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Influence of Riboflavin Targeting on Tumor Accumulation and Internalization of Peptostar Based Drug Delivery Systems
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-11-25 , DOI: 10.1021/acs.bioconjchem.0c00593 Milita Darguzyte 1 , Regina Holm 2 , Jasmin Baier 1 , Natascha Drude 1 , Jennifer Schultze 3 , Kaloian Koynov 3 , David Schwiertz 2 , Seyed Mohammadali Dadfar 1 , Twan Lammers 1 , Matthias Barz 2 , Fabian Kiessling 1, 4
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-11-25 , DOI: 10.1021/acs.bioconjchem.0c00593 Milita Darguzyte 1 , Regina Holm 2 , Jasmin Baier 1 , Natascha Drude 1 , Jennifer Schultze 3 , Kaloian Koynov 3 , David Schwiertz 2 , Seyed Mohammadali Dadfar 1 , Twan Lammers 1 , Matthias Barz 2 , Fabian Kiessling 1, 4
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Riboflavin carrier protein (RCP) and riboflavin transporters (RFVTs) have been reported to be highly overexpressed in various cancer cells. Hence, targeting RCP and RFVTs using riboflavin may enhance tumor accumulation and internalization of drug delivery systems. To test this hypothesis, butyl-based 3-arm peptostar polymers were synthesized consisting of a lysine core (10 units per arm) and a sarcosine shell (100 units per arm). The end groups of the arms and the core were successfully modified with riboflavin and the Cy5.5 fluorescent dye, respectively. While in phosphate buffered saline the functionalized peptostars showed a bimodal behavior and formed supramolecular structures over time, they were stable in the serum maintaining their hydrodynamic diameter of 12 nm. Moreover, the polymers were biocompatible and the uptake of riboflavin targeted peptostars in A431 and PC3 cells was higher than in nontargeted controls and could be blocked competitively. In vivo, the polymers showed a moderate passive tumor accumulation, which was not significantly different between targeted and nontargeted peptostars. Nonetheless, at the histological level, internalization into tumor cells was strongly enhanced for the riboflavin-targeted peptostars. Based on these results, we conclude that passive accumulation is dominating the accumulation of peptostars, while tumor cell internalization is strongly promoted by riboflavin targeting.
中文翻译：
核黄素靶向对基于Peptostar的药物递送系统的肿瘤积累和内在化的影响
核黄素载体蛋白（RCP）和核黄素转运蛋白（RFVT）据报道在各种癌细胞中高度过表达。因此，使用核黄素靶向RCP和RFVT可能会增强肿瘤积累和药物递送系统的内在化。为了检验该假设，合成了由赖氨酸核心（每臂10个单位）和肌氨酸外壳（每臂100个单位）组成的丁基基3臂peptostar聚合物。分别用核黄素和Cy5.5荧光染料成功修饰了臂和核心的端基。尽管功能化肽星在磷酸盐缓冲盐水中显示出双峰行为并随时间形成超分子结构，但它们在血清中稳定并保持其流体动力学直径为12 nm。此外，这些聚合物具有生物相容性，并且核黄素靶向肽星在A431和PC3细胞中的摄取要高于非靶向对照，并且可能被竞争性阻断。在体内，聚合物显示出中等程度的被动肿瘤蓄积，在靶向和非靶向肽星之间没有显着差异。然而，在组织学水平上，针对核黄素的肽星大大增强了向肿瘤细胞的内在化。根据这些结果，我们得出结论，被动积累在肽星的积累中占主导地位，而核黄素靶向强烈促进肿瘤细胞的内在化。有针对性的和无针对性的肽星之间没有显着差异。然而，在组织学水平上，针对核黄素的肽星大大增强了向肿瘤细胞的内在化。根据这些结果，我们得出结论，被动积累在肽星的积累中占主导地位，而核黄素靶向强烈促进肿瘤细胞的内在化。有针对性的和无针对性的肽星之间没有显着差异。然而，在组织学水平上，针对核黄素的肽星大大增强了向肿瘤细胞的内在化。根据这些结果，我们得出结论，被动积累在肽星的积累中占主导地位，而核黄素靶向强烈促进肿瘤细胞的内在化。
更新日期：2020-12-16
中文翻译：
核黄素靶向对基于Peptostar的药物递送系统的肿瘤积累和内在化的影响
核黄素载体蛋白（RCP）和核黄素转运蛋白（RFVT）据报道在各种癌细胞中高度过表达。因此，使用核黄素靶向RCP和RFVT可能会增强肿瘤积累和药物递送系统的内在化。为了检验该假设，合成了由赖氨酸核心（每臂10个单位）和肌氨酸外壳（每臂100个单位）组成的丁基基3臂peptostar聚合物。分别用核黄素和Cy5.5荧光染料成功修饰了臂和核心的端基。尽管功能化肽星在磷酸盐缓冲盐水中显示出双峰行为并随时间形成超分子结构，但它们在血清中稳定并保持其流体动力学直径为12 nm。此外，这些聚合物具有生物相容性，并且核黄素靶向肽星在A431和PC3细胞中的摄取要高于非靶向对照，并且可能被竞争性阻断。在体内，聚合物显示出中等程度的被动肿瘤蓄积，在靶向和非靶向肽星之间没有显着差异。然而，在组织学水平上，针对核黄素的肽星大大增强了向肿瘤细胞的内在化。根据这些结果，我们得出结论，被动积累在肽星的积累中占主导地位，而核黄素靶向强烈促进肿瘤细胞的内在化。有针对性的和无针对性的肽星之间没有显着差异。然而，在组织学水平上，针对核黄素的肽星大大增强了向肿瘤细胞的内在化。根据这些结果，我们得出结论，被动积累在肽星的积累中占主导地位，而核黄素靶向强烈促进肿瘤细胞的内在化。有针对性的和无针对性的肽星之间没有显着差异。然而，在组织学水平上，针对核黄素的肽星大大增强了向肿瘤细胞的内在化。根据这些结果，我们得出结论，被动积累在肽星的积累中占主导地位，而核黄素靶向强烈促进肿瘤细胞的内在化。
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