Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment.
Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment.
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用于全身性抗癌药物和siRNA的全层纳米颗粒，用于潜在的三阴性乳腺癌治疗。
DOI：
10.1021/nn4047925
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发表时间：
2013-11-26
期刊：
影响因子：
17.1
通讯作者：
Hammond, Paula T.
中科院分区：
文献类型：
--
作者：
Deng, Zhou J.;Morton, Stephen W.;Ben-Akiva, Elana;Dreaden, Erik C.;Shopsowitz, Kevin E.;Hammond, Paula T.
关键词：
已经通过模块化和受控的逐层过程开发了一个单一的纳米颗粒平台，以共同递送siRNA，该siRNA敲除肿瘤细胞中的耐药途径和化疗药物，以挑战高度侵袭性形式的三阴性乳腺癌。通过交替沉积siRNA和聚-L-精氨酸在纳米颗粒上形成逐层膜;纳米颗粒表面上的单个双层可以有效地装载多达3，500个siRNA分子，并且所得的LbL纳米颗粒表现出28小时的延长的血清半衰期。在动物模型中，通过静脉给药的一次剂量显著降低了肿瘤中靶基因的表达，降低了近80%。通过在多柔比星负载的脂质体顶部产生siRNA负载的膜，我们确定了与靶向多药耐药蛋白1的siRNA的有效组合疗法，其在体外将多柔比星功效显著增强4倍，并且与对照治疗相比导致肿瘤体积减少高达8倍，而没有观察到毒性。结果表明，使用逐层膜来修饰具有协同siRNA的简单脂质体多柔比星递送构建体可以导致对Doxil或其他常见化疗药物治疗无反应的癌症中的显著肿瘤减少。这种方法提供了一种治疗侵袭性和耐药性癌症的潜在策略，以及一个模块化平台，用于在单一纳米颗粒递送系统中针对癌症类型定制广泛的受控多药疗法。
A single nanoparticle platform has been developed through the modular and controlled layer-bylayer process to co-deliver siRNA that knocks down a drug-resistance pathway in tumor cells and a chemotherapy drug to challenge a highly aggressive form of triple-negative breast cancer. Layer-by-layer films were formed on nanoparticles by alternately depositing siRNA and poly-L-arginine; a single bilayer on the nanoparticle surface could effectively load up to 3,500 siRNA molecules, and the resulting LbL nanoparticles exhibit an extended serum half-life of 28 hours. In animal models, one dose via intravenous administration significantly reduced the target gene expression in the tumors by almost 80%. By generating the siRNA-loaded film atop a doxorubicin-loaded liposome, we identified an effective combination therapy with siRNA targeting multidrug resistance protein 1, which significantly enhanced doxorubicin efficacy by 4 fold in vitro and led to up to an 8-fold decrease in tumor volume compared to the control treatments with no observed toxicity. The results indicate that the use of layer-by-layer films to modify a simple liposomal doxorubicin delivery construct with a synergistic siRNA can lead to significant tumor reduction in the cancers that are otherwise nonresponsive to treatment with Doxil or other common chemotherapy drugs. This approach provides a potential strategy to treat aggressive and resistant cancers, and a modular platform for a broad range of controlled multidrug therapies customizable to the cancer type in a singular nanoparticle delivery system.
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