文章：

VIP236的发现：一种靶向αvβ3的小分子药物偶联物，通过中性粒细胞弹性蛋白酶介导激活7-乙基喜树碱有效载荷，用于实体瘤治疗

Discovery of VIP236, an αvβ3-Targeted Small-Molecule–Drug Conjugate with Neutrophil Elastase-Mediated Activation of 7-Ethyl Camptothecin Payload for Treatment of Solid Tumors

原文发布日期：1 September 2023

DOI: 10.3390/cancers15174381

类型: Article

开放获取: 是

英文摘要：

The emerging field of small-molecule–drug conjugates (SMDCs) using small-molecule biomarker-targeted compounds for tumor homing may provide new perspectives for targeted delivery. Here, for the first time, we disclose the structure and the synthesis of VIP236, an SMDC designed for the treatment of metastatic solid tumors by targeting αvβ3 integrins and extracellular cleavage of the 7-ethyl camptothecin payload by neutrophil elastase in the tumor microenvironment. Imaging studies in the Lewis lung mouse model using an elastase cleavable quenched substrate showed pronounced elastase activity in the tumor. Pharmacokinetics studies of VIP236 in tumor-bearing mice demonstrated high stability of the SMDC in plasma and high tumor accumulation of the cleaved payload. Studies in bile-duct-cannulated rats showed that biliary excretion of the unmodified conjugate is the primary route of elimination. Treatment- and time-dependent phosphorylation of H2AX, a marker of DNA damage downstream of topoisomerase 1 inhibition, verified the on-target activity of the payload cleaved from VIP236 in vivo. Treatment with VIP236 resulted in long-lasting tumor regression in subcutaneous patient-derived xenograft (PDX) models from patients with non-small-cell lung, colon, and renal cancer as well as in two orthotopic metastatic triple-negative breast cancer PDX models. In these models, a significant reduction of brain and lung metastases also was observed.

摘要翻译： 

利用小分子生物标志物靶向化合物实现肿瘤归巢的小分子药物偶联物（SMDCs）这一新兴领域，可能为靶向递送提供新的视角。本文首次公开了VIP236的结构与合成方法，这是一种通过靶向αvβ3整合素、并在肿瘤微环境中经中性粒细胞弹性蛋白酶切割释放7-乙基喜树碱有效载荷，用于治疗转移性实体瘤的SMDC。在Lewis肺癌小鼠模型中，使用弹性蛋白酶可切割淬灭底物进行的成像研究显示肿瘤内存在显著的弹性蛋白酶活性。荷瘤小鼠体内药代动力学研究表明，VIP236在血浆中具有高稳定性，且切割后的有效载荷在肿瘤中高度积累。胆管插管大鼠实验表明，未经修饰的偶联物主要通过胆汁排泄途径消除。作为拓扑异构酶1抑制下游DNA损伤标志物的H2AX蛋白呈现治疗与时间依赖性磷酸化，证实了VIP236在体内释放的有效载荷具有靶向活性。在非小细胞肺癌、结肠癌和肾癌患者的皮下人源肿瘤异种移植（PDX）模型以及两种原位转移性三阴性乳腺癌PDX模型中，VIP236治疗能实现持久的肿瘤消退。在这些模型中，还观察到脑转移和肺转移的显著减少。

原文链接：

Discovery of VIP236, an αvβ3-Targeted Small-Molecule–Drug Conjugate with Neutrophil Elastase-Mediated Activation of 7-Ethyl Camptothecin Payload for Treatment of Solid Tumors