Design Synthesis and Biological Evaluation of Novel Polyaminocarboxylate Ligand-Based Theranostic Conjugate for Antibody-Targeted Cancer Therapy and Near-Infrared Optical Imaging

摘要

We report design, synthesis, and evaluation of polyaminocarboxylate ligand-based antibody conjugate for potential application in targeted cancer therapy and near infrared fluorescent imaging. We synthesized a new polyaminocarboxylate chelate (CAB-NE3TA) as a potential anti-cancer agent. CAB-NE3TA displayed potent inhibitory activities against different cancer cell lines. We then designed a multifunctional theranostic platform (CAB-NE3TA-PAN-IR800) constructed on an EGFR-targeted antibody (panitumumab, PAN) labeled with a near IR fluorescent dye. We also built the first atomistic model of the EGFR-PAN complex and loaded it with the cytotoxic CAB-NE3TA and the near IR dye. The therapeutic (CAB-NE3TA-PAN) and theranostic (CAB-NE3TA-PAN-IR800) conjugates were evaluated using EGFR-positive A431 (human skin cancer) cell xenograft mouse model. Biodistribution studies using near IR fluorescence imaging demonstrated that the CAB-NE3TA-PAN labeled with the IR800 dye selectively targeted the A431 tumors in mice and resulted in prolonged retention in the tumor tissue and displayed excellent clearance in blood and normal organs. The therapeutic conjugate was capable of significantly inhibiting tumor growth, leading to nearly complete disappearance of tumors in the mice. The results of our pilot in vivo studies support further evaluation of the novel ligand-based therapeutic and theranostic conjugates for targeted iron chelation cancer therapy and imaging applications.