C60-Derivatives: Applications in Electric-Field Cancer Therapy (EFCT)

Thursday, 28 May 2015: 15:20
Lake Ontario (Hilton Chicago)
S. J. Corr (Baylor College of Medicine), L. Vergara (BAYLOR COLLEGE OF MEDICINE), Y. Mackeyev (Rice University), J. C. S. Ho (Baylor College of Medicine), L. J. Wilson (Rice University Department of Chemistry), and S. A. Curley (Baylor College of Medicine)
Electrical-field cancer therapy (EFCT) is a non-invasive means of inducing tumor necrosis by exposing cancer to electric fields (EFs) at a multitude of frequencies (10 Hz – 200 MHz). Clinical cancer trials have shown that safe levels of amplitude-modulated (AM) EFs (0.1 Hz-114 kHz) administered via an intrabuccal tongue-shaped probe elicit therapeutic responses1, 2. Separate clinical studies have also shown therapeutic benefits through the use of insulated electrodes powered at higher frequencies of 100-300 kHz3-6. Although EFs have been shown to cause thermal and non-thermal cancer destruction, their mechanisms are poorly investigated and still not fully understood1-6. Furthermore, EFs can enhance the efficacy of chemotherapy drugs at dosages far less than is currently used in the clinic. However, there are still critical barriers that are impeding the use of this technology in an FDA-approved clinical setting. Namely; (i) the ability to image and predict the heating effects of EF exposure upon internal organs, tissues, and tumors; and (ii) a method to optimize and target EF-induced thermal and non-thermal anti-cancer effects to reduce neighboring healthy cell toxicity.

We have published on the ability of highly water soluble C60-serinol (C60-ser) to be used as a transfection agent7 and the molecule’s ability to non-covalently internalize within a melanoma antibody in significant quantities without significantly affecting antibody-antigen binding8. These abilities are second to the molecule’s non-toxicity. We have also developed a C60-ser conjugate with a fluorescent label (PF-633) for intracellular tracking. This complex directly competes with unlabeled C60-ser without altering biological behavior9. Tracking the fluorescence we discovered C60-serPF can cross both cellular and nuclear membranes without producing any damage to the cell. Furthermore, C60-serPF internalizes within living cells in association with serum proteins through multiple energy-dependent pathways (not passive internalization).

In a mouse model of liver cancer, the C60-serPF conjugate is detected in most tissues, permeating through the altered vasculature of the tumor and the tightly-regulated blood brain barrier while evading the reticulo-endothelial system. These findings suggest C60-ser can serve as a potential delivery vehicle for therapeutic agents with intranuclear activity (DNA plasmids, drugs such as paclitaxel, gemcitabine, camptothecin, cisplatin, siRNA, transcription factors, epigenetic agents, etc.) to treat cancer. Targeted delivery of these vehicles can be achieved by their binding with tumor-specific antibodies, due to the known affinity of water-soluble fullerenes for antibodies to form immunoconjugates.

In this study, we have investigated the interactions of variable frequency EFs (10 HZ – 250 MHz) with various C60 derivatives (Figure 1) as a means of enhancing the efficacy of EFCT. We report on the enhanced toxicity of C60-Gemcitabine/Paclitaxel/Camptothecin conjugates, when used in conjunction with EFCT, as well as the intracellular distribution of fluorescently tagged (PF-633) C60-ser, as a function of EF exposure.


1.         Barbault, A.; Costa, F. P.; Bottger, B.; Munden, R. F.; Bomholt, F.; Kuster, N.; Pasche, B. Journal of experimental & clinical cancer research : CR 2009, 28, 51.

2.         Costa, F. P.; de Oliveira, A. C.; Meirelles, R.; Machado, M. C. C.; Zanesco, T.; Surjan, R.; Chammas, M. C.; de Souza Rocha, M.; Morgan, D.; Cantor, A.; Zimmerman, J.; Brezovich, I.; Kuster, N.; Barbault, A.; Pasche, B. British journal of cancer 2011, 105, (5), 640-8.

3.         Kirson, E.; Giladi, M.; Gurvich, Z.; Itzhaki, A.; Mordechovich, D.; Schneiderman, R.; Wasserman, Y.; Ryffel, B.; Goldsher, D.; Palti, Y. Clin Exp Metastasis 2009, 26, (7), 633-640.

4.         Kirson, E. D.; Dbaly, V.; Tovarys, F.; Vymazal, J.; Soustiel, J. F.; Itzhaki, A.; Mordechovich, D.; Steinberg-Shapira, S.; Gurvich, Z.; Schneiderman, R.; Wasserman, Y.; Salzberg, M.; Ryffel, B.; Goldsher, D.; Dekel, E.; Palti, Y. Proceedings of the National Academy of Sciences of the United States of America 2007, 104, (24), 10152-7.

5.         Kirson, E. D.; Gurvich, Z.; Schneiderman, R.; Dekel, E.; Itzhaki, A.; Wasserman, Y.; Schatzberger, R.; Palti, Y. Cancer research 2004, 64, (9), 3288-95.

6.         Zimmerman, J. W.; Pennison, M. J.; Brezovich, I.; Yi, N.; Yang, C. T.; Ramaker, R.; Absher, D.; Myers, R. M.; Kuster, N.; Costa, F. P.; Barbault, A.; Pasche, B. British journal of cancer 2012, 106, (2), 307-13.

7.         Sitharaman, B.; Zakharian, T. Y.; Saraf, A.; Misra, P.; Ashcroft, J.; Pan, S.; Pham, Q. P.; Mikos, A. G.; Wilson, L. J.; Engler, D. A. Molecular Pharmaceutics 2008, 5, (4), 567-578.

8.         Ashcroft, J. M.; Tsyboulski, D. A.; Hartman, K. B.; Zakharian, T. Y.; Marks, J. W.; Weisman, R. B.; Rosenblum, M. G.; Wilson, L. J. Chemical Communications 2006, (28), 3004-3006.

9.         Raoof, M.; Mackeyev, Y.; Cheney, M. A.; Wilson, L. J.; Curley, S. A. Biomaterials 2012, 33, (10), 2952-2960.