Skip to main content

Advertisement

SpringerLink
Log in

Intravital Microscopic Analysis of Vascular Perfusion and Macromolecule Extravasation after Photodynamic Vascular Targeting Therapy

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Photodynamic therapy (PDT), involving the combination of a photosensitizer and light, is being evaluated as a vascular disrupting therapy and drug delivery enhancement modality based on its effects on vascular perfusion and barrier function. Since tumor vasculature is the common route for the delivery of both blood and therapeutic agents, it is important to compare the effects of PDT on blood perfusion and substance transport.

Materials and Methods

Tumor blood cell velocity and the extravasation of high molecular weight dextran molecules were continuously monitored by intravital fluorescence microscopy for up to 60 min after PDT using three doses of verteporfin in the MatLyLu prostate tumor model.

Results

PDT induced tumor perfusion disruption via thrombus formation. PDT using a higher dose of verteporfin was more effective in inhibiting blood perfusion while a lower dose verteporfin-PDT was more potent in enhancing dextran extravasation. The increase in dextran extravasation induced by PDT was dependent upon dextran molecular weight. A lower molecular weight dextran obtained a higher tumor accumulation after PDT than a higher molecular weight dextran.

Conclusions

PDT with verteporfin had different effects on tumor vascular perfusion versus the extravasation of macromolecules. Optimal PDT conditions should be adjusted based on the therapeutic application.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. C. Bouzin and O. Feron. Targeting tumor stroma and exploiting mature tumor vasculature to improve anti-cancer drug delivery. Drug Resist. Updat. 10:109–20 (2007).

    Article  PubMed  CAS  Google Scholar 

  2. D. W. Siemann, M. C. Bibby, G. G. Dark, A. P. Dicker, F. A. Eskens, M. R. Horsman, D. Marme, and P. M. Lorusso. Differentiation and definition of vascular-targeted therapies. Clin. Cancer Res. 11:416–20 (2005).

    PubMed  CAS  Google Scholar 

  3. F. Yuan. Transvascular drug delivery in solid tumors. Semin. Radiat. Oncol. 8:164–75 (1998).

    Article  PubMed  CAS  Google Scholar 

  4. G. P. van Nieuw Amerongen and V. W. van Hinsbergh. Targets for pharmacological intervention of endothelial hyperpermeability and barrier function. Vasc. Pharmacol. 39:257–72 (2002).

    Article  CAS  Google Scholar 

  5. 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 

  6. D. E. Dolmans, D. Fukumura, and R. K. Jain. Photodynamic therapy for cancer. Nat. Rev. Cancer. 3:380–7 (2003).

    Article  PubMed  CAS  Google Scholar 

  7. B. Chen, B. W. Pogue, P. J. Hoopes, and T. Hasan. Vascular and cellular targeting for photodynamic therapy. Crit. Rev. Eukaryot Gene Expr. 16:279–305 (2006).

    PubMed  Google Scholar 

  8. J. W. Snyder, W. R. Greco, D. A. Bellnier, L. Vaughan, and B. W. Henderson. Photodynamic therapy: a means to enhanced drug delivery to tumors. Cancer Res. 63:8126–31 (2003).

    PubMed  CAS  Google Scholar 

  9. B. Chen, B. W. Pogue, J. M. Luna, R. L. Hardman, P. J. Hoopes, and T. Hasan. Tumor vascular permeabilization by vascular-targeting photosensitization: effects, mechanism, and therapeutic implications. Clin. Cancer Res. 12:917–23 (2006).

    Article  PubMed  CAS  Google Scholar 

  10. R. K. Jain, L. L. Munn, and D. Fukumura. Dissecting tumour pathophysiology using intravital microscopy. Nat. Rev. Cancer 2:266–76 (2002).

    Article  PubMed  CAS  Google Scholar 

  11. T. R. Tennant, H. Kim, M. Sokoloff, and C. W. Rinker-Schaeffer. The Dunning model. Prostate 43:295–302 (2000).

    Article  PubMed  CAS  Google Scholar 

  12. B. Chen, B. W. Pogue, X. Zhou, J. A. O’Hara, N. Solban, E. Demidenko, P. J. Hoopes, and T. Hasan. Effect of tumor host microenvironment on photodynamic therapy in a rat prostate tumor model. Clin. Cancer Res. 11:720–7 (2005).

    PubMed  CAS  Google Scholar 

  13. B. Chen, B. W. Pogue, P. J. Hoopes, and T. Hasan. Combining vascular and cellular targeting regimens enhances the efficacy of photodynamic therapy. Int. J. Radiat. Oncol. Biol. Phys. 61:1216–26 (2005).

    PubMed  CAS  Google Scholar 

  14. U. Schmidt-Erfurth and T. Hasan. Mechanisms of action of photodynamic therapy with verteporfin for the treatment of age-related macular degeneration. Surv. Ophthalmol. 45:195–214 (2000).

    Article  PubMed  CAS  Google Scholar 

  15. V. H. Fingar, P. K. Kik, P. S. Haydon, P. B. Cerrito, M. Tseng, E. Abang, and T. J. Wieman. Analysis of acute vascular damage after photodynamic therapy using benzoporphyrin derivative (BPD). Br. J. Cancer. 79:1702–8 (1999).

    Article  PubMed  CAS  Google Scholar 

  16. V. H. Fingar, T. J. Wieman, S. A. Wiehle, and P. B. Cerrito. The role of microvascular damage in photodynamic therapy: the effect of treatment on vessel constriction, permeability, and leukocyte adhesion. Cancer Res. 52:4914–21 (1992).

    PubMed  CAS  Google Scholar 

  17. V. H. Fingar. Vascular effects of photodynamic therapy. J. Clin. Laser Med. Surg. 14:323–8 (1996).

    PubMed  CAS  Google Scholar 

  18. B. Krammer. Vascular effects of photodynamic therapy. Anticancer Res. 21:4271–7 (2001).

    PubMed  CAS  Google Scholar 

  19. W. J. de Vree, M. C. Essers, H. S. de Bruijn, W. M. Star, J. F. Koster, and W. Sluiter. Evidence for an important role of neutrophils in the efficacy of photodynamic therapy in vivo. Cancer Res. 56:2908–11 (1996).

    PubMed  Google Scholar 

  20. W. J. de Vree, A. N. Fontijne-Dorsman, J. F. Koster, and W. Sluiter. Photodynamic treatment of human endothelial cells promotes the adherence of neutrophils in vitro. Br. J. Cancer. 73:1335–40 (1996).

    PubMed  Google Scholar 

  21. T. M. Busch. Local physiological changes during photodynamic therapy. Lasers Surg. Med. 38:494–9 (2006).

    Article  PubMed  Google Scholar 

  22. B. W. Pogue, R. D. Braun, J. L. Lanzen, C. Erickson, and M. W. Dewhirst. Analysis of the heterogeneity of pO2 dynamics during photodynamic therapy with verteporfin. Photochem. Photobiol. 74:700–6 (2001).

    Article  PubMed  CAS  Google Scholar 

  23. D. Fukumura and R. K. Jain. Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J. Cell Biochem. 101:937–49 (2007).

    Article  PubMed  CAS  Google Scholar 

  24. F. Borle, A. Radu, C. Fontolliet, H. van den Bergh, P. Monnier, and G. Wagnieres. Selectivity of the photosensitiser Tookad for photodynamic therapy evaluated in the Syrian golden hamster cheek pouch tumour model. Br. J. Cancer. 89:2320–6 (2003).

    Article  PubMed  CAS  Google Scholar 

  25. G. Bazzoni. Endothelial tight junctions: permeable barriers of the vessel wall. Thromb Haemost. 95:36–42 (2006).

    PubMed  CAS  Google Scholar 

  26. M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J. Natl. Cancer Inst. 98:335–44 (2006).

    Article  PubMed  CAS  Google Scholar 

  27. A. Pluen, Y. Boucher, S. Ramanujan, T. D. McKee, T. Gohongi, E. di Tomaso, E. B. Brown, Y. Izumi, R. B. Campbell, D. A. Berk, and R. K. Jain. Role of tumor–host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proc. Natl. Acad. Sci. U S A. 98:4628–33 (2001).

    Article  PubMed  CAS  Google Scholar 

  28. E. Debefve, B. Pegaz, J. P. Ballini, Y. N. Konan, and H. van den Bergh. Combination therapy using aspirin-enhanced photodynamic selective drug delivery. Vasc. Pharmacol. 46:171–80 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work is supported by Department of Defense (DOD) Grant W81XWH-06-1-0148 and Lindback Foundation. The authors would like to gratefully acknowledge Dr. Brian Pogue for reading the manuscript and QLT Inc. for providing photosensitizer verteporfin.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, Pennsylvania, 19104, USA

    Chong He, Priyanka Agharkar & Bin Chen

  2. Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Bin Chen

Authors
  1. Chong He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Priyanka Agharkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bin Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

He, C., Agharkar, P. & Chen, B. Intravital Microscopic Analysis of Vascular Perfusion and Macromolecule Extravasation after Photodynamic Vascular Targeting Therapy. Pharm Res 25, 1873–1880 (2008). https://doi.org/10.1007/s11095-008-9604-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-008-9604-5

KEY WORDS

Search

Navigation