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Radiation-Guided Targeting of Combretastatin Encapsulated Immunoliposomes to Mammary Tumors

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Abstract

Purpose

Radiation upregulates expression of endothelial cell adhesion molecules providing a potential avenue for targeting drugs to irradiated tissue. Induced upregulation of E-selectin can be used to target immunoliposomes to solid tumors. The effects of targeting immunoliposomes containing the antivascular drug combretastatin disodium phosphate (CA4P) to irradiated mammary tumors were investigated in this study.

Methods

Mice bearing transplanted MCa-4 mouse mammary tumors were assigned to one of the factorial treatments permuting the administration of free CA4P, tumor irradiation, CA4P encapsulated liposomes, and CA4P encapsulated immunoliposomes (conjugated with anti-E-selectin). Single and fractionated dosing of radiation and/or CA4P was evaluated.

Results

For single dose treatments the group that received a single dose of radiation plus a single dose of immunoliposomes showed a significant delay in tumor growth compared to all other treatment groups. Fractionated radiation plus fractionated doses of immunoliposomes resulted in further tumor growth delay; however, it was not significantly different from other fractionated dose treatment groups that combined radiation and CA4P.

Conclusions

Targeting of antivascular drugs to irradiated tumors via ligand-bearing liposomes results in significant tumor growth delay. This effect can be further potentiated using a fractionated irradiation dosing schedule combined with fractionated immunoliposome treatments.

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References

  1. P. E. Thorpe. Vascular targeting agents as cancer therapeutics. Clin. Cancer Res. 10:415–427 (2004). doi:10.1158/1078-0432.CCR-0642-03.

    Article  PubMed  Google Scholar 

  2. R. Murata, J. Overgaard, and M. R. Horsman. Comparative effects of combretastatin A-4 disodium phosphate and 5,6-dimethylxanthenone-4-acetic acid on blood perfusion in a murine tumour and normal tissues. Int. J. Radiat. Biol. 77:195–204 (2001). doi:10.1080/09553000010007695.

    Article  PubMed  CAS  Google Scholar 

  3. D. J. Chaplin, G. R. Pettit, and S. A. Hill. Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate. Anticancer Res. 19:189–195 (1999).

    PubMed  CAS  Google Scholar 

  4. K. Grosios, S. E. Holwell, A. T. McGown, G. R. Pettit, and M. C. Bibby. In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug. Br. J. Cancer. 81:1318–1327 (1999). doi:10.1038/sj.bjc.6692174.

    Article  PubMed  CAS  Google Scholar 

  5. A. Gabizon, H. Shmeeda, and Y. Barenholz. Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies. Clin. Pharmacokinet. 42:419–436 (2003). doi:10.2165/00003088-200342050-00002.

    Article  PubMed  CAS  Google Scholar 

  6. R. M. Schiffelers, G. A. Koning, T. L. ten Hagen, M. H. Fens, A. J. Schraa, A. P. Janssen, R. J. Kok, G. Molema, and G. Storm. Anti-tumor efficacy of tumor vasculature-targeted liposomal doxorubicin. J. Control. Release. 91:115–122 (2003). doi:10.1016/S0168-3659(03)00240-2.

    Article  PubMed  CAS  Google Scholar 

  7. W. Landuyt, B. Ahmed, S. Nuyts, J. Theys, M. O. P. de Beeck, A. Rijnders, J. Anne, A. van Oosterom, B. W. van den, and P. Lambin. In vivo antitumor effect of vascular targeting combined with either ionizing radiation or anti-angiogenesis treatment. Int. J. Radiat. Oncol. Biol. Phys. 49:443–450 (2001). doi:10.1016/S0360-3016(00)01470-X.

    Article  PubMed  CAS  Google Scholar 

  8. W. R. Wilson, A. E. Li, D. S. M. Cowan, and B. G. Siim. Enhancement of tumor radiation response by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid. Int. J. Radiat. Oncol. Biol. Phys. 42:905–908 (1998). doi:10.1016/S0360-3016(98)00358-7.

    PubMed  CAS  Google Scholar 

  9. M. F. Kiani, H. Yuan, X. Chen, L. Smith, M. W. Gaber, and D. J. Goetz. Targeting microparticles to select tissue via radiation-induced upregulation of endothelial cell adhesion molecules. Pharm. Res. 19:1317–1322 (2002). doi:10.1023/A:1020350708672.

    Article  PubMed  CAS  Google Scholar 

  10. C. B. Pattillo, F. Sari-Sarraf, R. Nallamothu, B. M. Moore, G. C. Wood, and M. F. Kiani. Targeting of the antivascular drug combretastatin to irradiated tumors results in tumor growth delay. Pharm. Res. 22:1117–1120 (2005). doi:10.1007/s11095-005-5646-0.

    Article  PubMed  CAS  Google Scholar 

  11. D. R. Stacy, B. Lu, and D. E. Hallahan. Radiation-guided drug delivery systems. Expert Rev. Anticancer Ther. 4:283–288 (2004). doi:10.1586/14737140.4.2.283.

    Article  PubMed  CAS  Google Scholar 

  12. H. Yuan, D. J. Goetz, M. W. Gaber, A. C. Issekutz, T. E. Merchant, and M. F. Kiani. Radiation-induced up-regulation of adhesion molecules in brain microvasculature and their modulation by dexamethasone. Radiat. Res. 163:544–551 (2005). doi:10.1667/RR3361.

    Article  PubMed  CAS  Google Scholar 

  13. G. R. Pettit, S. B. Singh, M. R. Boyd, E. Hamel, R. K. Pettit, J. M. Schmidt, and F. Hogan. Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6(1a). J. Med. Chem. 38:1666–1672 (1995). doi:10.1021/jm00010a011.

    Article  PubMed  CAS  Google Scholar 

  14. H. Leontiadou, A. E. Mark, and S. J. Marrink. Molecular dynamics simulations of hydrophilic pores in lipid bilayers. Biophys. J. 86:2156–2164 (2004).

    Article  PubMed  CAS  Google Scholar 

  15. G. R. Bartlett. Phosphorus assay in column chromatography. J. Biol. Chem. 234:466–468 (1959).

    PubMed  CAS  Google Scholar 

  16. C. B. Pattillo. Liposomal targeting of the antivascular drug combretastatin to irradiated tumors. Ph. D. Dissertation, Temple University 2007.

  17. B. M. Fenton, S. F. Paoni, J. Lee, C. J. Koch, and E. M. Lord. Quantification of tumour vasculature and hypoxia by immunohistochemical staining and HbO2 saturation measurements. Br. J. Cancer. 79:464–471 (1999). doi:10.1038/sj.bjc.6690072.

    Article  PubMed  CAS  Google Scholar 

  18. S. L. Young, and D. J. Chaplin. Combretastatin A4 phosphate: background and current clinical status. Expert Opin. Investig. Drugs. 13:1171–1182 (2004). doi:10.1517/13543784.13.9.1171.

    Article  PubMed  CAS  Google Scholar 

  19. J. H. Bilenker, K. T. Flaherty, M. Rosen, L. Davis, M. Gallagher, J. P. Stevenson, W. Sun, D. Vaughn, B. Giantonio, R. Zimmer, M. Schnall, and P. J. O'Dwyer. Phase I trial of combretastatin a-4 phosphate with carboplatin. Clin. Cancer Res. 11:1527–1533 (2005). doi:10.1158/1078-0432.CCR-04-1434.

    Article  PubMed  CAS  Google Scholar 

  20. J. P. Stevenson, M. Rosen, W. Sun, M. Gallagher, D. G. Haller, D. Vaughn, B. Giantonio, R. Zimmer, W. P. Petros, M. Stratford, D. Chaplin, S. L. Young, M. Schnall, and P. J. O'Dwyer. Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow. J. Clin. Oncol. 21:4428–4438 (2003). doi:10.1200/JCO.2003.12.986.

    Article  PubMed  CAS  Google Scholar 

  21. G. J. Rustin, S. M. Galbraith, H. Anderson, M. Stratford, L. K. Folkes, L. Sena, L. Gumbrell, and P. M. Price. Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results. J. Clin. Oncol. 21:2815–2822 (2003). doi:10.1200/JCO.2003.05.185.

    Article  PubMed  CAS  Google Scholar 

  22. A. Dowlati, K. Robertson, M. Cooney, W. P. Petros, M. Stratford, J. Jesberger, N. Rafie, B. Overmoyer, V. Makkar, B. Stambler, A. Taylor, J. Waas, J. S. Lewin, K. R. McCrae, and S. C. Remick. A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer. Cancer Res. 62:3408–3416 (2002).

    PubMed  CAS  Google Scholar 

  23. R. Nallamothu, G. C. Wood, C. B. Pattillo, R. C. Scott, M. F. Kiani, B. M. Moore, and L. A. Thoma. A tumor vasculature targeted liposome delivery system for combretastatin A4: design, characterization, and in vitro evaluation. AAPS PharmSciTech. 7:E32 (2006). doi:10.1208/pt070232.

    Article  PubMed  Google Scholar 

  24. J. M. Brown. Tumor hypoxia in cancer therapy. Methods Enzymol. 435:297–321 (2007).

    PubMed  CAS  Google Scholar 

  25. R. Nallamothu, G. C. Wood, M. F. Kiani, B. M. Moore, F. P. Horton, and L. A. Thoma. A targeted liposome delivery system for combretastatin A4: formulation optimization through drug loading and in vitro release studies. PDA J. Pharm. Sci. Technol. 60:144–155 (2006).

    PubMed  CAS  Google Scholar 

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Acknowledgements

Fred J. Donelson is a Pre-Doctoral Fellow of the American Heart Association, Great Rivers Affiliate. This work was supported by grants from the Susan G. Komen for the Cure, the DOD Breast Cancer Research Program, and the Pennsylvania Department of Health.

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Authors and Affiliations

  1. Department of Mechanical Engineering, Temple University, 1947 N. 12th St., Philadelphia, Pennsylvania, 19122, USA

    Christopher B. Pattillo, Fred J. Donelson & Mohammad F. Kiani

  2. Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

    Berenice Venegas & Parkson L.-G. Chong

  3. Department of Neuroscience, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

    Luis Del Valle

  4. Department of Radiology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

    Linda C. Knight

  5. Department of Radiation Oncology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

    Mohammad F. Kiani

Authors
  1. Christopher B. Pattillo
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  2. Berenice Venegas
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  3. Fred J. Donelson
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  4. Luis Del Valle
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  5. Linda C. Knight
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  6. Parkson L.-G. Chong
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  7. Mohammad F. Kiani
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Correspondence to Mohammad F. Kiani.

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CBP and BV made equal contribution to this work.

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Pattillo, C.B., Venegas, B., Donelson, F.J. et al. Radiation-Guided Targeting of Combretastatin Encapsulated Immunoliposomes to Mammary Tumors. Pharm Res 26, 1093–1100 (2009). https://doi.org/10.1007/s11095-009-9826-1

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  • DOI: https://doi.org/10.1007/s11095-009-9826-1

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