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Contrast-Enhanced MRI-Guided Photodynamic Cancer Therapy with a Pegylated Bifunctional Polymer Conjugate

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Abstract

Purpose

To study contrast-enhanced MRI guided photodynamic therapy with a pegylated bifunctional polymer conjugate containing an MRI contrast agent and a photosensitizer for minimally invasive image-guided cancer treatment.

Methods

Pegylated and non-pegylated poly-(l-glutamic acid) conjugates containing mesochlorin e6, a photosensitizer, and Gd(III)-DO3A, an MRI contrast agent, were synthesized. The effect of pegylation on the biodistribution and tumor targeting was non-invasively visualized in mice bearing MDA-MB-231 tumor xenografts with MRI. MRI-guided photodynamic therapy was carried out in the tumor bearing mice. Tumor response to photodynamic therapy was evaluated by dynamic contrast enhanced MRI and histological analysis.

Results

The pegylated conjugate had longer blood circulation, lower liver uptake and higher tumor accumulation than the non-pegylated conjugate as shown by MRI. Site-directed laser irradiation of tumors resulted in higher therapeutic efficacy for the pegylated conjugate than the non-pegylated conjugate. Moreover, animals treated with photodynamic therapy showed reduced vascular permeability on DCE-MRI and decreased microvessel density in histological analysis.

Conclusions

Pegylation of the polymer bifunctional conjugates reduced non-specific liver uptake and increased tumor uptake, resulting in significant tumor contrast enhancement and high therapeutic efficacy. The pegylated poly(l-glutamic acid) bifunctional conjugate is promising for contrast enhanced MRI guided photodynamic therapy in cancer treatment.

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References

  1. V. F. Dima, M. D. Ionescu, C. Balotescu, and S. F. Dima. Photodynamic therapy and come clinical applications in oncology. Rom. Arch. Microbiol. Immunol. 61:159–205 (2002).

    CAS  Google Scholar 

  2. T. J. Dougherty, C. J. Gomer, B. W. Henderson, G. Jori, D. Kessel, M. Korbelik, J. Moan, and Q. Peng. Photodynamic therapy. J. Natl. Cancer Inst. 90:889–905 (1998).

    Article  PubMed  CAS  Google Scholar 

  3. K. R. Weishaupt, C. J. Gomer, and T. J. Dougherty. Identification of singlet oxygen as the cytotoxic agent in photoactivation of murine tumors. Cancer Res. 36:2326–2329 (1976).

    PubMed  CAS  Google Scholar 

  4. R. R. Allison, G. H. Downie, R. Cuenca, X. H. Hu, J. H. C. Childs, and C. H. Sibata. Photosensitizers in clinical PDT. Photodiagn. Photodynam. Ther. 1:27–42 (2004).

    Google Scholar 

  5. J. Shiah, Y.-E. Sun, C. M. Peterson, R. C. Straight, and J. Kopecek. Antitumor activity of N-(2-hydroxypropyl) methacrylamide copolymer-mesochlorin e6 and adriamycin conjugates in combination treatments. Clin. Cancer Res. 6:1008–1015 (2000).

    PubMed  CAS  Google Scholar 

  6. F. N. Jiang, D. J. Liu, H. Neyndorff, M. Chester, S. Y. Jiang, and J. G. Levy. Photodynamic killing of human squamous cell carcinoma cells using a monoclonal antibody-photosensitizer conjugate. J. Natl. Cancer Inst. 83:1218–1225 (1991).

    Article  PubMed  CAS  Google Scholar 

  7. C. F. van Nostrum. Polymeric micelles to deliver photosensitizers for photodynamic therapy. Adv. Drug Del. Rev. 56:9–16 (2004).

    Article  CAS  Google Scholar 

  8. A. S. L. Derycke, and P. A. M. de Witte. Liposomes for photodynamic therapy. Adv. Drug Del. Rev. 56:17–30 (2004).

    Article  CAS  Google Scholar 

  9. H. Maeda, J. Wu, T. Sawa, Y. Matsumura, and K. Hori. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control Rel. 65:271–284 (2000).

    Article  CAS  Google Scholar 

  10. M. B. Vrouenraets, G. W. M. Visser, G. B. Snow, and G. A. M. S. van Dongen. Basic principles, applications in oncology and improved selectivity of photodynamic therapy. Anticancer Res. 23:505–522 (2003).

    PubMed  CAS  Google Scholar 

  11. E. van Leengoed, J. Versteeg, N. van der Veen, A. van den Berg-Blok, H. Marijnissen, and W. Star. Tissue-localizing properties of some photosensitizers studied by in vivo fluorescence imaging. J. Photochem. Photobiol. B. 6:111–119 (1990).

    Article  PubMed  Google Scholar 

  12. S. K. Pandey, A. L. Gryshuk, M. Sajjad, X. Zheng, Y. Chen, M. M. Abouzeid, J. Morgan, I. Charamisinau, H. A. Nabi, A. Oseroff, and R. K. Pandey. Multimodality agents for tumor imaging (PET, fluorescence) and photodynamic therapy. A possible “see and treat” approach. J. Med. Chem. 48:6286–6295 (2005).

    Article  PubMed  CAS  Google Scholar 

  13. K. Stefflova, J. Chen, and G. Zheng. Killer beacons for combined cancer imaging and therapy. Curr. Med. Chem. 14:2110–2125 (2007).

    Article  PubMed  CAS  Google Scholar 

  14. G. Li, A. Slansky, M. P. Dobhal, L. N. Goswami, A. Graham, Y. Chen, P. Kanter, R. A. Alberico, J. Spernyak, J. Morgan, R. Mazurchuk, A. Oseroff, Z. Grossman, and R. K. Pandey. Chlorophyll-a analogues conjugated with aminobenzyl-DTPA as potential bifunctional ligands for magnetic resonance imaging and photodynamic therapy. Bioconjug. Chem. 16:32–42 (2005).

    Article  PubMed  CAS  Google Scholar 

  15. R. Kopelman, L. Y. Koo, M. Philbert, B. A. Moffat, G. R. Reddy, G. McConville, P. Hall, D. E. Chenevert, T. L. Bhojani, and S. M. Buck. Multifunctional nanoparticles platforms for in vivo MRI enhancement and photodynamic therapy of a rat brain cancer. J. Magn. Mater. 293:404–410 (2005).

    Article  CAS  Google Scholar 

  16. S. Gross, A. Gilead, A. Scherz, M. Neeman, and Y. Solomon. Monitoring photodynamic therapy of solid tumors online by BOLD-contrast MRI. Nat. Med. 9:1327–1331 (2003).

    Article  PubMed  CAS  Google Scholar 

  17. A. Vaidya, Y. Sun, T. Ke, E. K. Jeong, and Z. R. Lu. Contrast enhanced MRI-guided photodynamic therapy for site-specific cancer treatment. Magn. Reson. Med. 56:761–767 (2006).

    Article  PubMed  CAS  Google Scholar 

  18. T. Lammers, R. Kuhnlein, M. Kissel, V. Subr, T. Etrych, R. Pola, M. Pechar, K. Ulbrich, G. Storm, P. Huber, and P. Peschke. Effect of physicochemical modification on the biodistribution and tumor accumulation of HPMA copolymers. J. Control Rel. 110:103–118 (2005).

    Article  CAS  Google Scholar 

  19. P. Bailon, A. Palleroni, C. A. Schaffer, C. L. Spence, W. J. Fung, J. E. Porter, G. K. Ehrlich, W. Pan, Z. X. Xu, M. W. Modi, A. Farid, W. Berthold, and M. Graves. Rational design of a potent, long lasting form of interferon: a 40kDa branched poly-ethylene glycol-conjugated interferon alpha-2a for the treatment of hepatitis C. Bioconjug. Chem. 12:195–202 (2001).

    Article  PubMed  CAS  Google Scholar 

  20. A. N. Lukyanov, R. M. Sawant, W. C. Hartner, and V. P. Torchilin. PEGylated dextran as long-circulating pharmaceutical carrier. J. Biomater. Sci. Polym. Ed. 15:621–630 (2004).

    Article  PubMed  CAS  Google Scholar 

  21. F. M. Veronese, O. Schiavon, G. Pasult, R. Mendichi, L. Andersson, A. Tsirk, J. Ford, G. Wu, S. Kneller, J. Davies, and R. Duncan. PEG-doxorubicin conjugates: influence of polymer structure on drug release, in vitro cytotoxicity, biodistribution, and antitumor activity. Bioconjug. Chem. 16:775–784 (2005).

    Article  PubMed  CAS  Google Scholar 

  22. D. E. Owens III, and N. A. Peppas. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 307:93–102 (2006).

    Article  PubMed  CAS  Google Scholar 

  23. A. Beeby, L. M. Bushby, D. Maffeo, and J. A. G. Williams. Intramolecular sensitization of lanthanide(III) luminescence by acetophenone-containing ligands: the critical effect of para-substituents and solvent. J. Chem. Soc, Dalton Trans. 1:48–52 (2002).

    Article  CAS  Google Scholar 

  24. Z. P. Liang, and P. C. Lauterbur. Principles of Magnetic Resonance Imaging. IEEE, New York, NY, 1999.

    Google Scholar 

  25. Y. Feng, Y. Zong, T. Ke, E. K. Jeong, D. L. Parker, and Z. R. Lu. Pharmacokinetics, biodistribution and contrast enhanced MR blood pool imaging of Gd-DTPA cystine copolymers and Gd-DTPA cystine diethyl ester copolymers in rat model. Pharm. Res. 23:1736–1742 (2006).

    Article  PubMed  CAS  Google Scholar 

  26. D. M. Shames, R. Kuwatsuru, V. Vexler, A. Muhler, and R. C. Brasch. Measurement of capillary permeability to macromolecules by dynamic magnetic resonance imaging: a quantitative noninvasive technique. Magn. Resn. Med. 29:616–622 (1993).

    Article  CAS  Google Scholar 

  27. L. L. Emerson, S. R. Tripp, B. C. Baird, L. J. Layfield, and L. R. Rohr. A comparison of immunohistochemical stain quality in conventional and rapid microwave processed tissues. Am. J. Clin. Pathol. 125:176–183 (2006).

    PubMed  Google Scholar 

  28. J. M. Harris, N. E. Martin, and M. Modi. PEGylation: A novel process for modifying pharmacokinetics. Clin Pharmacokinet. 7:539–551 (2001).

    Google Scholar 

  29. M. R. Hamblin, J. L. Miller, I. Rizvi, B. Ortel, E. V. Maytin, and T. Hassan. Pegylation of a chlorin e6 polymer conjugates increases tumor targeting of photosensitizer. Cancer Res. 61:7155–7162 (2001).

    PubMed  CAS  Google Scholar 

  30. M. R. Hamblin, J. L. Miller, I. Rizvi, H. G. Loew, and T. Hasan. Pegylation of charged polymer-photosensitizer conjugates: effects on photodynamic efficacy. Br J Cancer. 89:937–943 (2003).

    Article  PubMed  CAS  Google Scholar 

  31. F. Ye, T. Ke, E. K. Jeong, X. Wang, Y. Sun, M. Johnson, and Z.-R. Lu. Noninvasive visualization of in vivo drug delivery of poly(L-glutamic acid) using contrast-enhanced MRI. Mol. Pharm. 3:507–15 (2006).

    Article  PubMed  CAS  Google Scholar 

  32. J. Zheng, J. Liu, M. Dunne, D. A. Jaffray, and C. Allen. In vivo performance of a liposomal vascular contrast agent for CT and MR-based image guidance applications. Pharm. Res. 24:1193–1201 (2007).

    Article  PubMed  CAS  Google Scholar 

  33. Y. Wang, F. Ye, E. K. Jeong, Y. Sun, D. L. Parker, and Z.-R. Lu. Noninvasive visualization of pharmacokinetics, biodistribution and tumor targeting of poly[N-(2-hydroxypropyl)methacrylamide] in mice using contrast enhanced MRI. Pharm. Res. 24:1208–16 (2007).

    Article  PubMed  CAS  Google Scholar 

  34. M. T. Peracchia, C. Vauthier, C. Passirani, P. Couvreur, and D. Labarre. Complement consumption by poly(ethylene glycol) in different conformations chemically coupled to poly(isobutyl 2-cyanoacrylate) nanoparticles. Life Sci. 61:749–761 (1997).

    Article  PubMed  CAS  Google Scholar 

  35. M. Triesscheijn, M. Ruevekamp, M. Aalders, P. Bass, and F. A. Stewart. Outcome of mTHPC mediated photodynamic therapy is primarily determined by the vascular response. Photochem. Photobiol. 81:1161–1167 (2005).

    Article  PubMed  CAS  Google Scholar 

  36. R. Brasch, and K. Turetschek. MRI characterization of tumors and grading angiogenesis using macromolecular contrast media: a status report. Eur J Radiol. 34:148–155 (2000).

    Article  PubMed  CAS  Google Scholar 

  37. R. M. Stephen, and R. J. Gillies. Promise and progress for functional and molecular imaging of response to targeted therapies. Pharm. Res. 24:1172–1185 (2007).

    Article  PubMed  CAS  Google Scholar 

  38. H. Dvorak, J. Nagy, J. Dvorak, and A. Dvorak. Identification and characterization of the blood vessels of solid tumor that are leaky to circulating macromolecules. Am. J. Pathol. 133:95–109 (1988).

    PubMed  CAS  Google Scholar 

  39. Y. Zong, X. Wang, K. C. Goodrich, A. M. Mohs, D. L. Parker, and Z. R. Lu. Contrast-enhanced MRI with new biodegradable macromolecular Gd (III) complexes in tumor bearing mice. Magn Reson Med. 53:835–842 (2005).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This research was supported in part by NIH grant R01 CA097465. We thank Melody Johnson of CAMT, University of Utah, Salt Lake City, Utah and Sheryl Tripp of ARUP Laboratories, Salt Lake City, Utah for their technical assistance.

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Authors and Affiliations

  1. Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, 84112, USA

    Anagha Vaidya, Yongen Sun, Yi Feng & Zheng-Rong Lu

  2. Department of Pathology, University of Utah, Salt Lake City, Utah, 84112, USA

    Lyska Emerson

  3. Department of Radiology, University of Utah, Salt Lake City, Utah, 84112, USA

    Eun-Kee Jeong

  4. 421 Wakara Way, Suite 318, Salt Lake City, Utah, 84108, USA

    Zheng-Rong Lu

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  1. Anagha Vaidya
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  5. Eun-Kee Jeong
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Correspondence to Zheng-Rong Lu.

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Vaidya, A., Sun, Y., Feng, Y. et al. Contrast-Enhanced MRI-Guided Photodynamic Cancer Therapy with a Pegylated Bifunctional Polymer Conjugate. Pharm Res 25, 2002–2011 (2008). https://doi.org/10.1007/s11095-008-9608-1

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  • DOI: https://doi.org/10.1007/s11095-008-9608-1

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