Combined delivery of paclitaxel and tanespimycin via micellar nanocarriers: pharmacokinetics, efficacy and metabolomic analysis.
Combined delivery of paclitaxel and tanespimycin via micellar nanocarriers: pharmacokinetics, efficacy and metabolomic analysis.
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DOI：
10.1371/journal.pone.0058619
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tan C
中科院分区：
文献类型：
--
作者：
Katragadda U;Fan W;Wang Y;Teng Q;Tan C
尽管在临床前研究中观察到有希望的抗癌疗效，但紫杉醇和坦螺旋霉素（17-AAG）联合治疗在I期临床试验中产生了微弱的反应。与紫杉醇/17-AAG组合疗法相关的一个严重问题是使用大量有毒有机表面活性剂和溶剂来溶解药物。本研究的目的是评价用于紫杉醇和17-AAG在体内同时递送的胶束制剂。在携带人卵巢肿瘤异种移植物的小鼠中评估紫杉醇/17-AAG负载的胶束。与同等剂量的游离药物相比，静脉注射紫杉醇/17-AAG载药胶束导致紫杉醇和17-AAG的肿瘤浓度分别增加3.5倍和1.7倍，而正常器官中的药物水平没有显著改变。使用吲哚菁绿标记的胶束的全身近红外成像进一步证实了胶束药物的增强的肿瘤蓄积。随后，与游离药物（每周20 mg/kg紫杉醇，每周两次37.5 mg/kg 17-AAG）相比，检查紫杉醇/17-AAG负载的胶束的抗癌功效。我们发现，紫杉醇/17-AAG-负载胶束引起肿瘤生长的几乎完全停滞，而游离药物治疗的肿瘤在3周治疗期结束后不久经历快速生长。此外，通过质子核磁共振进行的比较代谢组学分析显示，在用紫杉醇/17-AAG负载的胶束处理的小鼠的肿瘤中，葡萄糖、乳酸盐和丙氨酸显著降低，同时谷氨酰胺、谷氨酸盐、天冬氨酸盐、胆碱、肌酸和乙酸盐水平增加。我们在当前的工作中已经证明了一种安全有效的纳米制剂，用于联合递送紫杉醇和17-AAG，并发现了肿瘤中独特的代谢组学特征，这些特征与紫杉醇/17-AAG联合疗法的良好治疗反应相关。
Despite the promising anticancer efficacy observed in preclinical studies, paclitaxel and tanespimycin (17-AAG) combination therapy has yielded meager responses in a phase I clinical trial. One serious problem associated with paclitaxel/17-AAG combination therapy is the employment of large quantities of toxic organic surfactants and solvents for drug solubilization. The goal of this study was to evaluate a micellar formulation for the concurrent delivery of paclitaxel and 17-AAG in vivo. Paclitaxel/17-AAG-loaded micelles were assessed in mice bearing human ovarian tumor xenografts. Compared with the free drugs at equivalent doses, intravenous administration of paclitaxel/17-AAG-loaded micelles led to 3.5- and 1.7-fold increase in the tumor concentrations of paclitaxel and 17-AAG, respectively, without significant altering drug levels in normal organs. The enhanced tumor accumulation of the micellar drugs was further confirmed by the whole-body near infrared imaging using indocyanine green-labeled micelles. Subsequently, the anticancer efficacy of paclitaxel/17-AAG-loaded micelles was examined in comparison with the free drugs (weekly 20 mg/kg paclitaxel, twice-weekly 37.5 mg/kg 17-AAG). We found that paclitaxel/17-AAG-loaded micelles caused near-complete arrest of tumor growth, whereas the free drug-treated tumors experienced rapid growth shortly after the 3-week treatment period ended. Furthermore, comparative metabolomic profiling by proton nuclear magnetic resonance revealed significant decrease in glucose, lactate and alanine with simultaneous increase in glutamine, glutamate, aspartate, choline, creatine and acetate levels in the tumors of mice treated with paclitaxel/17-AAG-loaded micelles. We have demonstrated in the current wok a safe and efficacious nano-sized formulation for the combined delivery of paclitaxel and 17-AAG, and uncovered unique metabolomic signatures in the tumor that correlate with the favorable therapeutic response to paclitaxel/17-AAG combination therapy.
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影响因子：
11.2
作者：
Sawai, Ayana;Chandarlapaty, Sarat;Solit, David B.
通讯作者：
Solit, David B.
影响因子：
11.5
作者：
Kim, TY;Kim, DW;Bang, YJ
通讯作者：
Bang, YJ
DOI：
10.1158/1078-0432.ccr-11-1000
发表时间：
2012-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Neckers L;Workman P
通讯作者：
Workman P
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
DOI：
10.1038/nrc3162
发表时间：
2011-11-17
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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