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中性粒细胞弹性蛋白酶促进整合素靶向缀合物的连接子断裂和紫杉醇释放。

Neutrophil Elastase Promotes Linker Cleavage and Paclitaxel Release from an Integrin-Targeted Conjugate.

机构信息

Università degli Studi di Milano, Dipartimento di Chimica, Via C. Golgi, 19, I-20133, Milan, Italy.

Medicinal Chemistry Wuppertal, Bayer AG, 42113, Wuppertal, Germany.

出版信息

Chemistry. 2019 Feb 1;25(7):1696-1700. doi: 10.1002/chem.201805447. Epub 2018 Dec 27.

DOI:10.1002/chem.201805447
PMID:30452790
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6471013/
Abstract

This work takes advantage of one of the hallmarks of cancer, that is, the presence of tumor infiltrating cells of the immune system and leukocyte-secreted enzymes, to promote the activation of an anticancer drug at the tumor site. The peptidomimetic integrin ligand cyclo(DKP-RGD) was found to accumulate on the surface of α β integrin-expressing human renal cell carcinoma 786-O cells. The ligand was conjugated to the anticancer drug paclitaxel through a Asn-Pro-Val (NPV) tripeptide linker, which is a substrate of neutrophil-secreted elastase. In vitro linker cleavage assays and cell antiproliferative experiments demonstrate the efficacy of this tumor-targeting conjugate, opening the way to potential therapeutic applications.

摘要

这项工作利用了癌症的一个标志，即免疫系统的肿瘤浸润细胞和白细胞分泌的酶的存在，以促进抗癌药物在肿瘤部位的激活。发现肽模拟整合素配体环(DKP-RGD)在表达αβ整合素的人肾癌细胞 786-O 细胞表面积累。该配体通过天冬酰胺-脯氨酸-缬氨酸 (NPV) 三肽接头与抗癌药物紫杉醇偶联，该接头是中性粒细胞分泌的弹性蛋白酶的底物。体外接头切割测定和细胞增殖抑制实验证明了这种肿瘤靶向缀合物的功效，为潜在的治疗应用开辟了道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00dd/6471013/522121b24880/CHEM-25-1696-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00dd/6471013/4304556d352a/CHEM-25-1696-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00dd/6471013/3f8dc811e0ef/CHEM-25-1696-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00dd/6471013/522121b24880/CHEM-25-1696-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00dd/6471013/4304556d352a/CHEM-25-1696-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00dd/6471013/3f8dc811e0ef/CHEM-25-1696-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00dd/6471013/522121b24880/CHEM-25-1696-g003.jpg

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Succinimide-Based Conjugates Improve IsoDGR Cyclopeptide Affinity to αβ without Promoting Integrin Allosteric Activation.
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A Small Molecule-Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an αß Binder for the Treatment of Multiple Cancer Types.一种小分子药物偶联物（SMDC），由与αβ结合剂相连的修饰喜树碱有效载荷组成，用于治疗多种癌症类型。
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