Department of Chemistry, Illinois Institute of Technology, 3101 South Dearborn Street, LS 182, Chicago, IL, 60616, USA.
Department of Biomedical Engineering, Armour College of Engineering, Illinois Institute of Technology, Chicago, IL, 60616, USA.
ChemMedChem. 2018 Dec 20;13(24):2606-2617. doi: 10.1002/cmdc.201800598. Epub 2018 Nov 26.
We report the design, synthesis, and evaluation of polyaminocarboxylate ligand-based antibody conjugates for potential application in targeted cancer therapy and near-infrared (NIR) fluorescence imaging. We synthesized a new polyaminocarboxylate chelate (CAB-NE3TA) as a potential anticancer agent. CAB-NE3TA displayed potent inhibitory activities against various cancer cell lines. We then designed a multifunctional theranostic platform (CAB-NE3TA-PAN-IR800) constructed on an epidermal growth factor receptor (EGFR)-targeted antibody (panitumumab, PAN) labeled with a NIR fluorescent dye. We also built the first atomistic model of the EGFR-PAN complex and loaded it with the cytotoxic CAB-NE3TA and the NIR dye. The therapeutic (CAB-NE3TA-PAN) and theranostic (CAB-NE3TA-PAN-IR800) conjugates were evaluated using an EGFR-positive A431 (human skin cancer) cell xenograft mouse model. Biodistribution studies using NIR 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.
我们报告了聚氨基羧酸盐配体抗体偶联物的设计、合成和评估，用于潜在的靶向癌症治疗和近红外（NIR）荧光成像应用。我们合成了一种新的聚氨基羧酸盐螯合物（CAB-NE3TA）作为潜在的抗癌剂。CAB-NE3TA 对各种癌细胞系表现出强大的抑制活性。然后，我们设计了一种多功能治疗诊断平台（CAB-NE3TA-PAN-IR800），构建在表皮生长因子受体（EGFR）靶向抗体（panitumumab，PAN）上，并用近红外荧光染料标记。我们还构建了 EGFR-PAN 复合物的第一个原子模型，并将其与细胞毒性 CAB-NE3TA 和 NIR 染料一起加载。使用 EGFR 阳性 A431（人皮肤癌）细胞异种移植小鼠模型评估治疗（CAB-NE3TA-PAN）和治疗诊断（CAB-NE3TA-PAN-IR800）偶联物。使用 NIR 荧光成像进行的生物分布研究表明，用 IR800 染料标记的 CAB-NE3TA-PAN 选择性靶向小鼠中的 A431 肿瘤，并导致在肿瘤组织中的保留时间延长，并且在血液和正常器官中的清除率极好。治疗性偶联物能够显著抑制肿瘤生长，导致小鼠中的肿瘤几乎完全消失。我们的初步体内研究结果支持进一步评估新型基于配体的治疗和治疗诊断偶联物，用于靶向铁螯合癌症治疗和成像应用。
