Epidermal growth factor-mediated targeting of chlorin e6 selectively potentiates its photodynamic activity.
Certain tumor cells, such as squamous carcinoma cells, express an increased number of epidermal growth factor (EGF) receptors. Therefore, we studied the targeted delivery of the photocytotoxic compound Sn-(IV)chlorin e6 monoethylenediamine [SnCe6(ED)] to tumors that overexpress the EGF receptor. EGF was conjugated to SnCe6(ED) through a carrier, such as dextran (Dex) and human serum albumin (HSA), and the photocytotoxicity on the EGF receptor-overexpressing MDA-MB-468 breast adenocarcinoma cell line was evaluated. The photobiological activities of these EGF conjugates, of the conjugates of the photosensitizer to HSA or Dex, or of the photosensitizer alone were compared. The affinity of EGF for its receptor was substantially impaired when conjugated in EGF-Dex-SnCe6(ED), in contrast to EGF-HSA-SnCe6(ED). In corresponding results, EGF-HSA-SnCe6(ED) displayed a high photocytotoxicity (IC50, 63 nM) on MDA-MB-468 cells at a light dose of 27 kJ/m2, whereas EGF-Dex-SnCe6(ED) showed very limited photocytotoxicity. EGF-HSA-SnCe6(ED) was no longer photocytotoxic in the presence of a competing EGF concentration. The high photocytotoxicity of EGF-HSA-SnCe6(ED) was shown to be the result of a high intracellular concentration in MDA-MB-468 cells, which could be lowered dramatically by incubating the conjugate with a competing EGF concentration. In contrast, EGF-Dex-SnCe6(ED) accumulated poorly in MDA-MB-468 cells, in agreement with its low EGF receptor affinity and photocytotoxicity. EGF-HSA-SnCe6(ED) produced much more intracellular reactive oxygen species on light irradiation than EGF-Dex-SnCe6(ED). It is concluded that the photodynamic activity of the EGF-HSA conjugate of SnCe6(ED) on MDA-MB-468 breast adenocarcinoma cells is EGF specific and is much more potent than EGF-Dex-SnCe6(ED) or free SnCe6.
Gijsens
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Laboratorium voor Farmaceutische Biologie en Fytofarmacologie, Faculteit Farmaceutische Wetenschappen, KU Leuven, Belgium.
Missiaen
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Merlevede
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de Witte
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D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001667:Binding, Competitive; D001692:Biological Transport; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002735:Chlorophyllides; D003911:Dextrans / Q000378:metabolism; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D010778:Photochemotherapy; D011166:Porphyrins / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D012709:Serum Albumin / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection; D014407:Tumor Cells, Cultured
D002735:Chlorophyllides; D003911:Dextrans; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; C062985:phytochlorin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors