Abstract
Photodynamic therapy (PDT) is a promising cancer treatment approach with the advantages of low toxicity and noninvasive characteristics. In this study, a series of metalloporphyrin–indomethacin conjugates tethered with poly(ethylene glycol) (PEG) chains were prepared and characterized. The singlet oxygen production of the conjugates was evaluated through 2′, 7′-dichlorofluorescin (DCFH) method. Because of the heavy atom effect, the metal porphyrin complexes exhibited the higher singlet oxygen (1O2) quantum yield than that of free base porphyrin. The order of 1O2 yield of the synthesized porphyrins was PtPor > PdPor > ZnPor > Por. The MTT assay using HeLa cells verified the low cytotoxicity of porphyrin–indomethacin conjugates in the dark. Upon irradiation, the platinated porphyrin (PtPor) showed the highest therapeutic activity among these conjugates, probably due to its high efficiency of 1O2 generation. The cellular uptake and subcellular localization of the conjugates were further evaluated through a confocal laser scanning microscope. The results showed that the conjugates were primarily localized in the lysosomes of HeLa cells.
Similar content being viewed by others
References
Zhu S, Yao S, Wu F, Jiang L, Wong KL, Zhou J, Wang K (2017) Platinated porphyrin as a new organelle and nucleus dual-targeted photosensitizer for photodynamic therapy. Org Biomol Chem 15:5764–5771
Wu F, Chen J, Li Z, Su H, Leung KCF, Wang H, Zhu X (2018) Red/near-infrared emissive metalloporphyrin-based nanodots for magnetic resonance imaging-guided photodynamic therapy in vivo. Part Part Syst Charact 35:1800208
Xu Z, Yu F, Wu F, Zhang H, Wang K, Zhang X (2015) Synthesis, DNA photocleavage, singlet oxygen photogeneration and two photon absorption properties of ruthenium-phenanthroline porphyrins. J Porphyr Phthalocya 19:1–7
Berg K, Golab J, Korbelik M, Russell D (2011) Drug delivery technologies and immunological aspects of photodynamic therapy. Photoch Photobio Sci 10:647–648
Lovell JF, Liu TW, Chen J, Zheng G (2010) Activatable photosensitizers for imaging and therapy. Chem Rev 110:2839–2857
Ethirajan M, Chen Y, Joshi P, Pandey RK (2011) The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chem Soc Rev 40:340–362
Zhu S, Wu F, Wang K, Zheng Y, Li Z, Zhang X, Wong WK (2015) Photocytotoxicity, cellular uptake and subcellular localization of amidinophenylporphyrins as potential photodynamic therapeutic agents: an in vitro cell study. Bioorg Med Chem Lett 25:4513–4517
Zheng Y, Zhu S, Jiang L, Wu F, Huang C, Li Z, Wong KL, Xu Z, Wang K (2017) Synthesis, singlet oxygen generation, photocytotoxicity and subcellular localization of azobisporphyrins as potentially photodynamic therapeutic agents in vitro cell study. J Porphyr Phthalocya 21:122–127
Yao S, Zheng Y, Jiang L, Xie C, Wu F, Huang C, Zhang X, Wong KL, Li Z, Wang K (2018) Methylene violet 3RAX-conjugated porphyrin for photodynamic therapy: synthesis, DNA photocleavage, and cell study. RSC Adv 8:4472–4477
Hayashi K, Nakamura M, Miki H, Ozaki S, Abe M, Matsumoto T, Ishimura K (2014) Photostable iodinated silica/porphyrin hybrid nanoparticles with heavy-atom effect for wide-field photodynamic/photothermal therapy using single light source. Adv Funct Mater 24:503–513
Harris JM, Chess RB (2003) Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2:214–221
Nawalany K, Rusin A, Kepczynski M, Filipczak P, Kumorek M, Kozik B, Nowakowska M (2012) Novel nanostructural photosensitizers for photodynamic therapy: in vitro studies. Int J Pharmaceut 430:129–140
Huang H, Wang D, Zhang Y, Zhou Y, Geng J, Chitgupi U, Cook TR, Xia J, Lovell JF (2016) Axial PEGylation of tin octabutoxy naphthalocyanine extends blood circulation for photoacoustic vascular imaging. Bioconjugate Chem 27:1574–1578
Wu F, Su H, Cai Y, Wong WK, Jiang W, Zhu X (2018) Porphyrin-implanted carbon nanodots for photoacoustic imaging and in vivo breast cancer ablation. ACS Appl Bio Mater 1:110–117
Brunelli C, Amici C, Angelini M, Fracassi C, Belardo G, Santoro MG (2012) The non-steroidal anti-inflammatory drug indomethacin activates the eIF2α kinase PKR, causing a translational block in human colorectal cancer cells. Biochem J 443:379–386
Yang K, Zhang X, Yang F, Wu F, Zhang X, Wang K (2017) DNA photocleavage and binding modes of methylene violet 3RAX and its derivatives: effect of functional groups. Aust J Chem 70:830–836
Han L, Peng B, Ma Q, Ma J, Li J, Li W, Laporte K (2013) Indometacin ameliorates high glucose-induced proliferation and invasion via modulation of e-cadherin in pancreatic cancer cells. Curr Med Chem 20:4142–4152
Marydasan B, Nair AK, Ramaiah D (2013) Optimization of triplet excited state and singlet oxygen quantum yields of picolylamine-porphyrin conjugates through zinc insertion. J Phys Chem B 117:13515–13522
Mathai S, Smith TA, Ghiggino KP (2007) Singlet oxygen quantum yields of potential porphyrin-based photosensitisers for photodynamic therapy. Photochem Photobio Sci 6:995–1002
Uddin MJ, Crews BC, Blobaum AL, Kingsley PJ, Gorden DL, McIntyre JO, Matrisian LM, Subbaramaiah K, Dannenberg AJ, Piston DW, Marnett LJ (2010) Selective visualization of cyclooxygenase-2 in inflammation and cancer by targeted fluorescent imaging agents. Cancer Res 70:3618–3627
Acknowledgements
The work was supported by the National Natural Science Foundation of China (NSFC) (21601142, 81503036) and the Natural Science Foundation of Hubei Province (2017CFB689).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Wu, F., Yang, M., Zhang, J. et al. Metalloporphyrin–indomethacin conjugates as new photosensitizers for photodynamic therapy. J Biol Inorg Chem 24, 53–60 (2019). https://doi.org/10.1007/s00775-018-1626-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00775-018-1626-9