[Targeting of chlorine E6 by EGF increasing its photodynamic activity in selective ways].
Certain tumor cells, such as squamous carcinoma cells, express an increased number of epidermal growth factor (EGF) receptors. The goal of this study was the targeted delivery of the photocytotoxic compound Sn(IV)chlorine e6 monoethylenediamine++ (SnCe6(ED)) to tumors that overexpress the EGF receptor. Therefore EGF was conjugated to SnCe6(ED) through a carrier, such as dextran (Dex) and human serum albumin (HSA), followed by the evaluation of the photocytotoxicity on the EGF receptor overexpressing MDA-MB-468 cell line. The photobiologic activity of these conjugates was then compared to a conjugate of the photosensitizer to HSA or dextran, or to the photosensitizer alone. In contrast to EGF-HSA-SnCe6(ED), the affinity of EGF for its receptor was substantially impaired upon conjugation in EGF-Dex-SnCe6(ED). In correlation with these results, EGF-HSA-SnCe6(ED) displayed a high cytotoxicity (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. In the presence of a competing EGF concentration (10 microM), EGF-HSA-SnCe6(ED) was not cytotoxic anymore. The high photocytoxicity of EGF-HSA-SnCe6(ED) was shown to be a 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) displayed very poor accumulation in MDA-MB-468 cells, in agreement with its low EGF receptor affinity and photocytoxicity. Besides, it could be demonstrated that EGF-HSA-SnCe6(ED) produced intracellularly ROS (reactive oxygen species) upon light irradiation, more than EGF-Dex-SnCe6(ED) did. It was concluded that, in contrast to EGF-Dex-SnCe6(ED) the photodynamic activity of the EGF-HSA conjugate of SnCe6(ED) on MDA-MB-468 breast adenocarcinoma cells is EGF-specific and more potent than free SnCe6(ED).
Gijsens
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Laboratorium voor Farmaceutische Biologie, Faculteit Farmaceutische Wetenschappen, KU-Leuven.
De Witte
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D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002735:Chlorophyllides; D003911:Dextrans / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D010778:Photochemotherapy / Q000379:methods*; D011166:Porphyrins / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D012709:Serum Albumin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002735:Chlorophyllides; D003911:Dextrans; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; D012709:Serum Albumin; C062985:phytochlorin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors