Drug Delivery and Translational Research ( IF 5.7 ) Pub Date : 2022-07-11 , DOI: 10.1007/s13346-022-01204-8 Federica De Lorenzi 1 , Larissa Yokota Rizzo 1 , Rasika Daware 1 , Alessandro Motta 1 , Maike Baues 1 , Matthias Bartneck 2 , Michael Vogt 3 , Marc van Zandvoort 4, 5 , Leonard Kaps 6, 7 , Qizhi Hu 8 , Marielle Thewissen 8 , Luca Casettari 9 , Cristianne J F Rijcken 8 , Fabian Kiessling 10, 11 , Alexandros Marios Sofias 1, 12, 13 , Twan Lammers 1
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Polymeric micelles are increasingly explored for tumor-targeted drug delivery. CriPec® technology enables the generation of core‐crosslinked polymeric micelles (CCPMs) based on thermosensitive (mPEG-b-pHPMAmLacn) block copolymers, with high drug loading capacity, tailorable size, and controlled drug release kinetics. In this study, we decorated clinical-stage CCPM with the αvβ3 integrin-targeted cyclic arginine-glycine-aspartic acid (cRGD) peptide, which is one of the most well-known active targeting ligands evaluated preclinically and clinically. Using a panel of cell lines with different expression levels of the αvβ3 integrin receptor and exploring both static and dynamic incubation conditions, we studied the benefit of decorating CCPM with different densities of cRGD. We show that incubation time and temperature, as well as the expression levels of αvβ3 integrin by target cells, positively influence cRGD-CCPM uptake, as demonstated by immunofluorescence staining and fluorescence microscopy. We demonstrate that even very low decoration densities (i.e., 1 mol % cRGD) result in increased engagement and uptake by target cells as compared to peptide-free control CCPM, and that high cRGD decoration densities do not result in a proportional increase in internalization. In this context, it should be kept in mind that a more extensive presence of targeting ligands on the surface of nanomedicines may affect their pharmacokinetic and biodistribution profile. Thus, we suggest a relatively low cRGD decoration density as most suitable for in vivo application.
Graphical Abstract
中文翻译：
分析 cRGD 装饰的临床阶段核心交联聚合物胶束的目标参与和细胞摄取
越来越多地探索聚合物胶束用于肿瘤靶向药物递送。CriPec® 技术能够生成基于热敏 (mPEG-b-pHPMAmLac n ) 嵌段共聚物的核心交联聚合物胶束 (CCPM)，具有高载药量、可定制的尺寸和受控的药物释放动力学。在这项研究中，我们用 α v β 3整合素靶向环精氨酸-甘氨酸-天冬氨酸 (cRGD) 肽装饰了临床阶段的 CCPM，它是临床前和临床评估中最著名的活性靶向配体之一。使用一组具有不同 α v β 3表达水平的细胞系整合素受体并探索静态和动态孵育条件，我们研究了用不同密度的 cRGD 装饰 CCPM 的好处。我们展示了孵育时间和温度，以及 α v β 3的表达水平免疫荧光染色和荧光显微镜证实，靶细胞整合素对 cRGD-CCPM 摄取有积极影响。我们证明，与无肽对照 CCPM 相比，即使非常低的装饰密度（即 1 mol % cRGD）也会导致靶细胞的参与和摄取增加，并且高 cRGD 装饰密度不会导致内化成比例增加。在这种情况下，应该记住，纳米药物表面更广泛存在的靶向配体可能会影响它们的药代动力学和生物分布特征。因此，我们建议相对较低的 cRGD 装饰密度最适合体内应用。
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