Mechanically interlocked molecular architectures of valinomycin as cancer targeted prodrugs
Mechanically interlocked molecular architectures of valinomycin as cancer targeted prodrugs
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DOI：
10.1002/nano.202100368
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发表时间：
2022-08-01
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影响因子：
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通讯作者：
Cabral，Horacio
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文献类型：
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作者：
Tachihara，Yoshihiro;Nakagawa，Yasuhiro;Cabral，Horacio
大环药物是治疗多种疾病的有前途的药物。然而，这些化合物通常存在递送限制，例如组织选择性低和细胞摄取差，这可能会损害功效和临床转化。在这里，我们提出了一种基于大环药物组装成生物活性轮烷的分子机器方法。为了证明这个概念，我们使用剧毒的大环缬氨霉素（Val）作为主体分子，并在筛选了几种客体化合物后确定二肼苯达嗪（Dihyd）作为客体分子。 Val-Dihyd 复合物通过 pH 敏感的腙键，用异硫氰酸荧光素 (FITC) 封端 Dihyd 中的一个酰肼基团，并用 Y 形支化聚乙二醇 (PEG) 封端另一个酰肼基团，从而实现机械互锁。因此，负载 Val 的轮烷 (Vrot) 在生理 pH 下稳定，但在模拟肿瘤内和内体环境的温和酸性条件下释放 Val。体外研究表明，在胰腺癌细胞中，Vrot 的细胞毒性低于游离 Val，而用环精氨酸-甘氨酸-天冬氨酸 (cRGD) 肽修饰 Vrot 可通过增强细胞摄取来增强细胞毒性。这些结果表明大环药物轮烷用于产生癌症靶向前药的潜力。
Macrocyclic drugs are promising agents for treating a variety of diseases. However, these compounds usually present delivery limitations, such as low tissue selectivity and poor cellular uptake, which may impair efficacy and clinical translation. Here, we propose a molecular machine approach for delivering macrocyclic drugs based on their assembly into bioactive rotaxanes. To prove this concept, we use the extremely toxic macrocycle valinomycin (Val) as the host molecule, and identify dihydralazine (Dihyd) as a guest molecule after screening several guest compounds. The Val‐Dihyd complex is mechanically interlocked by capping one hydrazide group in Dihyd with fluorescein isothiocyanate (FITC) and the other with a Y‐shape branched poly(ethylene glycol) (PEG) via a pH‐sensitive hydrazone bond. Thus, the Val‐loaded rotaxanes (Vrot) are stable at physiological pH, but release Val at mild acidic conditions mimicking intratumoral and endosomal environments. In vitro studies revealed Vrot is less cytotoxic than free Val in pancreatic cancer cells, while modifying Vrot with cyclic arginine‐glycine‐aspartic acid (cRGD) peptides promotes the cytotoxicity by enhancing cellular uptake. These results indicate the potential of rotaxanes of macrocyclic drugs for generating cancer targeted prodrugs.