A series of zinc(II) dipicolylamine (ZnDPA)-based drug conjugates have been synthesized to probe the potential of phosphatidylserine (PS) as a new antigen for small molecule drug conjugate (SMDC) development. Using in vitro cytotoxicity and plasma stability studies, PS-binding assay, in vivo pharmacokinetic studies, and maximum tolerated dose profiles, we provided a roadmap and the key parameters required for the development of the ZnDPA based drug conjugate. In particular, conjugate 24 induced tumor regression in the COLO 205 xenograft model and exhibited a more potent antitumor effect with a 70% reduction of cytotoxic payload compared to that of the marketed irinotecan when dosed at the same regimen. In addition to the validation of PS as an effective pharmacodelivery target for SMDC, our work also provided the foundation that, if applicable, a variety of therapeutic agents could be conjugated in the same manner to treat other PS-associated diseases.

中文翻译：

---

靶向肿瘤相关的磷脂酰丝氨酸与新的基于二吡啶甲胺锌的药物缀合物

已经合成了一系列基于锌（II）二聚烯丙基胺（ZnDPA）的药物偶联物，以探测磷脂酰丝氨酸（PS）作为开发小分子药物偶联物（SMDC）的新抗原的潜力。使用体外细胞毒性和血浆稳定性研究，PS结合测定，体内药代动力学研究以及最大耐受剂量曲线，我们提供了开发基于ZnDPA的药物偶联物所需的路线图和关键参数。特别是缀合物24与市售伊立替康相比，在相同方案下给药时，可在COLO 205异种移植模型中诱导肿瘤消退，并表现出更有效的抗肿瘤作用，细胞毒性有效载荷降低70％。除了将PS确认为SMDC的有效药物递送靶标外，我们的工作还提供了以下基础：如果适用，可以以相同方式结合多种治疗剂来治疗其他与PS相关的疾病。