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The PDT activity of free and pegylated pheophorbide a against an amelanotic melanoma transplanted in C57/BL6 mice

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Summary

Pheophorbide a (Pba) is a chlorophyll catabolite that has been proposed as photosensitizer in photodynamic therapy. In a previous study we conjugated Pba to monomethoxy-polyethylene glycol (mPEG-Pba), to increase its solubility and pharmacokinetics. Here, we compare the photodynamic therapy efficacy of free Pba and mPEG-Pba to cure a subcutaneous amelanotic melanoma transplanted in C57/BL6 mice. The photosensitizers, i.p. injected (30 mg/kg), showed no toxicity when the animals were kept in the dark. But, after photoactivation with a 660 nm laser (fluence of 193 J/cm2), both photosensitizers, in particular mPEG-Pba, showed a strong efficacy to cure the tumor, both in terms of tumor growth delay and increase of Kaplan-Meier median survival time. Together, our in vivo data demonstrate that mPEG-conjugated Pba is a promising photosensitizer for the photodynamic therapy of cancer.

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References

  1. Dolmans DE, Fukimura D, Jain RK (2003) Photodynamic therapy for cancer. Nat Rev Cancer 3:380–387

    Article  PubMed  CAS  Google Scholar 

  2. Dougherty TJ, Gomer CJ, Henderson BW et al (1998) Photodynamic therapy. J Natl Cancer Inst 90:889–905

    Article  PubMed  CAS  Google Scholar 

  3. Pervaiz S (2001) Reactive oxygen-dependent production of novel photochemotherapeutic agents. FASEB J 15:612–617

    Article  PubMed  CAS  Google Scholar 

  4. Juarranz A, Jaén P, Sanz-Rodríguez F et al (2008) Photodynamic therapy of cancer. Basic principles and applications. Clin Transl Oncol 10:148–154

    Article  PubMed  CAS  Google Scholar 

  5. Detty MR, Gibson SL, Wagner SJ (2004) Current clinical and preclinical photosensitizers for use in photodynamic therapy. J Med Chem 47:3897–3915

    Article  PubMed  CAS  Google Scholar 

  6. Schuitmaker JJ, Baas P, van Leengoed HL et al (1996) Photodynamic therapy: a promising new modality for the treatment of cancer. J Photochem Photobiol B 34:3–12

    Article  PubMed  CAS  Google Scholar 

  7. Agostinis P, Berg K, Cengel KA et al (2011) Photodynamic therapy of cancer: an update. CA Cancer J Clin 61:250–281

    Article  PubMed  Google Scholar 

  8. Derycke AS, Kamuhabwa A, Gijsens A et al (2004) Transferrin-conjugated liposome targeting of photosensitizer AlPcS4 to rat bladder carcinoma cells. J Natl Cancer Inst 96:1620–1630

    Article  PubMed  CAS  Google Scholar 

  9. Master AM, Qi Y, Oleinick NL et al (2011) EGFR-mediated intracellular delivery of Pc 4 nanoformulation for targeted photodynamic therapy of cancer: in vitro studies. Nanomedicine. doi:10.1016/j.nano.2011.09.012

  10. Abu-Yousif AO, Moor AC, Zheng X et al (2012) Epidermal growth factor receptor-targeted photosensitizer selectively inhibits EGFR signaling and induces targeted phototoxicity in ovarian cancer cells. Cancer Lett. doi:10.1016/j.canlet.2012.01.014

  11. Giuntini F, Alonso CM, Boyle RW (2011) Synthetic approaches for the conjugation of porphyrin and related macrocycles to peptides and proteins. Photochem Photobiol Sci 10:759–791

    Article  PubMed  CAS  Google Scholar 

  12. Srivatsan A, Ethirajan M, Pandey SK et al (2011) Conjugation of cRGD peptide to chlorophyll a based photosensitizer (HPPH) alters its pharmacokinetics with enhanced tumor-imaging and photosensitizing (PDT) efficacy. Mol Pharm 8:1186–1197

    Article  PubMed  CAS  Google Scholar 

  13. Bhatti M, Yahioglu G, Milgrom LR et al (2008) Targeted photodynamic therapy with multiply-loaded recombinant antibody fragments. Int J Cancer 122:1155–1163

    Article  PubMed  CAS  Google Scholar 

  14. Van Dongen GA, Visser GW, Vrouenraets MB (2004) Photosensitizer-antibody conjugates for detection and therapy of cancer. Adv Drug Deliv Rev 56:31–52

    Article  PubMed  Google Scholar 

  15. Gupta S, Dwarakanath BS, Chaudhury NK et al (2011) In vitro and in vivo targeted delivery of photosensitizers to the tumor cells for enhanced photodynamic effects. J Cancer Res Ther 7:314–324

    Article  PubMed  Google Scholar 

  16. Shieh YA, Yang SJ, Wei MF et al (2010) Aptamer-based tumor-targeted drug delivery for photodynamic therapy. ACS Nano 4:1433–1442

    Article  PubMed  CAS  Google Scholar 

  17. Zheng X, Pandey RK (2008) Porphyrin-carbohydrate conjugates: impact of carbohydrate moieties in photodynamic therapy (PDT). Anticancer Agents Med Chem 8:241–268

    Article  PubMed  CAS  Google Scholar 

  18. Di Stasio B, Frochot C, Dumas D et al (2005) The 2- aminoglucosamide motif improves cellular uptake and photodynamic activity of tetraphenylporphyrin. Eur J Med Chem 40:1111–1122

    Article  PubMed  Google Scholar 

  19. Gravier J, Schneider R, Frochot C et al (2008) Improvement of metatetra(hydroxyphenyl)chlorin-like photosensitizer selectivity with folate-based targeted delivery. Synthesis and in vivo delivery studies. J Med Chem 51:3867–3877

    Article  PubMed  CAS  Google Scholar 

  20. Hamblin MR, Miller JL, Rizvi I et al (2001) Pegylation of a chlorin(e6) polymer conjugate increases tumor targeting of photosensitizer. Cancer Res 61:7155–7162

    PubMed  CAS  Google Scholar 

  21. Hamblin MR, Miller JL, Rizvi I et al (2003) Pegylation of charged polymer photosensitizer conjugates: effects on photodynamic efficacy. Br J Cancer 89:937–943

    Article  PubMed  CAS  Google Scholar 

  22. Chouikrat R, Seve A, Vanderesse R et al (2012) Non polymeric nanoparticles for photodynamic therapy applications: recent developments. Curr Med Chem 19:781–792

    Article  PubMed  CAS  Google Scholar 

  23. Wieder ME, Hone DC, Cook MJ et al (2006) Intracellular photodynamic therapy with photosensitizer-nanoparticle conjugates: cancer therapy using a 'Trojan horse'. Photochem Photobiol Sci 5:727–734

    Article  PubMed  CAS  Google Scholar 

  24. Stuchinskaya T, Moreno M, Cook MJ et al (2011) Targeted photodynamic therapy of breast cancer cells using antibody-phthalocyanine-gold nanoparticle conjugates. Photochem Photobiol Sci 10:822–831

    Article  PubMed  CAS  Google Scholar 

  25. Couleaud P, Morosini V, Frochot C et al (2010) Silica-based nanoparticles for photodynamic therapy applications. Nanoscale 2:1083–1095

    Article  PubMed  CAS  Google Scholar 

  26. Zhu Z, Tang Z, Phillips JA et al (2008) Regulation of singlet oxygen generation using single-walled carbon nanotubes. J Am Chem Soc 130:10856–10857

    Article  PubMed  CAS  Google Scholar 

  27. Huang P, Lin J, Yang D et al (2011) Photosensitizer-loaded dendrimer-modified multi-walled carbon nanotubes for photodynamic therapy. J Control Release 152(Suppl 1):e33–e34

    Article  PubMed  CAS  Google Scholar 

  28. Sortino S, Mazzaglia A, Monsù Scolaro L et al (2006) Nanoparticles of cationic amphiphilic cyclodextrins entangling anionic porphyrins as a “carrier-sensitizer” system in photodynamic cancer therapy. Biomaterials 27:4256–4265

    Article  PubMed  CAS  Google Scholar 

  29. McCarthy JR, Perez JM, Bruckner C et al (2005) Polymeric nanoparticle preparation that eradicates tumors. Nano Lett 5:2552–2556

    Article  PubMed  CAS  Google Scholar 

  30. Takamiya K, Tsuchiya T, Ohta H (2000) Degradation pathways of chlorophyll: what has gene cloning revealed? Trends Plan Sci 5:426–431

    Article  CAS  Google Scholar 

  31. Rapozzi V, Zacchigna M, Biffi S et al (2010) Conjugated PDT drug. Photosensitizing activity and tissue distribution of PEGylated pheophorbide a. Cancer Biol Ther 10:1–12

    Article  Google Scholar 

  32. Taub AF (2008) Photodynamic therapy in dermatology. In: Hamblin MR, Mroz P (eds) Advances in photodynamic therapy: basic, translational and clinical, Artech House, Boston, pp 419–442

  33. Soncin M, Busetti A, Reddi E et al (1997) Pharmacokinetic and phototherapeutic properties of axially substitued Si(IV)-tetradibenzobarreleno-octabutoxyphtalocyanines. J Photochem Photobiol B 40:163–167

    Article  PubMed  CAS  Google Scholar 

  34. Fabris C, Vicente MGH, Hao E et al (2007) Tumour-localizing and-photosensitizing properties of meso-tetra(4-nido-carboranylphenyl)porphyrin. J Photochem Photobiol B: Biol 89:131–136

    Article  CAS  Google Scholar 

  35. Camerin M, Magaraggia M, Soncin M et al (2010) The in vivo efficacy of phthalocyanine-nanoparticle conjugates for the photodynamic therapy of amelanotic melanoma. Eur J Cancer 46:1910–1918

    Article  PubMed  CAS  Google Scholar 

  36. Nelson JS, McCullough JL, Berns MW (1988) Photodynamic therapy of human- malignant melanoma xenografts in at hymic nude mice. J Natl Cancer Inst 80:56–60

    Article  PubMed  CAS  Google Scholar 

  37. Campaner P, Drioli S, Bonora GM (2006) Synthesis of selectively end-modified high-molecular weight polyethylenglycol. Lett Org Chem 10:773–779

    Article  Google Scholar 

  38. Röeder B, Hanke TH, Oelckers ST et al (2000) Photophysical properties of pheophorbide a in solution and in a model membrane systems. J Porphyr Phtalocyanines 4:37–44

    Article  Google Scholar 

  39. Sternberg ED, Dolphin D, Bruckner C (1998) Porphyrin based photosensitizers for use in photodynamic therapy. Tetrahedron 54:4151–4202

    Article  CAS  Google Scholar 

  40. Xodo LE, Rapozzi V, Zacchigna M et al (2012) The chlorophyll catabolite pheophorbide a as a photosensitizer for the photodynamic therapy. Curr Med Chem 19:799–807

    Article  PubMed  CAS  Google Scholar 

  41. Tang PM, Zhang DM, Xuan NH et al (2009) Photodynamic therapy ninhibits p-glycoprotein mediated multidrug resistanve via JNK activation in human hepatocellular carcinoma using the photosensitizer pheophorbide a. Mol Cancer 8:56–67

    Article  PubMed  Google Scholar 

  42. Rapozzi V, Miculan M, Xodo LE (2009) Evidence that photoactivated pheophorbide a causes in human cancer cells a photodynamic effect involving lipid peroxidation. Cancer Biol Ther 8:1318–1327

    Article  PubMed  CAS  Google Scholar 

  43. Hajri A, Wack S, Meyer C et al (2002) In vitro and in vivo efficacy of Photofrin and Pheophorbide a, a bacteriochlorin, in photodynamic therapy of colonic cancer cells. Photochem Photobiol 75:140–148

    Article  PubMed  CAS  Google Scholar 

  44. Hoi SW, Wong HM, Chan JY et al (2011) Photodynamic therapy of pheophorbide a inhibits the proliferation of human breast tumour via both caspase-dependent and -independent apoptotic pathways in in vitro and in vivo models. Phytother Res. doi:10.1002/ptr.3607

  45. Knop K, Hoogenboom R, Fischer D, Schubert US (2010) Poly(ethylene glycol) in drug delivery:pros and cons as well as potential alternatives. Angew Chem Int Ed Engl 49:6288–6308

    Article  PubMed  CAS  Google Scholar 

  46. Rapozzi V, Umezawa K, Xodo LE (2011) Role of NF-kB/Snail/RKIP loop in the response of tumor cells to photodynamic therapy. Lasers Surg Med 43:575–585

    PubMed  Google Scholar 

  47. Torres M (2003) Mitogen-activated protein kinase pathways in redox signaling. Front Biosci 8:d369–d391

    Article  PubMed  CAS  Google Scholar 

  48. Landeer HM, Milbank AJ, Tauras JM et al (1996) Redox regulation of cell signaling. Nature 381:380–381

    Article  Google Scholar 

  49. Chan WH (2011) Photodynamic therapy induces apoptotic pathway involving calcium, nitric oxide, p53, p21-activated kinase 2, and c-jun N-terminal kinase and inactivates survival signal in human umbilical vein endothelial cells. Int J Mol Sci 12:1041–1059

    Article  PubMed  CAS  Google Scholar 

  50. Berlett BS, Stadtman ER (1997) Protein oxidation in aging, disease and oxidative stress. J Biol Chem 272:20313–20316

    Article  PubMed  CAS  Google Scholar 

  51. Wiegell SR, Fabricius S, Stender IM et al (2011) A randomized, multicentre study of directed daylight exposure times of 1½ vs. 2½ h in daylight-mediated photodynamic therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp. Br J Dermatol 164:1083–1090

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This work has been carried out with the financial support of the FVG (Regione Friuli Venezia Giulia) and AIRC, the Italian Association for Cancer Research (IG 2010).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Medical and Biological Sciences, School of Medicine, P.le Kolbe 4, 33100, Udine, Italy

    Valentina Rapozzi & Luigi E. Xodo

  2. Department of Life Science, University of Trieste, Via Giorgieri 7-9, 34100, Trieste, Italy

    Sonia Zorzet

  3. Department of Chemical and Pharmaceutical Sciences, University of Trieste, P.le Europa 1, Trieste, 34100, Italy

    Marina Zacchigna & Sara Drioli

Authors
  1. Valentina Rapozzi
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  2. Sonia Zorzet
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  3. Marina Zacchigna
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  5. Luigi E. Xodo
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Corresponding author

Correspondence to Luigi E. Xodo.

Additional information

Valentina Rapozzi and Sonia Zorzet, have equally contributed to this work.

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Rapozzi, V., Zorzet, S., Zacchigna, M. et al. The PDT activity of free and pegylated pheophorbide a against an amelanotic melanoma transplanted in C57/BL6 mice. Invest New Drugs 31, 192–199 (2013). https://doi.org/10.1007/s10637-012-9844-4

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  • DOI: https://doi.org/10.1007/s10637-012-9844-4

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