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Selective Integrin Ligands Promote Cell Internalization of the Antineoplastic Agent Fluorouracil
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-09-02 , DOI: 10.1021/acsptsci.1c00094 Monica Baiula 1 , Martina Cirillo 2 , Giulia Martelli 2 , Valentina Giraldi 1, 2 , Elisa Gasparini 2 , Alessandro Claudio Anelli 2 , Santi Mario Spampinato 1 , Daria Giacomini 2
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-09-02 , DOI: 10.1021/acsptsci.1c00094 Monica Baiula 1 , Martina Cirillo 2 , Giulia Martelli 2 , Valentina Giraldi 1, 2 , Elisa Gasparini 2 , Alessandro Claudio Anelli 2 , Santi Mario Spampinato 1 , Daria Giacomini 2
Affiliation
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Drug conjugates consisting of an antineoplastic drug and a targeting receptor ligand could be effective to overcome the heavy side effects of unselective anticancer agents. To address this need, we report here the results of a project aimed to study agonist and antagonist integrin ligands as targeting head of molecular cargoes for the selective delivery of 5-fluorouracil (5-FU) to cancer or noncancer cells. Initially, two fluorescent β-lactam-based integrin ligands were synthesized and tested for an effective and selective internalization mediated by α4β1 or α5β1 integrins in Jurkat and K562 cells, respectively. No cellular uptake was observed for both fluorescent compounds in HEK293 noncancerous control cells. Afterward, three conjugates composed of the β-lactam-based integrin ligand, suitable linkers, and 5-FU were realized. The best compound E, acting as α5β1 integrin agonist, is able to selectively deliver 5-FU into tumor cells, successfully leading to cancer cell death.
中文翻译：
选择性整合素配体促进抗肿瘤药物氟尿嘧啶的细胞内化
由抗肿瘤药物和靶向受体配体组成的药物缀合物可以有效克服非选择性抗癌药物的严重副作用。为了满足这一需求，我们在此报告了一个项目的结果，该项目旨在研究激动剂和拮抗剂整联蛋白配体作为靶向分子货物的头部，用于选择性地将 5-氟尿嘧啶 (5-FU) 递送至癌细胞或非癌细胞。最初，合成了两种基于 β-内酰胺的荧光整合素配体，并分别在 Jurkat 和 K562 细胞中测试了 α 4 β 1或 α 5 β 1整合素介导的有效和选择性内化。在 HEK293 非癌对照细胞中没有观察到两种荧光化合物的细胞摄取。随后，实现了由基于β-内酰胺的整合素配体、合适的接头和5-FU组成的三种缀合物。最好的化合物E作为α 5 β 1整合素激动剂，能够选择性地将5-FU递送到肿瘤细胞中，成功导致癌细胞死亡。
更新日期：2021-10-08
中文翻译：
选择性整合素配体促进抗肿瘤药物氟尿嘧啶的细胞内化
由抗肿瘤药物和靶向受体配体组成的药物缀合物可以有效克服非选择性抗癌药物的严重副作用。为了满足这一需求，我们在此报告了一个项目的结果，该项目旨在研究激动剂和拮抗剂整联蛋白配体作为靶向分子货物的头部，用于选择性地将 5-氟尿嘧啶 (5-FU) 递送至癌细胞或非癌细胞。最初，合成了两种基于 β-内酰胺的荧光整合素配体，并分别在 Jurkat 和 K562 细胞中测试了 α 4 β 1或 α 5 β 1整合素介导的有效和选择性内化。在 HEK293 非癌对照细胞中没有观察到两种荧光化合物的细胞摄取。随后，实现了由基于β-内酰胺的整合素配体、合适的接头和5-FU组成的三种缀合物。最好的化合物E作为α 5 β 1整合素激动剂，能够选择性地将5-FU递送到肿瘤细胞中，成功导致癌细胞死亡。
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