EGFR-Targeted Photodynamic Treatment of Triple Negative Breast Cancer Cell Lines Using Porphyrin–Peptide Conjugates: Synthesis and Mechanistic Insight

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, limiting the efficacy of conventional targeted therapies. As a result, novel therapeutic strategies are urgently needed. Photodynamic therapy (PDT), which relies on the activation of photosensitizers (PSs) by light to induce cytotoxic effects, has emerged as a promising alternative for TNBC treatment. Furthermore, the conjugation of PSs with targeting peptides has demonstrated enhanced selectivity and therapeutic efficacy, particularly for porphyrin-based photosensitizers. In this study, we report the synthesis of novel porphyrin-peptide conjugates designed to selectively target the epidermal growth factor receptor (EGFR), which is frequently overexpressed in TNBC. The conjugates were prepared via thiol displacement of the meso-nitro group in a 5,15-diarylporphyrin scaffold using EGFR-binding peptides. Photodynamic activity was evaluated in two EGFR-overexpressing TNBC cell lines. Cellular uptake of the conjugates correlated with EGFR expression levels, and PDT treatment resulted in differential induction of necrosis, apoptosis, and autophagy. Notably, the conjugates significantly inhibited EGFR-expressing cell line migration, a critical hallmark of metastatic progression. These findings underscore the potential of EGFR-targeted porphyrin-peptide conjugates as promising PDT agents for the treatment of TNBC.