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.

中文翻译：

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用于抗体靶向癌症治疗和近红外光学成像的基于聚氨基羧酸酯配体的治疗诊断缀合物的设计、合成和生物学评价

我们报告了基于聚氨基羧酸酯配体的抗体缀合物的设计、合成和评估，其在靶向癌症治疗和近红外（NIR）荧光成像中的潜在应用。我们合成了一种新的聚氨基羧酸螯合物（CAB-NE3TA）作为潜在的抗癌剂。CAB-NE3TA 对多种癌细胞系表现出有效的抑制活性。然后，我们设计了一个多功能治疗诊断平台（CAB-NE3TA-PAN-IR800），该平台基于用近红外荧光染料标记的表皮生长因子受体（EGFR）靶向抗体（帕尼单抗，PAN）构建。我们还构建了 EGFR-PAN 复合物的第一个原子模型，并为其加载了细胞毒性 CAB-NE3TA 和近红外染料。使用 EGFR 阳性 A431（人皮肤癌）细胞异种移植小鼠模型对治疗 (CAB-NE3TA-PAN) 和治疗诊断 (CAB-NE3TA-PAN-IR800) 缀合物进行评估。使用近红外荧光成像的生物分布研究表明，用 IR800 染料标记的 CAB-NE3TA-PAN 选择性地靶向小鼠的 A431 肿瘤，导致在肿瘤组织中长时间保留，并在血液和正常器官中显示出优异的清除率。该治疗缀合物能够显着抑制肿瘤生长，导致小鼠体内的肿瘤几乎完全消失。我们的体内试验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缀合物，用于靶向铁螯合癌症治疗和成像应用。