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Linker Hydrophilicity Modulates the Anticancer Activity of RGD-Cryptophycin Conjugates.
Chemistry - A European Journal ( IF 4.3 ) Pub Date : 2020-09-21 , DOI: 10.1002/chem.202003471
Michele Anselmi 1, 2 , Adina Borbély 1 , Eduard Figueras 1 , Carmela Michalek 1 , Isabell Kemker 1 , Luca Gentilucci 2 , Norbert Sewald 1
Affiliation  

Most anticancer agents are hydrophobic and can easily penetrate the tumor cell membrane by passive diffusion. This may impede the development of highly effective and tumor‐selective treatment options. A hydrophilic β‐glucuronidase‐cleavable linker was used to connect the highly potent antimitotic agent cryptophycin‐55 glycinate with the αvβ3 integrin ligand c(RGDfK). Incorporation of the self‐immolative linker containing glucuronic acid results in lower cytotoxicity than that of the free payload, suggesting that hydrophilic sugar linkers can preclude passive cellular uptake. In vitro drug‐release studies and cytotoxicity assays demonstrated the potential of this small molecule–drug conjugate, providing guidance for the development of therapeutics containing hydrophobic anticancer drugs.

中文翻译:

连接体亲水性调节 RGD-隐藻素缀合物的抗癌活性。

大多数抗癌剂都是疏水性的,可以通过被动扩散轻松穿透肿瘤细胞膜。这可能会阻碍高效和肿瘤选择性治疗方案的开发。使用亲水性 β-葡萄糖醛酸酶可裂解接头将高效抗有丝分裂剂 Cryptophycin-55 甘氨酸盐与 α v β 3整联蛋白配体c (RGDfK) 连接起来。掺入含有葡萄糖醛酸的自毁连接体会导致比游离有效负载更低的细胞毒性,这表明亲水性糖连接体可以阻止被动细胞摄取。体外药物释放研究和细胞毒性测定证明了这种小分子药物缀合物的潜力,为开发含有疏水性抗癌药物的疗法提供了指导。
更新日期:2020-09-21
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