Enzymatic drug release cascade from polymeric prodrug nanoassemblies enables targeted chemotherapy.
Enzymatic drug release cascade from polymeric prodrug nanoassemblies enables targeted chemotherapy.
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DOI：
10.1016/j.jconrel.2022.06.007
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发表时间：
2022-06
期刊：
影响因子：
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通讯作者：
Jiajia Xiang;Jing Liu;Xin Liu;Quan Zhou;Zhihao Zhao;Ying Piao;Shiqun Shao;Zhuxian Zhou;Jianbin Tang;Youqing Shen
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文献类型：
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作者：
Jiajia Xiang;Jing Liu;Xin Liu;Quan Zhou;Zhihao Zhao;Ying Piao;Shiqun Shao;Zhuxian Zhou;Jianbin Tang;Youqing Shen
癌症药物递送系统通常在运输期间遭受过早的药物泄漏和/或在癌细胞内的低效药物释放。我们在这里提出了一个聚合物前药纳米组装，同时解决这些问题。该纳米组装体包含具有用于通过醚键进行药物缀合的新型三价苯基硼酸酯部分的聚合物前药以及β-拉帕酮（Lapa）。虽然醚键在生理条件下几乎不允许药物释放，但Lapa分子可以通过NAD（P）H：醌氧化还原酶-1催化在癌细胞中特异性地诱导活性氧（ROS）爆发，其触发醚键的裂解，从而级联放大癌细胞中的药物释放。因此，纳米组装体表现出比正常细胞高得多的对癌细胞的细胞毒性，并且与临床使用的伊立替康相比，还提高了治疗功效并降低了副作用。我们预计这种策略可以应用于其他药物递送平台，以实现更精确的药物释放。
Cancer drug delivery systems often suffer from premature drug leakage during transportation and/or inefficient drug release within cancer cells. We present here a polymeric prodrug nanoassembly that addresses these problems simultaneously. This nanoassembly comprises a polymeric prodrug with novel trivalent phenylboronate moieties for drug conjugationviaether linkages, as well asβ-lapachone (Lapa). While the ether linkage enables nearly no drug release under physiological conditions, the Lapa molecules can induce the reactive oxygen species (ROS) burst specifically in cancer cellsviaNAD(P)H: quinone oxidoreductase-1 catalysis, which triggers the cleavage of the ether bonds and thus cascade amplification drug release in cancer cells. As a result, the nanoassemblies exhibit much higher cytotoxicity against cancer cells than normal cells, and also increased therapeutic efficacy and reduced side effects compared to the clinically used irinotecan. We anticipate that this strategy can be applied to other drug delivery platforms to enable more precise drug release.