Epidermal Growth Factor-mediated Targeting of Chlorin e sub(6) 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 e sub(6) monoethylenediamine [SnCe sub(6)(ED)] to tumors that overexpress the EGF receptor. EGF was conjugated to SnCe sub(6)(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-SnCe sub(6)(ED), in contrast to EGF-HSA-SnCe sub(6)(ED). In corresponding results, EGF-HSA-SnCe sub(6)(ED) displayed a high photocytotoxicity (IC sub(50), 63 nM) on MDA-MB-468 cells at a light dose of 27 kJ/m super(2), whereas EGF-Dex-SnCe sub(6)(ED) showed very limited photocytotoxicity. EGF-HSA-SnCe sub(6)(ED) was no longer photocytotoxic in the presence of a competing EGF concentration. The high photocytotoxicity of EGF-HSA-SnCe sub(6)(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-SnCe sub(6)(ED) accumulated poorly in MDA-MB-468 cells, in agreement with its low EGF receptor affinity and photocytotoxicity. EGF-HSA-SnCe sub(6)(ED) produced much more intracellular reactive oxygen species on light irradiation than EGF-Dex-SnCe sub(6)(ED). It is concluded that the photodynamic activity of the EGF-HSA conjugate of SnCe sub(6)(ED) on MDA-MB-468 breast adenocarcinoma cells is EGF specific and is much more potent than EGF-Dex-SnCe sub(6)(ED) or free SnCe sub(6).