Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery
Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery
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DOI：
10.1073/pnas.1120508109
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发表时间：
2012-05-22
影响因子：
11.1
通讯作者：
Wang, Andrew Z.
中科院分区：
文献类型：
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作者：
Karve, Shrirang;Werner, Michael E.;Wang, Andrew Z.
纳米粒(NP)载体的前景之一是重新配制由于药理学挑战而失败的临床开发的有希望的治疗药物。然而，目前的纳米医学研究一直集中在现有的和新的治疗方法的交付上。在这里，我们以Wortmannin(WtMN)为模型药物，证明了使用NPs来恢复废弃化合物的临床潜力的原理。WtMN是一种有效的磷脂酰肌醇3‘激酶相关的抑制剂，但由于药物传递的困难而未能在临床上翻译。我们设计了WtMn的NP配方，并证明了与WtMn相比，NP WtMn具有更高的溶解度和更低的毒性。为了确定NP WtMn的临床翻译潜力，我们在体内和体外对其作为放射增敏剂进行了评估。在三种癌细胞中，NP WtMn被发现是一种有效的放射增敏剂，并且在体外明显比常用的放射增敏剂顺铂更有效。NP WtMn的放射增敏作用机制可能是通过抑制DNA依赖的蛋白激酶磷酸化来实现的。最后，在两种小鼠异种移植肿瘤模型中，NP WtMn被证明是一种有效的放射增敏剂。我们的结果表明，NP药物递送系统可以通过克服药物递送挑战来促进WTMN等废弃药物的再选择。
One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3' kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.