A number of cancer-targeting peptide-drug conjugates (PDCs) have been explored as alternatives to antibody-drug conjugates (ADCs) for targeted cancer therapy. However, the much shorter circulation half-life of PDCs compared with ADCs in vivo has limited their therapeutic value and thus their translation into the clinic, highlighting the need to develop new approaches for extending the half-life of PDCs. Here, we report a new strategy for targeted cancer therapy of a PDC based on a molecular hybrid between an antihapten antibody and a hapten-labeled PDC. An anticotinine antibody (Ab^cot) was used as a model antihapten antibody. The anticancer drug SN38 was linked to a cotinine-labeled aptide specific to extra domain B of fibronectin (cot-APT_EDB), yielding the model PDC, cot-APT_EDB-SN38. The cotinine-labeled PDC showed specific binding to and cytotoxicity toward an EDB-overexpressing human glioblastoma cell line (U87MG) and also formed a hybrid complex (HC) with Ab^cot in situ, designated HC[cot-APT_EDB–SN38/Ab^cot]. In glioblastoma-bearing mice, in situ HC[cot-APT_EDB–SN38/Ab^cot] significantly extended the circulation half-life of cot-APT_EDB-SN38 in blood, and it enhanced accumulation and penetration within the tumor and, ultimately, inhibition of tumor growth. These findings suggest that the present platform holds promise as a new, targeted delivery strategy for PDCs in anticancer therapy.

中文翻译：

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靶向药物治疗的肽药物偶联物的抗体辅助递送

已经探索了许多靶向癌症的肽-药物缀合物（PDC），作为用于靶向癌症治疗的抗体-药物缀合物（ADC）的替代品。但是，与体内ADC相比，PDC的循环半衰期短得多，因而限制了它们的治疗价值，因此限制了它们在临床上的转化，这突出表明需要开发新的方法来延长PDC的半衰期。在这里，我们报告了基于抗半抗原抗体和半抗原标记的PDC之间的分子杂交的PDC靶向癌症治疗的新策略。抗可卡因抗体（Ab ^cot）用作模型抗半抗原抗体。将抗癌药物SN38与对纤连蛋白的额外结构域B（cot-APT _EDB）特异的可替宁标记的适肽相连，产生了模型PDC，cot-APT_EDB -SN38。可替宁标记的PDC对过表达EDB的人胶质母细胞瘤细胞系（U87MG）具有特异性结合并具有细胞毒性，并且还与原位Ab ^cot形成杂合复合体（HC），称为HC [cot-APT _EDB –SN38 / Ab ^cot ]。在带有胶质母细胞瘤的小鼠中，原位HC [cot-APT _EDB –SN38 / Ab ^cot ]可以显着延长cot-APT _EDB -SN38在血液中的循环半衰期，并增强肿瘤内的积累和渗透，最终，抑制肿瘤生长。这些发现表明，该平台有望作为抗癌治疗中PDC的新型靶向递送策略。