Department of Organic Chemistry, Faculty of Science, Palacký University, Tr. 17. Listopadu 12, 771 46 Olomouc, Czech Republic.
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 779 00 Olomouc, Czech Republic.
Mol Pharm. 2021 Jun 7;18(6):2385-2396. doi: 10.1021/acs.molpharmaceut.1c00219. Epub 2021 May 7.
In this work, we report two concepts of drug delivery based on small-molecule drug conjugates with the ability of specific targeting and drug release monitoring via ratiometric fluorescence. The functionality of these concepts has been verified by two model systems consisting of three parts: (i) fluorescent aminoBODIPY for real-time detection of conjugate cleavage, (ii) a c(RGDfK) peptide specific for αβ integrin receptors targeting angiogenesis in most solid tumors or redBODIPY for conjugate cleavage monitoring via FRET, and (iii) pegylated-2-phenyl-3-hydroxy-4(1)-quinolinone (3HQ) as a model drug. The model drug release is based on a self-immolative disulfide linker sensitive to environments containing thiols, especially glutathione, which is overexpressed in cancer cells. The results show effective thiol-mediated cleavage of the fluorescent reporter and the subsequent liberation of the drug in a tube. The conjugate with c(RGDfK) was confirmed to penetrate the cells via interaction with integrin receptors. Drug release from this conjugate is possible to monitor inside the cells. Further, the synthetic approach to the conjugates and the method of fluorescence monitoring of the drug release have also been described.
在这项工作中，我们报告了两种基于小分子药物偶联物的药物传递概念，这些偶联物具有通过比率荧光进行特异性靶向和药物释放监测的能力。这两个概念的功能已通过两个模型系统得到验证，这些模型系统由三个部分组成：(i) 用于实时检测偶联物裂解的荧光氨基 BODIPY，(ii) 针对大多数实体瘤中血管生成的 αβ 整合素受体的 c(RGDfK) 肽或用于通过 FRET 监测偶联物裂解的红色 BODIPY，以及 (iii) 作为模型药物的聚乙二醇化-2-苯基-3-羟基-4(1)-喹啉酮(3HQ)。模型药物释放基于对含有巯基的环境敏感的自耗竭二硫键连接体，特别是在癌细胞中过度表达的谷胱甘肽。结果表明，荧光报告分子的有效巯基介导裂解，随后在管中释放药物。已确认带有 c(RGDfK)的偶联物通过与整合素受体相互作用穿透细胞。可以监测细胞内这种偶联物的药物释放。此外，还描述了偶联物的合成方法和药物释放的荧光监测方法。
