53(7):1409–1415, 2006.PubMedCrossRefGoogle Scholar
  11. 11.
    Ellis, T. L., P. A. Garcia, J. H. Rossmeisl, N. Henao-Guerrero, J. Robertson, and R. V. Davalos. Nonthermal irreversible electroporation for intracranial surgical applications. J. Neurosurg. 114(3):681–688, 2011.PubMedCrossRefGoogle Scholar
  12. 12.
    Fedorov, V. V., V. P. Nikolski, and I. R. Efimov. Effect of electroporation on cardiac electrophysiology. Methods Mol. Biol. 423:433–448, 2008.PubMedCrossRefGoogle Scholar
  13. 13.
    Frandsen, S. K., H. Gissel, P. Hojman, T. Tramm, J. Eriksen, and J. Gehl. Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis. Cancer Res. 72(6):1336–1341, 2012.PubMedCrossRefGoogle Scholar
  14. 14.
    Garcia, P. A., J. H. Rossmeisl, Jr., and R. V. Davalos. Electrical conductivity changes during irreversible electroporation treatment of brain cancer. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2011:739–742, 2011.PubMedGoogle Scholar
  15. 15.
    Garcia, P. A., J. H. Rossmeisl, Jr., R. E. Neal, 2nd, T. L. Ellis, J. D. Olson, N. Henao-Guerrero, J. Robertson, and R. V. Davalos. Intracranial nonthermal irreversible electroporation: in vivo analysis. J. Membr. Biol. 236(1):127–136, 2010.PubMedCrossRefGoogle Scholar
  16. 16.
    Gehl, J. G. Electroporation: theory and methods, perspectives for drug delivery, gene therapy and research. Acta Physiol. Scand. 177(4):437–447, 2003.PubMedCrossRefGoogle Scholar
  17. 17.
    Goel, R., K. Anderson, J. Slaton, F. Schmidlin, G. Vercellotti, J. Belcher, and J. C. Bischof. Adjuvant approaches to enhance cryosurgery. J. Biomech. Eng. 131(7):074003, 2009.PubMedCrossRefGoogle Scholar
  18. 18.
    Goel, R., D. Swanlund, J. Coad, G. F. Paciotti, and J. C. Bischof. TNF-α-based accentuation in cryoinjury—dose, delivery, and response. Mol. Cancer Ther. 6(7):2039–2047, 2007.PubMedCrossRefGoogle Scholar
  19. 19.
    Golberg, A., and M. L. Yarmush. Nonthermal irreversible electroporation: fundamentals, applications, and challenges. IEEE Trans. Biomed. Eng. 60(3):707–714, 2013.PubMedCrossRefGoogle Scholar
  20. 20.
    Gothelf, A., L. M. Mir, and J. Gehl. Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. Cancer Treat. Rev. 29(5):371–387, 2003.PubMedCrossRefGoogle Scholar
  21. 21.
    Guo, Y., Y. Zhang, R. Klein, G. M. Nijm, A. V. Sahakian, R. A. Omary, G.-Y. Yang, and A. C. Larson. Irreversible electroporation therapy in the liver: longitudinal efficacy studies in a rat model of hepatocellular carcinoma. Cancer Res. 70(4):1555–1563, 2010.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Karatekin, E., O. Sandre, H. Guitouni, N. Borghi, P.-H. Puech, and F. Brochard-Wyart. Cascades of transient pores in giant vesicles: line tension and transport. Biophys. J. 84(3):1734–1749, 2003.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Lavee, J., G. Onik, P. Mikus, and B. Rubinsky. A novel nonthermal energy source for surgical epicardial atrial ablation: irreversible electroporation. Heart Surg. Forum 10:162–167, 2007.CrossRefGoogle Scholar
  24. 24.
    Lee, R. C. Physical mechanisms of tissue injury in electrical trauma. IEEE Trans. Educ. 34(3):223–230, 1991.CrossRefGoogle Scholar
  25. 25.
    Long, G., G. Bakos, P. K. Shires, L. Gritter, J. W. Crissman, J. L. Harris, and J. W. Clymer. Histological and finite element analysis of cell death due to irreversible electroporation. TCRT Express, 2013.Google Scholar
  26. 26.
    Lu, D. S., S. S. Raman, D. J. Vodopich, M. Wang, J. Sayre, and C. Lassman. Effect of vessel size on creation of hepatic radiofrequency lesions in pigs assessment of the ‘heat sink’ effect. Am. J. Roentgenol. 178(1):47–51, 2002.CrossRefGoogle Scholar
  27. 27.
    Miller, L., J. Leor, and B. Rubinsky. Cancer cells ablation with irreversible electroporation. Technol. Cancer Res. Treat. 4(6):699–705, 2005.PubMedGoogle Scholar
  28. 28.
    Mir, L. M. Therapeutic perspectives of in vivo cell electropermeabilization. Bioelectrochemistry 53(1):1–10, 2001.PubMedCrossRefGoogle Scholar
  29. 29.
    Moldovan, D., D. Pinisetty, and R. V. Devireddy. Molecular dynamics simulation of pore growth in lipid bilayer membranes in the presence of edge-active agents. Appl. Phys. Lett. 91(20):204104–204104-3, 2007.CrossRefGoogle Scholar
  30. 30.
    Onik, G., P. Mikus, and B. Rubinsky. Irreversible electroporation: implications for prostate ablation. Technol. Cancer Res. Treat. 6(4):295–300, 2007.PubMedGoogle Scholar
  31. 31.
    Pech, M., A. Janitzky, J. J. Wendler, C. Strang, S. Blaschke, O. Dudeck, J. Ricke, and U. B. Liehr. Irreversible electroporation of renal cell carcinoma: a first-in-man phase I clinical study. Cardiovasc. Intervent. Radiol. 34(1):132–138, 2011.PubMedCrossRefGoogle Scholar
  32. 32.
    Powell, K. T., and J. C. Weaver. Transient aqueous pores in bilayer membranes: a statistical theory. Bioelectrochem. Bioenerg. 15(2):211–227, 1986.CrossRefGoogle Scholar
  33. 33.
    Qin, Z., J. Jiang, G. Long, B. Lindgren, and J. C. Bischof. Irreversible electroporation: an in vivo study with dorsal skin fold chamber. Ann. Biomed. Eng. 41:619–629, 2013.PubMedCrossRefGoogle Scholar
  34. 34.
    Rubinsky, B., G. Onik, and P. Mikus. Irreversible electroporation: a new ablation modality—clinical implications. Technol. Cancer Res. Treat. 6(1):37–48, 2007.PubMedGoogle Scholar
  35. 35.
    Rubinsky, J., G. Onik, P. Mikus, and B. Rubinsky. Optimal parameters for the destruction of prostate cancer using irreversible electroporation. J. Urol. 180(6):2668–2674, 2008.PubMedCrossRefGoogle Scholar
  36. 36.
    Sersa, G., T. Jarm, T. Kotnik, A. Coer, M. Podkrajsek, M. Sentjurc, D. Miklavcic, M. Kadivec, S. Kranjc, A. Secerov, and M. Cemazar. Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma. Br. J. Cancer 98(2):388–398, 2008.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Shafiee, H., P. A. Garcia, and R. V. Davalos. A preliminary study to delineate irreversible electroporation from thermal damage using the Arrhenius equation. J. Biomech. Eng. 131(7):074509, 2009.PubMedCrossRefGoogle Scholar
  38. 38.
    Toner, M., and E. G. Cravalho. Kinetics and likelihood of membrane rupture during electroporation. Phys. Lett. A 143(8):409–412, 1990.CrossRefGoogle Scholar
  39. 39.
    Tovar, O., and L. Tung. Electroporation and recovery of cardiac cell membrane with rectangular voltage pulses. Am. J. Physiol. Heart Circ. Physiol. 263(4):H1128–H1136, 1992.Google Scholar
  40. 40.
    Tracy, C. R., W. Kabbani, and J. A. Cadeddu. Irreversible electroporation (IRE): a novel method for renal tissue ablation. BJU Int. 107(12):1982–1987, 2011.PubMedCrossRefGoogle Scholar
  41. 41.
    Troiano, G. C., K. J. Stebe, R. M. Raphael, and L. Tung. The effects of gramicidin on electroporation of lipid bilayers. Biophys. J. 76(6):3150–3157, 1999.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Troiano, G. C., L. Tung, V. Sharma, and K. J. Stebe. The reduction in electroporation voltages by the addition of a surfactant to planar lipid bilayers. Biophys. J. 75(2):880–888, 1998.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Tsong, T. Y. Electroporation of cell membranes. Biophys. J. 60(2):297–306, 1991.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Tung, L., G. C. Troiano, V. Sharma, R. M. Raphael, and K. J. Stebe. Changes in electroporation thresholds of lipid membranes by surfactants and peptides. Ann. N. Y. Acad. Sci. 888(1):249–265, 1999.PubMedCrossRefGoogle Scholar
  45. 45.
    Weaver, J. C. Electroporation of cells and tissues. IEEE Trans. Plasma Sci. 28(1):24–33, 2000.CrossRefGoogle Scholar
  46. 46.
    Weaver, J. C., and Y. A. Chizmadzhev. Theory of electroporation: a review. Bioelectrochem. Bioenerg. 41(2):135–160, 1996.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2013

Authors and Affiliations

  1. 1.Department of Mechanical EngineeringUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Biomedical EngineeringUniversity of MinnesotaMinneapolisUSA
  3. 3.Department of Urological SurgeryUniversity of MinnesotaMinneapolisUSA

Personalised recommendations