Evaluation of New Radiolabeled Anti-Egfr Peptide Modified by Bis(semicarbazone) Metal Chelator as Theranostic Strategy in Colorectal and Head and Neck Cancers

Colorectal cancer (CRC) and head and neck squamous cell carcinoma (HNSCC) remain major challenges in oncology due to their high incidence, aggressive behavior, and frequent resistance to targeted therapies. Dysregulation of the epidermal growth factor receptor (EGFR) signaling pathway is a common molecular hallmark of both malignancies and is strongly associated with poor prognosis. Although anti-EGFR therapies are clinically available, their efficacy is limited by intrinsic and acquired resistance mechanisms, including RAS mutations in CRC and activation of alternative signaling pathways in HNSCC. These limitations highlight the need for innovative strategies that combine precise molecular targeting with alternative mechanisms of tumor control. In this context, nuclear medicine theranostics, integrating diagnosis and therapy within a single molecular platform, represents a promising approach. This study aims to evaluate, in preclinical models, a novel radiolabeled anti-EGFR peptide (coded for intellectual property protection) conjugated to a bis(semicarbazone) metal chelator as a potential theranostic agent for colorectal and head and neck cancers. A bis(semicarbazone)-based bifunctional chelator was synthesized and conjugated to a coded anti-EGFR peptide, enabling stable coordination with diagnostic (68Ga) and therapeutic (67Cu/64Cu) radionuclides. The resulting compound will be characterized in terms of radiochemical purity and stability. In vitro studies will be conducted using EGFR-positive CRC and HNSCC cell lines, employing both two-dimensional cultures and three-dimensional spheroid models to evaluate binding specificity, internalization, cytotoxicity, and mechanisms of cell death. Molecular effects on proliferative and apoptotic signaling pathways will be investigated. In vivo experiments will include biodistribution, acute toxicity, and imaging evaluation by micro-PET/SPECT/CT in healthy mice and tumor-bearing xenograft models, as well as assessment of antitumor efficacy in therapeutic settings. It is expected that the radiolabeled peptide–chelator conjugate will demonstrate high radiochemical stability and selective interaction with EGFR-overexpressing tumor cells. In vitro assays are anticipated to show efficient tumor targeting, adequate penetration in three-dimensional tumor models, and induction of tumor cell death through radiation-mediated mechanisms. In vivo studies are expected to reveal favorable pharmacokinetic profiles, enhanced tumor uptake, limited nonspecific accumulation, and acceptable safety margins. This project is expected to generate robust preclinical evidence supporting the use of a bis(semicarbazone)-modified, radiolabeled anti-EGFR peptide as an innovative theranostic platform for colorectal and head and neck cancers. The proposed strategy may contribute to improved patient stratification, high-contrast molecular imaging, and the development of targeted radiotherapeutic approaches, addressing key limitations of current EGFR-directed treatments.