Abstract
The epidermal growth factor-epidermal growth factor receptor (EGF-EGFR) pathway has become the main focus of selective chemotherapeutic intervention. As a result, two classes of EGFR inhibitors have been clinically approved, namely monoclonal antibodies and small molecule kinase inhibitors. Despite an initial good response rate to these drugs, most patients develop drug resistance. Therefore, new treatment approaches are needed. In this work, we aimed to find a new EGFR-specific, short cyclic peptide, which could be used for targeted drug delivery. Phage display peptide technology and biopanning were applied to three EGFR expressing cells, including cells expressing the EGFRvIII mutation. DNA from the internalized phage was extracted and the peptide inserts were sequenced using next-generation sequencing (NGS). Eleven peptides were selected for further investigation using binding, internalization, and competition assays, and the results were confirmed by confocal microscopy and peptide docking. Among these eleven peptides, seven showed specific and selective binding and internalization into EGFR positive (EGFR+ve) cells, with two of them-P6 and P9-also demonstrating high specificity for non-small cell lung cancer (NSCLC) and glioblastoma cells, respectively. These peptides were chemically conjugated to camptothecin (CPT). The conjugates were more cytotoxic to EGFR+ve cells than free CPT. Our results describe a novel cyclic peptide, which can be used for targeted drug delivery to cells overexpressing the EGFR and EGFRvIII mutation.
Overview
- The study aims to find a new EGFR-specific, short cyclic peptide for targeted drug delivery to cells overexpressing the EGFR and EGFRvIII mutation. The methodology used includes phage display peptide technology and biopanning, DNA extraction, NGS, binding, internalization, and competition assays, and peptide docking. The primary objective is to identify peptides with specific and selective binding and internalization into EGFR+ve cells, which can be chemically conjugated to camptothecin (CPT) for targeted drug delivery. The study seeks to answer the question of whether a new cyclic peptide can be used for targeted drug delivery to cells overexpressing the EGFR and EGFRvIII mutation.
Comparative Analysis & Findings
- Eleven peptides were selected for further investigation, and seven of them showed specific and selective binding and internalization into EGFR+ve cells. Two of these peptides-P6 and P9-demonstrated high specificity for NSCLC and glioblastoma cells, respectively. The conjugates of these peptides with camptothecin (CPT) were more cytotoxic to EGFR+ve cells than free CPT. The study found that P6 and P9 are promising candidates for targeted drug delivery to cells overexpressing the EGFR and EGFRvIII mutation.
Implications and Future Directions
- The study's findings suggest that a new cyclic peptide can be used for targeted drug delivery to cells overexpressing the EGFR and EGFRvIII mutation. The study's limitations include the need for further preclinical and clinical studies to evaluate the safety and efficacy of the identified peptides. Future research directions could include the development of a targeted drug delivery system using the identified peptides and the evaluation of their efficacy in animal models and clinical trials. Additionally, the study could be extended to investigate the use of the identified peptides in combination with other targeted therapies for the treatment of NSCLC and glioblastoma.