Multivalent Peptide Nanotherapeutics Enhance Epidermal Growth Factor Receptor Binding, Modulate Associated Signaling, and Suppress Tumor Growth

Epidermal growth factor receptor (EGFR) is frequently overexpressed in epithelial malignancies and represents a well-validated therapeutic target. Although EGFR-targeting monoclonal antibodies and tyrosine kinase inhibitors have been widely used in clinics, their effectiveness is often hindered by resistance and adverse effects. Peptides offer a promising alternative due to their low immunogenicity and synthetic accessibility, yet their therapeutic application has been constrained by poor stability and weak receptor binding affinity. Here, we report the development of a multivalent EGFR-targeting dendrimer–peptide conjugate (G7-pEGFR) platform, generated by conjugating multiple EGFR-binding peptides to a generation 7 (G7) poly(amidoamine) (PAMAM) dendrimer. The multivalency markedly enhanced EGFR binding avidity and was associated with changes in EGFR-associated signaling markers, including lower levels of phosphorylated mitogen-activated protein kinase (MAPK) and c-Jun in EGFR-expressing cells. Importantly, intravenous injections of G7-pEGFR significantly delayed tumor growth in a syngeneic oral squamous cell carcinoma mouse model without noticeable toxicity. Tumor tissue analyses were consistent with changes in EGFR-associated signaling markers, reduced tumor cell proliferation, and increased apoptosis, although the phospho-EGFR and phospho-MAPK staining should be interpreted cautiously. These results collectively demonstrate the potential of G7-pEGFR as a modular nanomedicine platform for peptide-based, receptor-specific cancer therapy.