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Synthesis and evaluation of new 5-aminolevulinic acid derivatives as prodrugs of protoporphyrin for photodynamic therapy

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Abstract

Protoporphyrin IX (PpIX) is used as a photosensitizer in the photodynamic diagnosis (PDD) and photodynamic therapy (PDT) of cancer and is synthesized intracellularly from 5-aminolevulinic acid (5-ALA) precursors. Thirteen novel 5-ALA derivatives were designed and synthesized appropriately with tailored hydrophilicity and lipophilicity. The generation of PpIX was detected and their antitumor activity in vitro and in vivo was also investigated. It was shown that compounds 9b–c, 11b–c and 13a displayed a characteristic long wavelength absorption peak at 593 nm after 5 h incubation in mice fibrosarcoma S180 cells. After being exposed to 600 nm laser light irradiation, these compounds can inhibit cell proliferation in S180 cells in vitro. The growth of S180 cell tumors in Kunming mice was significantly inhibited by these compounds in vivo. Among these compounds, 13a has low dark toxicity and high phototoxicity, which makes it an effective and promising prodrug for PDT.

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References

  1. D. Kessel, Hematoporphyrin and HPD: photophysics, photochemistry and phototherapy, Photochem. Photobiol., 1984, 39, 851–859.

    Article  CAS  Google Scholar 

  2. P. Agostinis, K. Berg, and K. A. Cengel, Photodynamic therapy of cancer: an update, CA-Cancer J. Clin., 2011, 61, 250–281.

    Article  Google Scholar 

  3. D. E. Dolmans, D. Fukumura, and R. K. Jain, Photodynamic therapy for cancer, Nat. Rev. Cancer., 2003, 3, 380–387.

    Article  CAS  Google Scholar 

  4. J. C. Kennedy, and R. H. Pottier, New trends in photobiology: endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy, J. Photochem. Photobiol., B., 1992, 14, 275–292.

    Article  CAS  Google Scholar 

  5. C. Perotti, H. Fukuda, G. Divenosa, A. J. Macrobert, A. Batlle, and A. Casas, Porphyrin synthesis from ALA derivatives for photodynamic therapy. In vitro and in vivo studies, Br. J. Cancer., 2004, 90, 1660–1665.

    Article  CAS  Google Scholar 

  6. Q. Peng, K. Berg, J. Moan, M. Kongshaug, and J. M. Nesland, 5-Aminolevulinic acid-based photodynamic therapy: principles and experimental research, Photochem. Photobiol., 1997, 65, 235–251.

    Article  CAS  Google Scholar 

  7. E. Endlicher, P. Rümmele, F. Hausmann, R. Krieg, and R. Knüchel, Protoporphyrin IX distribution following local application of 5-aminolevulinic acid and its esterified derivatives in the tissue layers of the normal rat colon, Br. J. Cancer., 2001, 85, 1572–1576.

    Article  CAS  Google Scholar 

  8. P. Uehlinger, M. Zellweger, G. Wagnières, L. Juilleratjeanneret, D. B. H. Van, and N. Lange, 5-Aminolevulinic acid and its derivatives: physical chemical properties and protoporphyrin IX formation in cultured cells, J. Photochem. Photobiol., B., 2000, 54, 72–80.

    Article  CAS  Google Scholar 

  9. L. Bourré, F. Giuntini, I. M. Eggleston, M. Wilson, and A. J. Macrobert, Protoporphyrin IX enhancement by 5-aminolaevulinic acid peptide derivatives and the effect of RNA silencing on intracellular metabolism, Br. J. Cancer., 2009, 100, 723–731.

    Article  Google Scholar 

  10. M. J. Dixon, L. Bourre, A. J. MacRobert, and I. M. Eggleston, Novel prodrug approach to photodynamic therapy: Fmoc solid-phase synthesis of a cell permeable peptide incorporating 5-aminolaevulinic acid, Bioorg. Med. Chem. Lett., 2007, 17, 4518–4522.

    Article  CAS  Google Scholar 

  11. T. Feuerstein, G. Berkovitch-Luria, A. Nudelman, A. Rephaeli, and Z. Malik, Modulating ALA-PDT efficacy of mutlidrug resistant MCF-7 breast cancer cells using ALA prodrug, Photochem. Photobiol. Sci., 2011, 10, 1926–1933.

    Article  CAS  Google Scholar 

  12. G. Berkovitch-Luria, S. Yakobovitch, M. Weitman, A. Nudelman, G. Rozic, A. Rephaeli, and Z. Malik, A multifunctional 5-aminolevulinic acid derivative induces erythroid differentiation of K562 human erythroleukemic cells, Eur. J. Pharm. Sci., 2012, 47, 206–214.

    Article  CAS  Google Scholar 

  13. J.-M. Gaullier, K. Berg, Q. Peng, H. Anholt, P. K. Selbo, L.-W. Ma, and J. Moan, Use of 5-aminolevulinic acid esters to improve photodynamic therapy on cells in culture, Cancer Res., 1997, 57, 1481–1486.

    CAS  PubMed  Google Scholar 

  14. G. Berkovitch, D. Doron, A. Nudelman, Z. Malik, and A. Rephaeli, Novel multifunctional acyloxyalkyl ester prodrugs of 5-aminolevulinic acid display improved anticancer activity independent and dependent on photoactivation, J. Med. Chem., 2008, 51, 7356–7369.

    Article  CAS  Google Scholar 

  15. G. Berkovitch-Luria, M. Weitman, A. Nudelman, A. Rephaeli, and Z. Malik, Multifunctional 5-aminolevulinic acid prodrugs activating diverse cell-death pathways, Invest. New Drugs., 2012, 30, 1028–1038.

    Article  CAS  Google Scholar 

  16. N. Fotinos, M. A. Campo, F. Popowycz, R. Gurny, and N. Lange, 5-aminolevulinic acid derivatives in photomedicine: characteristics, application and perspectives, Photochem. Photobiol., 2006, 82, 994–1015.

    Article  CAS  Google Scholar 

  17. J. Webber, D. Kessel, and D. Fromm, Side effects and photosensitization of human tissues after aminolevulinic acid, J. Surg. Res., 1997, 68, 31–37.

    Article  CAS  Google Scholar 

  18. A. Casas, A. del C. Batlle, A. Butler, D. Robertson, E. Brown, A. MacRobert, and P. Riley, Comparative effect of ALA derivatives on protoporphyrin IX production in human and rat skin organ cultures, Br. J. Cancer., 1999, 80, 1525–1532.

    Article  CAS  Google Scholar 

  19. R. Schneider, L. Tirand, C. Frochot, R. Vanderesse, N. Thomas, J. Gravier, F. Guillemin, and M. Barberi-Heyob, Recent improvements in the use of synthetic peptides for a selective photodynamic therapy, Anti-Cancer Agents Med. Chem., 2006, 6, 469–488.

    Article  CAS  Google Scholar 

  20. Y. Berger, L. Ingrassia, R. Neier, and L. Juillerat-Jeanneret, Evaluation of dipeptide-derivatives of 5-aminolevulinic acid as precursors for photosensitizers in photodynamic therapy, Bioorg. Med. Chem., 2003, 11, 1343–1351.

    Article  CAS  Google Scholar 

  21. Y. Berger, A. Greppi, O. Siri, R. Neier, and L. Juillerat-Jeanneret, Ethylene glycol and amino acid derivatives of 5-aminolevulinic acid as new photosensitizing precursors of protoporphyrin IX in cells, J. Med. Chem., 2000, 43, 4738–4746.

    Article  CAS  Google Scholar 

  22. F. Giuntini, L. Bourre, A. J. MacRobert, M. Wilson, and I. M. Eggleston, Improved Peptide Prodrugs of 5-ALA for PDT: Rationalization of Cellular Accumulation and Protoporphyrin IX Production by Direct Determination of Cellular Prodrug Uptake and Prodrug Metabolization, J. Med. Chem., 2009, 52, 4026–4037.

    Article  CAS  Google Scholar 

  23. H. Brunner, F. Hausmann, and R. Knuechel, New 5-Aminolevulinic Acid Esters—Efficient Protoporphyrin Precursors for Photodetection and Photodynamic Therapy, Photochem. Photobiol., 2003, 78, 481–486.

    Article  CAS  Google Scholar 

  24. A. Godal, N. O. Nilsen, J. Klaveness, J. E. Braenden, J. M. Nesland, and Q. Peng, New derivatives of 5-aminolevulinic acid for photodynamic therapy: chemical synthesis and porphyrin production in in vitro and in vivo biological systems, J. Environ. Pathol., Toxicol. Oncol., 2006, 25, 109–126.

    Article  CAS  Google Scholar 

  25. J. Kloek, W. Akkermans, and G. van Henegouwen, Derivatives of 5-Aminolevulinic Acid for Photodynamic Therapy: Enzymatic Conversion into Protoporphyrin, Photochem. Photobiol., 1998, 67, 150–154.

    Article  CAS  Google Scholar 

  26. L. Pare, E. Marcuello, A. Altes, E. del Rio, L. Sedano, J. Salazar, A. Cortes, A. Barnadas, and M. Baiget, Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy, Br. J. Cancer., 2009, 100, 1368.

    Article  CAS  Google Scholar 

  27. C. Martucci, S. Franchi, E. Giannini, H. Tian, P. Melchiorri, L. Negri, and P. Sacerdote, Bv8, the amphibian homologue of the mammalian prokineticins, induces a proinflammatory phenotype of mouse macrophages, Br. J. Pharmacol., 2006, 147, 225–234.

    Article  CAS  Google Scholar 

  28. A. François, S. Battah, A. J. Macrobert, L. Bezdetnaya, F. Guillemin, and M. A. D’Hallewin, Fluorescence diagnosis of bladder cancer: a novel in vivo approach using 5-aminolevulinic acid (ALA) dendrimers, BJU Int., 2012, 110, E1155–E1162.

    Article  Google Scholar 

  29. L. Bourre, F. Giuntini, I. M. Eggleston, M. Wilson, and A. J. MacRobert, 5-Aminolaevulinic acid peptide prodrugs enhance photosensitization for photodynamic therapy, Mol. Cancer Ther., 2008, 7, 1720–1729.

    Article  CAS  Google Scholar 

  30. J. Kloek, and G. M. J. van Beijersbergen Henegouwen, Prodrugs of 5-Aminolevullinic Acid for Photodynamic Therapy, Photochem. Photobiol., 1997, 64, 994–1000.

    Article  Google Scholar 

  31. Y. Ninomiya, Y. Itoh, S. Tajima, and A. Ishibashi, In vitro and in vivo expression of protoporphyrin IX induced by lipophilic 5-aminolevulinic acid derivatives, J. Dermatol. Sci., 2001, 27, 114–120.

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (no. 21372042, 21402236), the Foundation of Shanghai Government (no. 14431906200, 15XD1523400, 15431904100, 14ZR1439900, 14ZR1439800, 15ZR1439900, 16ZR1400600, 15411960400), the Foundation of Donghua University (17D110513), and the Foundation of Songjiang District (no. 15SJGG45, 16SJGG20).

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Authors and Affiliations

  1. Department of Pharmaceutical Science & Technology, College of Chemistry and Biology, Donghua University, Shanghai, 201620, China

    Wei Zhu, Ying-Hua Gao, Chun-Hong Song, Zhi-Bin Lu, Tabbisa Namulinda & Zhi-Long Chen

  2. Shanghai Changhai Hospital, 200433, China

    Yi-Ping Han & Lai-Xing Wang

  3. Shanghai Xianhui Pharmaceutical Co. Ltd., Shanghai, 200433, China

    Yi-Jia Yan

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  1. Wei Zhu
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  2. Ying-Hua Gao
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Correspondence to Lai-Xing Wang or Zhi-Long Chen.

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Zhu, W., Gao, YH., Song, CH. et al. Synthesis and evaluation of new 5-aminolevulinic acid derivatives as prodrugs of protoporphyrin for photodynamic therapy. Photochem Photobiol Sci 16, 1623–1630 (2017). https://doi.org/10.1039/c7pp00203c

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