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具有白蛋白结合特性和免疫调节配体的三功能作用铂（IV）前药的结构-活性关系。

Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands.

机构信息

Faculty of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.

Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.

出版信息

J Med Chem. 2021 Aug 26;64(16):12132-12151. doi: 10.1021/acs.jmedchem.1c00770. Epub 2021 Aug 17.

DOI:10.1021/acs.jmedchem.1c00770
PMID:34403254
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8404199/
Abstract

Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum(IV) prodrugs, which, in addition to tumor targeting maleimide-mediated albumin binding, release the immunomodulatory ligand 1-methyl-d-tryptophan (1-MDT). Unexpectedly, structure-activity relationship analysis showed that the mode of 1-MDT conjugation distinctly impacts the reducibility and thus activation of the prodrugs. This in turn affected ligand release, pharmacokinetic properties, efficiency of immunomodulation, and the anticancer activity and in a mouse model . Moreover, we could demonstrate that the design of albumin-targeted multi-modal prodrugs using platinum(IV) is a promising strategy to enhance the cellular uptake of bioactive ligands with low cell permeability (1-MDT) and to improve their selective delivery into the malignant tissue. This will allow tumor-specific anticancer therapy supported by a favorably tuned immune microenvironment.

摘要

铂类配合物化疗对于临床抗癌治疗至关重要。然而，由于副作用和耐药性的问题，迫切需要进一步改进药物。在此，我们报告了三功能铂（IV）前药，除了肿瘤靶向马来酰亚胺介导的白蛋白结合外，还释放免疫调节配体 1-甲基-d-色氨酸（1-MDT）。出乎意料的是，构效关系分析表明，1-MDT 连接方式明显影响前药的还原能力，从而影响其激活。这反过来又影响配体释放、药代动力学特性、免疫调节效率以及在小鼠模型中的抗癌活性。此外，我们还证明了使用铂（IV）设计白蛋白靶向多模式前药是一种很有前途的策略，可以增强低细胞通透性生物活性配体（1-MDT）的细胞摄取，并将其选择性递送至恶性组织。这将允许在有利调节的免疫微环境的支持下进行肿瘤特异性抗癌治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b7/8404199/4a31ef4040e4/jm1c00770_0010.jpg
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