Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles
Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles
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DOI：
10.1158/1078-0432.ccr-07-4973
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发表时间：
2008-05-15
影响因子：
11.5
通讯作者：
Amiji, Mansoor M.
中科院分区：
文献类型：
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作者：
Devalapally, Harikrishna;Duan, Zhenfeng;Amiji, Mansoor M.
目的：为了调节细胞内神经酰胺水平，降低多药耐药卵巢腺癌的凋亡阈值，我们检测了他莫昔芬联合紫杉醇在可生物降解的多药耐药卵巢腺癌中的疗效和初步安全性。环氧乙烷改性聚（ε-己内酯）（PEO-PCL）纳米颗粒。紫杉醇和他莫昔芬单独或联合的体外细胞毒性和促凋亡活性，在野生型（SKOV 3）和MDR-1阳性（SKOV 3（TR））人卵巢腺癌细胞中检测。在雌性nu/nu小鼠中建立皮下SKOV 3和SKOV 3 TR异种移植物，并使用该模型评价抗肿瘤疗效和初步安全性。紫杉醇（20 mg/kg）和他莫昔芬（70 mg/kg）以单一药物或水溶液和PEO-PCL nanoparticle.Results中的组合形式静脉内施用。体外细胞毒性结果显示，紫杉醇和他莫昔芬组合施用使紫杉醇在SKOV 3细胞中的IC 50降低10倍，在SKOV 3 TR细胞中降低>3倍。当以纳米颗粒制剂施用时，紫杉醇/他莫昔芬联合疗法显示出甚至更显著的效果。在静脉内施用PEO-PCL纳米颗粒制剂中的紫杉醇/他莫昔芬组合后，观察到抗肿瘤功效的显著增强。此外，联合紫杉醇/他莫昔芬治疗没有引起任何急性毒性，如体重变化，血细胞计数，和hepatoxic.Conclusions：本研究的结果表明，紫杉醇和他莫昔芬在可生物降解的聚氧化乙烯-聚己内酯纳米粒子的组合可以作为一种有效的临床翻译策略，以克服卵巢癌的多药耐药。
Purpose: To modulate intracellular ceramide levels and lower the apoptotic threshold in multidrug-resistant ovarian adenocarcinoma, we have examined the efficacy and preliminary safety of tamoxifen coadministration with paclitaxel in biodegradable poly(ethylene oxide) modified poly (epsilon-caprolactone) (PEO-PCL) nanoparticles.Experimental Design: In vitro cytotoxicity and proapoptotic activity of paclitaxel and tamoxifen, either as single agent or in combination, was examined in wild-type (SKOV3) and MDR-1-positive (SKOV3(TR)) human ovarian adenocarcinoma cells. Subcutaneous SKOV3 and SKOV3TR xenografts were established in female nu/nu mice, and this model was used to evaluate the antitumor efficacy and preliminary safety. Paclitaxel (20 mg/kg) and tamoxifen (70 mg/kg) were administered i.v. either as a single agent or in combination in aqueous solution and in PEO-PCL nanoparticles.Results: In vitro cytotoxicity results showed that administration of paclitaxel and tamoxifen in combination lowered the IC50 of paclitaxel by 10-fold in SKOV3 cells and by >3-fold in SKOV3TR cells. The combination paclitaxel/tamoxifen co-therapy showed even more pronounced effect when administered in nanoparticle formulations. Upon i.v. administration of paclitaxel/tamoxifen combination in PEO-PCL nanoparticle formulations, significant enhancement in antitumor efficacy was observed. Furthermore, the combination paclitaxel/tamoxifen therapy did not induce any acute toxicity as measured by body weight changes, blood cell counts, and hepatotoxicity.Conclusions: The results of this study show that combination of paclitaxel and tamoxifen in biodegradable PEO-PCL nanoparticles can serve as an effective clinically translatable strategy to overcome multidrug resistance in ovarian cancer.