Synthesis, Molecular Docking, and Biological Activity of New EGFR-Targeted Photosensitizers Based on Cationic Porphyrins Encapsulated into Pluronic F127 Micelles.

Abstract

The development of new effective photosensitizers (PS) for photodynamic therapy (PDT) is one of the important tasks in medical and organic chemistry. PSs inhibiting epidermal growth factor receptors (EGFR) overexpressed in cancer cells are of particular importance. In this work, we proposed the design and molecular docking of novel hybrid photosensitizers based on meso-aryl-substituted porphyrins and the Erlotinib molecule, a clinically approved tyrosine kinase inhibitor. The spacer length between the macrocycles and Erlotinib, hydrophilicity, and hydrophobicity of the porphyrin ring substituents were varied in the obtained compounds to evaluate structure-activity relationships (SAR). Photophysical and photochemical characteristics were studied for all of the received compounds in the presence of solubilizers suitable for the creation of dosage forms. Nanomicelles based on Pluronic F127 were obtained and characterized for the received compounds. In vitro biological tests on three cancer cell lines, MCF-7 (breast carcinoma), A431 (epidermoid carcinoma), MDA-MB-231 (breast adenocarcinoma), and normal NKE cells (human kidney epithelial cells) were performed, which showed low dark toxicity as well as light-induced activity of conjugates in the nanomolar range. Confocal microscopy experiments showed preferred accumulation of UB-2 and a lower accumulation of UB-3 PSs. In the case of UB-3, we observed a pronounced colocalization with early endosome antigen (EEA1). Also, cell apoptosis and inhibition of phosphorylation of EGFR were demonstrated for the UB-3 compound. Thus, the proposed design of targeting PS containing cationic pyridyl moieties and a linker between the porphyrin macrocycle and Erlotinib can contribute to antitumor PDT.