Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy.
Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy.
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DOI：
10.1016/j.jconrel.2014.12.027
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发表时间：
2015-02-28
期刊：
影响因子：
--
通讯作者：
Gao J
中科院分区：
文献类型：
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作者：
Ma X;Huang X;Moore Z;Huang G;Kilgore JA;Wang Y;Hammer S;Williams NS;Boothman DA;Gao J
肺癌是最致命的癌症之一，目前的化疗策略缺乏广泛的特异性和疗效。最近，β-拉帕酮（β-lap）被证明在杀死非小细胞肺癌（NSCLC）细胞方面具有高度有效性，而不管它们的p53、细胞周期和半胱天冬酶状态如何。β-lap（临床形式，ARQ 501或761）的临床前和临床使用受到溶血性贫血导致的不良药代动力学和毒性的阻碍。在这里，我们报告了β-lap前药纳米治疗剂的开发和临床前评价，该前药纳米治疗剂由包封在生物相容性和可生物降解的聚（乙二醇）-b-聚（d，l-乳酸）（PEG-b-PLA）胶束中的β-lap的二酯衍生物组成。与母体药物相比，β-lap的双酯衍生物在PEG-b-PLA胶束中显示出更高的载药密度。在酯酶处理后，胶束递送的β-lap-dC 3和-dC 6前药转化为β-lap。使用A549和H596肺癌细胞的细胞毒性测定显示，两种胶束制剂均保持NAD（P）H：醌氧化还原酶1（NQO 1）依赖性细胞毒性。然而，β-lap-dC 3胶束对原位A549 NSCLC异种移植荷瘤小鼠的抗肿瘤疗效研究显示，长期存活率显著高于β-lap-dC 6胶束或β-lap-HPβCD复合物。β-lap-dC 3胶束的改善的治疗功效与肿瘤中β-lap的浓度-时间曲线下面积更高以及药效学终点增强（例如，PARP 1超活化、γ H2 AX和ATP耗竭）。β-Lap-dC 3前药胶束为NQO 1靶向治疗肺癌提供了一种有前途的策略，具有改善的安全性和抗肿瘤疗效。
Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, β-lapachone (β-lap) was shown to be highly efficacious in killing non-small cell lung cancer (NSCLC) cells regardless of their p53, cell cycle and caspase status. Pre-clinical and clinical use of β-lap (clinical form, ARQ501 or 761) is hampered by poor pharmacokinetics and toxicity due to hemolytic anemia. Here, we report the development and preclinical evaluation of β-lap prodrug nanotherapeutics consisting of diester derivatives of β-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(d,l-lactic acid) (PEG-b-PLA) micelles. Compared to the parent drug, diester derivatives of β-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered β-lap-dC3 and -dC6 prodrugs were converted to β-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintained NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of β-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over β-lap-dC6 micelles or β-lap-HPβCD complexes. Improved therapeutic efficacy of β-lap-dC3 micelles correlated with higher area under the concentration-time curves of β-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γH2AX, and ATP depletion). β-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy.