Beta-lapachone micellar nanotherapeutics for non-small cell lung cancer therapy.
Beta-lapachone micellar nanotherapeutics for non-small cell lung cancer therapy.
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DOI：
10.1158/0008-5472.can-09-3995
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发表时间：
2010-05-15
期刊：
影响因子：
11.2
通讯作者：
Gao J
中科院分区：
文献类型：
--
作者：
Blanco E;Bey EA;Khemtong C;Yang SG;Setti-Guthi J;Chen H;Kessinger CW;Carnevale KA;Bornmann WG;Boothman DA;Gao J
肺癌是癌症相关死亡的主要原因，目前的化疗缺乏足够的特异性和有效性。β-拉帕酮（β-lap）是一种新型抗癌药物，可被NAD（P）H：醌氧化还原酶-1（NQO 1）生物活化，NQO 1是一种在非小细胞肺癌（NSCLC）中特异性过表达的酶。在本文中，我们报告了以两种方式靶向NSCLC肿瘤的纳米药物策略：通过使用生物可活化剂β-lap的药效学和通过使用生物相容性纳米载体聚合物胶束的药代动力学，以实现药物稳定性，生物利用度和靶向递送。膜超声技术制备的β-Lap胶束较小（约30 nm），呈核壳结构，具有良好的释放动力学。在皮下接种A549肺肿瘤的小鼠中进行的药代动力学分析显示，血液循环延长（t1/2 ~ 28 h），肿瘤中蓄积增加。在皮下A549肺肿瘤和原位刘易斯肺癌模型小鼠中的抗肿瘤功效分析显示显著的肿瘤生长延迟和存活增加。总之，我们已经建立了一个临床上可行的β-lap纳米药物平台，具有增强的安全性，药代动力学和抗肿瘤疗效，用于NSCLC肿瘤的特异性治疗。
Lung cancer is the leading cause of cancer-related deaths with current chemotherapies lacking adequate specificity and efficacy. β-Lapachone (β-lap) is a novel anticancer drug that is bioactivated by NAD(P)H:quinone oxidoreductase-1 (NQO1), an enzyme found specifically overexpressed in non-small cell lung cancer (NSCLC). Herein we report a nanotherapeutic strategy that targets NSCLC tumors in two ways: pharmacodynamically through the use of a bioactivatable agent, β-lap and pharmacokinetically by using a biocompatible nanocarrier, polymeric micelles, to achieve drug stability, bioavailability, and targeted delivery. β-Lap micelles produced by a film sonication technique were small (~30 nm), displayed core-shell architecture, and possessed favorable release kinetics. Pharmacokinetic analyses in mice bearing subcutaneous A549 lung tumors showed prolonged blood circulation (t1/2 ~ 28 h) and increased accumulation in tumors. Antitumor efficacy analyses in mice bearing subcutaneous A549 lung tumors and orthotopic Lewis lung carcinoma models showed significant tumor growth delay and increased survival. In summary, we have established a clinically viable β-lap nanomedicine platform with enhanced safety, pharmacokinetics and antitumor efficacy for the specific treatment of NSCLC tumors.