Image-Guided Photodynamic Cancer Therapy

  • Zheng Rong Lu
  • Anagha Vaidya

Photodynamic therapy is a therapeutic modality with a long history. It has been historically known in ancient India and China for the treatment of skin disorders. In Western medicine, the first experimental evidence of photodynamic therapy was reported by Raab et al. who observed the lethality of acridine dyes to paramecium in the presence of light [1]. The photodynamic effect was further demonstrated by Tappeiner and colleagues who reported killing of basal cell carcinoma using eosin and light illumination [2]. More recently, Dougherty et al. developed a hematoporphyrin derivative, which was shown to kill cancer cells in vitro and mammary tumors in mouse models in vivo [3]. Photodynamic therapy has evolved as an effective therapeutic modality for cancer treatment. In 1995, the FDA approved photodynamic therapy using Photofrin for the treatment of advanced esophageal cancer. Recent developments in biomedical imaging provide new opportunities for photodynamic therapy. Modern imaging technologies can accurately detect and diagnose malignant tumors at an early stage and can effectively assess tumor response to cancer photodynamic therapy. Combining photodynamic therapy with imaging can provide image guidance for accurate laser irradiation of tumor and timely assessment of therapeutic efficacy of photodynamic therapy. Image-guided photodynamic therapy is a new, minimally invasive cancer treatment modality that can further improve the efficacy of photodynamic therapy.


Photodynamic Therapy Magnetic Resonance Imaging Contrast Agent Advanced Esophageal Cancer Polymer Conjugate Hematoporphyrin Derivative 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Raab O et al. Ueber die Wirkung fluoreszierenden Stoffe auf infusorien. Z Biol 1900; 39: 524–526.Google Scholar
  2. 2.
    von Tappeneimer H, Jesionek A. (1903) Therapeutische versuche mit fluorescierenden stoffen. Munch Med Wochenschr 1903; 47: 2042–2047.Google Scholar
  3. 3.
    Dougherty TJ, Gomer CJ, et al. Photodynamic therapy. J Natl Cancer Inst 1998; 90: 889–905.PubMedCrossRefGoogle Scholar
  4. 4.
    Phillips D. Chemical mechanisms in photodynamic therapy. Progr React Kinet 1997; 22: 175–300.Google Scholar
  5. 5.
    Oschner M. Photophysical and photobiological processes in photodynamic therapy of tumors. J Photochem Photobiol B 1997; 39: 1–18.Google Scholar
  6. 6.
    Dougherty TJ, Potter WR, Weishaupt KR. The structure of the active component of hematoporphyrin derivative. Prog Clin Biol Res 1984; 170: 301–314.PubMedGoogle Scholar
  7. 7.
    Busch TM, Hahn SM. Hypoxia and Photofrin uptake in the intraperitoneal carcinomatosis and sarcomatosis of photodynamic therapy patients. Clin Cancer Res 2004; 10: 4630–4638.PubMedCrossRefGoogle Scholar
  8. 8.
    Cramers P, Ruevekamp M, Oppelaar H, Dalesio O, Baas P, Stewart FA. Foscan uptake and tissue distribution in relation to photodynamic efficacy. Br J Cancer 2003; 88: 283–290.PubMedCrossRefGoogle Scholar
  9. 9.
    Hopper C, Kubler A, Lewis H, Tan IB, Putnam G. mTHPC-mediated photodynamic therapy for early oral squamous cell carcinoma. Int J Cancer 2004; 111: 138–146.PubMedCrossRefGoogle Scholar
  10. 10.
    Momma T, Hamblin MR, Wu HC, Hasan T. Photodynamic therapy of orthotopic prostate cancer with benzoporphyrin derivative: local control and distant metastasis. Cancer Res 1998; 58: 5425–5431.PubMedGoogle Scholar
  11. 11.
    Keam SJ, Scott LJ, Curran MP. Verteporfin: a review of its use in the management of subfoveal choroidal neovascularisation. Drugs 2003; 63: 2521–2554.PubMedCrossRefGoogle Scholar
  12. 12.
    Peng Q, Warloe T, Berg K, Moan J, Kongshaug M, Giercksky KE, Nesland JM. 5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges. Cancer 1997; 79: 2282–2308.PubMedCrossRefGoogle Scholar
  13. 13.
    Gupta AK, Ryder JE. Photodynamic therapy and topical aminolevulinic acid: an overview. Am J Clin Dermatol 2003; 4: 699–708.PubMedCrossRefGoogle Scholar
  14. 14.
    Siddiqui MA, Perry CM, Scott LJ. Topical methyl aminolevulinate. Am J Clin Dermatol 2004; 5: 127–137.PubMedCrossRefGoogle Scholar
  15. 15.
    Foster TH, Gao L. Dosimetry in photodynamic therapy: oxygen and the critical importance of capillary density. Radiat Res 1992; 130: 379–383.PubMedCrossRefGoogle Scholar
  16. 16.
    Coutier S, Bezdetnaya LN, Foster TH, Parache RM, Guilleminn F. Effect of irradiation fluence rate on the efficacy of photodynamic therapy and tumor oxygenation in meta-tetra (hydroxyphenyl) chlorin (mTHPC)-sensitized HT29 xenografts in nude mice. Radiat Res 2002; 158: 339–345.PubMedCrossRefGoogle Scholar
  17. 17.
    Muller S, Walt H, Dobler-Girziunaite D, Fiedler D, Haller U. Enhanced photodynamic effects using fractionated laser light. J Photochem Photobiol B. Biol 1998; 42: 67–70.CrossRefGoogle Scholar
  18. 18.
    Sitnik TM, Henderson BW. The effect of fluence rate on tumor and normal tissue responses to photodynamic therapy. Photochem Photobiol 1998; 67: 462–466.PubMedCrossRefGoogle Scholar
  19. 19.
    Kessel D, Reiners Jr JJ. Apoptosis and autophagy after mitochondrial or endoplasmic reticulum photodamage. Photochem Photobiol 2004; 83: 1024.CrossRefGoogle Scholar
  20. 20.
    Chen Y, Gibson SB. Is mitochondrial generation of reactive oxygen species a trigger for autophagy? Autophagy 2008; 4: 246–248.PubMedGoogle Scholar
  21. 21.
    Dellinger M. Apoptosis or necrosis following Photofrin photosensitization: influence of the incubation protocol. Photochem Photobiol 1996; 64: 183–187.CrossRefGoogle Scholar
  22. 22.
    Hampton JA, Selman SH. Mechanisms of cell killing in photodynamic therapy using a novel in vivo drug/in vitro light culture system. Photochem Photobiol 1992; 56: 235–243.PubMedCrossRefGoogle Scholar
  23. 23.
    Mizhushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008; 45: 1069–1075.CrossRefGoogle Scholar
  24. 24.
    Kessel D, Arroyo AS. Apoptotic and autophagic responses to Bcl-2 inhibition and photodamage. Photochem Photobiol 2007; 6: 1290–1295.CrossRefGoogle Scholar
  25. 25.
    Xue LY, Chiu SM, Azizuddin K, Joseph S, Olenick NL. The death of human cancer cells following photodynamic therapy: apoptosis competence is necessary for Bcl-2 protection but not for induction of autophagy. Photochem Photobiol 2007; 83: 1016–1023.PubMedCrossRefGoogle Scholar
  26. 26.
    Fingar VH. Vascular effects of photodynamic therapy. J Clin Laser Med Surg 1996; 14: 323–328.PubMedGoogle Scholar
  27. 27.
    Reed MW, Weiman TJ, Doak KW, Peitsch CG, Schuschke DA. The microvascular effects of photodynamic therapy: evidence for a possible role of cyclooxygenase products. Photochem Photobiol 1989; 50: 419–423.PubMedCrossRefGoogle Scholar
  28. 28.
    Kerdel FA, Soter NA, Lim HW. In vivo mediator release and degranulation of mast cells in hematoporphyrin derivative-induced phototoxicity in mice. J Invest Dermatol 1987; 88: 277–280.PubMedCrossRefGoogle Scholar
  29. 29.
    Selman SH, Keck RW, Klauning JE, Kriemer-Birnbaum M, Goldblatt PJ, Britton SL. Acute blood flow changes in transplantable FANFT-induced urothelial tumors treated with hematoporphyrin derivative and light. Surg Forum 1983; 34: 676–678.Google Scholar
  30. 30.
    Fingar VH, Weiman TJ, Wiehle SA, Cerrito PB. The role of microvascular damage in photodynamic therapy: the effect of treatment on vessel constriction, permeability, and leukocyte adhesion. Cancer Res 1992; 52: 4914–4921.PubMedGoogle Scholar
  31. 31.
    Krammer B. Vascular effects of photodynamic therapy. Anticancer Res 2001; 21: 4271–4277.PubMedGoogle Scholar
  32. 32.
    Fingar VH, Taber SW, Haydon PS, Harrison LT, Kempf SL, Wieman TJ. Vascular damage after photodynamic therapy of solid tumors: a view and comparison of effect in pre-clinical and clinical models at the University of Louisville. In Vivo 2000; 14: 93–100.PubMedGoogle Scholar
  33. 33.
    Jiang F, Zhang X et al. Combination therapy with antiangiogenic treatment and photodynamic therapy for the nude mouse bearing U87 glioblastoma. Photochem Photobiol 2008; 84: 128–137.PubMedGoogle Scholar
  34. 34.
    Kaiser PK. Verteporfin photodynamic therapy and anti-angiogenic drugs: potential for combination therapy in exudative age-related macular degeneration. Curr Med Res Opin 2007; 23: 477–487.PubMedCrossRefGoogle Scholar
  35. 35.
    Trachtenberg J, Bogaads A et al. Vascular targeted photodynamic therapy with palladium-bacteriopheophorbide photosensitizer for recurrent prostate cancer following definitive radiation therapy: assessment of safety and treatment response. J Urol 2007; 178: 1974–1979.PubMedCrossRefGoogle Scholar
  36. 36.
    Solban N, Rizvi I, Hasan T. Targeted photodynamic therapy. Lasers Med Surg 2006; 38: 522–531.CrossRefGoogle Scholar
  37. 37.
    Gomer CJ, Luna M et al. Cellular targets and molecular responses associated with photodynamic therapy. J Clin Laser Med Surg 1996; 14: 315–321.PubMedGoogle Scholar
  38. 38.
    Ryter SW, Gomer CJ. Nuclear factor kappa B binding activity in mouse L1210 cells following photofrin II-mediated photosensitization. Photochem Photobiol 1993; 58: 753–756.PubMedCrossRefGoogle Scholar
  39. 39.
    Kick G, Messer G, Goetz A, Plewig G. Photodynamic therapy induces expression of interleukin 6 by activation of AP-1 but not NF-kappa B DNA binding. Cancer Res 1995; 55: 2373–2379.PubMedGoogle Scholar
  40. 40.
    Gollnick SO, Liu X, Owczarczak B, Musser DA, Henderson BW. Altered expression of interleukin 6 and interleukin 10 as a result of photodynamic therapy in vivo. Cancer Res 1997; 57: 3904–3909.PubMedGoogle Scholar
  41. 41.
    Anderson C, Hrabovsky S et al. Elmets. Phthalocyanine photodynamic therapy: disparate effects of pharmacologic inhibitors on cutaneous photosensitivity and on tumor regression. Photochem Photobiol 1997; 65: 895–901.PubMedCrossRefGoogle Scholar
  42. 42.
    Kopecek J, Kopeckova P, Minko T, Lu Z. HPMA copolymer-anticancer drug conjugates: design, activity, and mechanism of action. Eur J Pharm Biopharm 2000; 50: 61–81.PubMedCrossRefGoogle Scholar
  43. 43.
    Lu ZR, Shiah JG, Sakuma S, Kopeckova P, Kopecek J. Design of novel bioconjugates for targeted drug delivery. J Control Release 2002; 78: 165–173.PubMedCrossRefGoogle Scholar
  44. 44.
    Gerlowski LE, Jain RK. Microvascular permeability of normal and neoplastic tissues. Microvasc Res 1986; 31: 288–305.PubMedCrossRefGoogle Scholar
  45. 45.
    Maeda H, Sawa T, Konno T. Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS. J Control Release 2001; 74: 47–61.PubMedCrossRefGoogle Scholar
  46. 46.
    Minko T, Kopeckova P, Kopecek J. Chronic exposure to HPMA copolymer-bound adriamycin does not induce multidrug resistance in a human ovarian carcinoma cell line. J Control Release 1999; 59: 133–148.PubMedCrossRefGoogle Scholar
  47. 47.
    Minko T, Kopeckova P, Pozharov V, Kopecek J. HPMA copolymer bound adriamycin overcomes MDR1 gene encoded resistance in a human ovarian carcinoma cell line. J Control Release 1998; 54: 223–233.PubMedCrossRefGoogle Scholar
  48. 48.
    Abe S, Otsuki M. Styrene maleic acid neocarzinostatin treatment for hepatocellular carcinoma. Curr Med Chem Anti-Canc Agents 2002; 715–726.Google Scholar
  49. 49.
    Brewerton LJ, Fung E, Snyder FF. Polyethylene glycol-conjugated adenosine phosphorylase: development of alternative enzyme therapy for adenosine deaminase deficiency. Biochim Biophys Acta 2003; 1637: 171–177.PubMedGoogle Scholar
  50. 50.
    Gianasi E, Wasil M, Evagorou EG, Keddle A, Wilson G, Duncan R. HPMA copolymer platinates as novel antitumour agents: in vitro properties, pharmacokinetics and antitumour activity in vivo. Eur J Cancer 1999; 35: 994–1002.PubMedCrossRefGoogle Scholar
  51. 51.
    Lu ZR, Kopeckova P, Kopecek J. Polymerizable Fab' antibody fragments for targeting of anticancer drugs. Nat Biotechnol 1999; 17: 1101–4.PubMedCrossRefGoogle Scholar
  52. 52.
    Lu ZR, Shiah JG, Kopeckova P, Kopecek J. Polymerizable Fab' antibody fragments targeted photodynamic cancer therapy in nude mice. STP Pharm Sci 2003; 13: 69–75.Google Scholar
  53. 53.
    Vaidya A, Sun Y, Ke T, Jeong EK, Lu ZR. Contrast enhanced MRI-guided photodynamic therapy for site-specific cancer treatment. Magn Reson Med 2006; 56: 761–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. Gadolinium (III) chelates as MRI contrast agents: Structure, dynamics, and applications. Chem Rev 1999; 99: 2293–2352.PubMedCrossRefGoogle Scholar
  55. 55.
    Vaidya A, Sun Y, Feng Y, Emerson L, Jeong EK, Lu ZR. Contrast-enhanced MRI-guided photodynamic cancer therapy with a pegylated bifunctional polymer conjugate. Pharm Res 2008; 25: 2002–2011.PubMedCrossRefGoogle Scholar
  56. 56.
    Liang ZP, Lauterbur PC. Principles of Magnetic Resonance Imaging: A Signal Processing Perspective. New York: IEEE Inc. 2000.Google Scholar
  57. 57.
    Lauffer RB. Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: theory and design. Chem Rev 1987; 87: 901–927.CrossRefGoogle Scholar
  58. 58.
    Weinmann HJ, Brasch RC, Press WR, Wesbey GE. Characteristics of gadolinium-DTPA complex: A potential NMR contrast agent. AJR 1984; 142: 619–624.PubMedGoogle Scholar
  59. 59.
    Hayne L, Maravilla K, Cohen W, Gerlach R. Gd-DTPA-BMA, a new nonionic MR contrast agent: preliminary clinical results and comparison with Magnevist. Radiology 1989; 173: 537–540.Google Scholar
  60. 60.
    Magerstadt M, Gansow OA, Brechbiel MW, Colcher D, Baltzer L, Knop RH, Girton ME, Naegele M. Gd(DOTA): an alternative to Gd(DTPA) as a T1,2 relaxation agent for NMR imaging or spectroscopy. Magn Reson Med 1986; 3: 808–812.PubMedCrossRefGoogle Scholar
  61. 61.
    Tweedle MF. The ProHance story: the making of a novel MRI contrast agent. Eur Radiol 1997; 7: 225–30.PubMedCrossRefGoogle Scholar
  62. 62.
    Zheng J, Liu J, Dunne M, Jaffray DA, Allen C. In Vivo Performance of a liposomal vascular contrast agent for CT and MR-based image guidance applications. Pharm Res 2007; 24: 1193–1121.PubMedCrossRefGoogle Scholar
  63. 63.
    Wang Y, Ye F, Jeong EK, Sun Y, Parker DL, Lu ZR. Noninvasive visualization of pharmacokinetics, biodistribution and tumor targeting of poly[N-(2-hydroxypropyl)methacrylamide] in mice using contrast enhanced MRI. Pharm Res 2007; 24: 1208–1216.PubMedCrossRefGoogle Scholar
  64. 64.
    Kacher DF, Jolesz FA. MR imaging--guided breast ablative therapy. Radiol Clin North Am 2004; 42: 947–962.PubMedCrossRefGoogle Scholar
  65. 65.
    Mortele KJ, Tuncali K, Cantisani V, Shankar S, vanSonnenberg E, Tempany C, Silverman SG. MRI-guided abdominal intervention. Abdom Imaging 2003; 28: 756–774.PubMedCrossRefGoogle Scholar
  66. 66.
    Nurko J, Edwards MJ. Image-guided breast surgery. Am J Surg 2005; 190: 221–227.PubMedCrossRefGoogle Scholar
  67. 67.
    Choyke PL, Dwyer AJ, Knopp MV. Functional tumor imaging with dynamic contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging 2003; 17: 509–520.PubMedCrossRefGoogle Scholar
  68. 68.
    Leach MO, Brindle KM, Evelhoch JL et al. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer 2005; 92: 1599–1610.PubMedCrossRefGoogle Scholar
  69. 69.
    Jordan BF, Runquist M, Raghunand N et al. The thioredoxin-1 inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) decreases vascular permeability in tumor xenografts monitored by dynamic contrast enhanced magnetic resonance imaging. Clin Cancer Res 2005; 11: 529–536.PubMedGoogle Scholar
  70. 70.
    Daldrup H, Shames DM, Wendland M et al. Correlation of dynamic contrast-enhanced MR imaging with histologic tumor grade: comparison of macromolecular and small-molecular contrast media. AJR Am J Roentgenol 1998; 171: 941–949.PubMedGoogle Scholar
  71. 71.
    Marzola P, Degrassi A, Calderan L et al. In vivo assessment of antiangiogenic activity of SU6668 in an experimental colon carcinoma model. Clin Cancer Res 2004; 10: 739–750.PubMedCrossRefGoogle Scholar
  72. 72.
    Stephen RM, Gillies RJ. Promise and progress for functional and molecular imaging of response to targeted therapies. Pharm Res 2007; 24: 1172–1185.Google Scholar
  73. 73.
    Preda A, Novikov V, Möglich M et al. MRI monitoring of Avastin antiangiogenesis therapy using B22956/1, a new blood pool contrast agent, in an experimental model of human cancer. J Magn Reson Imaging 2004; 20: 865–873.PubMedCrossRefGoogle Scholar
  74. 74.
    Cheng HL, Wallis C, Shou Z, Farhat WA. Quantifying angiogenesis in VEGF-enhanced tissue-engineered bladder constructs by dynamic contrast-enhanced MRI using contrast agents of different molecular weights. J Magn Reson Imaging 2007; 25: 137–145.PubMedCrossRefGoogle Scholar
  75. 75.
    Lu ZR, Mohs AM, Zong Y, Feng Y. Polydisulfide Gd(III) chelates as biodegradable macromolecular magnetic resonance imaging contrast agents. Intl J Nanomed 2006; 1: 31–40.CrossRefGoogle Scholar
  76. 76.
    Nguyen TD, Spincemaille P, Vaidya A, Prince MR, Lu ZR, Wang Y. Biodegradable intravascular (Gd-DTPA)-cystamine copolymer for contrast-enhanced steady-state free precession magnetic resonance angiography: comparison with MS-325 in a swine model. Mol Pharm 2006; 3: 558–565.PubMedCrossRefGoogle Scholar
  77. 77.
    Mohs A, Nguyen T, Lu ZR et al. Pegylation of Gd-DTPA Cystine Copolymers improves pharmacokinetics and tissue retention for magnetic resonance angiography. Magn Reson Med 2007; 58: 110–118.PubMedCrossRefGoogle Scholar
  78. 78.
    Feng Y, Jeong EK, Mohs A, Emerson L, Lu ZR. Characterization of tumor angiogenesis with dynamic contrast enhanced magnetic resonance imaging and biodegradable macromolecular contrast agents in mice. Magn Reson Med 2008; 60: 1347–1352.Google Scholar
  79. 79.
    Stephen RM, Gillies RJ. Promise and progress for functional and molecular imaging of response to targeted therapies. Pharm Res 2007; 24:1172–1185.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of UtahSalt Lake CityUSA

Personalised recommendations