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Epidermal Growth Factor-mediated Targeting of Chlorin e₆ Selectively Potentiates Its Photodynamic Activity

Laboratorium voor Farmaceutische Biologie en Fytofarmacologie, Faculteit Farmaceutische Wetenschappen, K.U. Leuven, B-3000 Leuven, Belgium [A. G., P. d. W.], and Laboratorium voor Fysiologie, Faculteit Geneeskunde [L. M.] and Laboratorium voor Biochemie, Faculteit Geneeskunde [W. M.], K.U. Leuven Campus Gasthuisberg O/N, B-3000 Leuven, Belgium

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.

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