Paclitaxel (PTX) is a potent anticancer agent, which is clinically administered by infusion for treating pulmonary metastasis of different cancers. Systemic injection of PTX is promising in treating pulmonary metastasis of various cancers but simultaneously leads to many severe complications in the body. In this study, we have demonstrated a noninvasive approach for delivering PTX to deep pulmonary tissues via an inhalable phospholipid-based nanocochleate platform and showed its potential in treating pulmonary metastasis of melanoma cancer. Nanocochleates have been previously explored for oral delivery of anticancer drugs; their application for aerosol-based administration has not been accomplished in the literature thus far. Our results showed that the PTX-carrying aerosol nanocochleates (PTX-CPTs) possessed excellent pulmonary surfactant action characterized by high surface activity and encouraging in vitro terminal airway patency when compared to the marketed Taxol formulation, which is known to contain a high amount of Cremophore EL. We observed under in vitro twin-impinger analysis that the PTX-CPT had a high tendency to get deposited in stage II (alveolar region of lungs), indicating the capability of CPT to reach the deep alveolar region. Further, while exposed to the human lung adenocarcinoma cell line (A549), the PTX-CPT showed excellent cytotoxicity mediated by enhanced cellular uptake via energy-dependent endocytosis. Aerosol-based administration of PTX-CPT in a pulmonary metastatic murine melanoma model (B16F10) resulted in significant (p < 0.05) tumor growth inhibition when compared to an intravenous dose of Taxol. Inhibition of tumor growth in aerosol-based PTX-CPT-treated animals was evident by the significant (p < 0.05) reduction in numbers of tumor nodules and percent metastasis area covered by melanoma cells in the lung when compared to other treatment groups. Overall, our finding suggests that PTX can be safely administered in the form of an aerosol using a newly developed CPT system, which serves a dual purpose as both a drug delivery carrier and a pulmonary surfactant in treating pulmonary metastasis.

中文翻译：

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紫杉醇自组装的纳米耳蜗的气雾剂治疗肺转移：支持肺力学的一种方法。

紫杉醇（PTX）是一种有效的抗癌药，临床上通过输注给药以治疗不同癌症的肺转移。全身注射PTX有望用于治疗各种癌症的肺转移，但同时会导致体内许多严重的并发症。在这项研究中，我们已经证明了通过可吸入的磷脂基纳米耳蜗平台将PTX递送至深部肺组织的非侵入性方法，并显示了其在治疗黑色素瘤癌症的肺转移中的潜力。以前已经研究过纳米耳蜗用于口服递送抗癌药。迄今为止，它们在基于气溶胶的给药中的应用尚未完成。我们的结果表明，与市售的紫杉醇配方相比，携带PTX的气溶胶纳米耳蜗（PTX-CPTs）具有出色的肺表面活性剂作用，具有高表面活性和令人鼓舞的体外终末呼吸道通畅性，后者已知含有大量的Cremophore EL。我们在体外双撞击器分析下观察到，PTX-CPT有很高的沉积在II期阶段（肺泡区域）的趋势，表明CPT能够到达深部的肺泡区域。此外，PTX-CPT暴露于人肺腺癌细胞系（A549）时，表现出优异的细胞毒性，该作用是通过能量依赖型内吞作用增强的细胞摄取介导的。在肺转移性鼠黑色素瘤模型（B16F10）中以气雾剂形式施用PTX-CPT导致显着（已知其中含有大量的Cremophore EL。我们在体外双撞击器分析下观察到，PTX-CPT有很高的沉积在II期阶段（肺泡区域）的趋势，表明CPT能够到达深部的肺泡区域。此外，PTX-CPT暴露于人肺腺癌细胞系（A549）时，表现出优异的细胞毒性，该作用是通过能量依赖型内吞作用增强的细胞摄取介导的。在肺转移性鼠黑色素瘤模型（B16F10）中以气雾剂形式施用PTX-CPT导致显着（已知其中含有大量的Cremophore EL。我们在体外双撞击器分析下观察到，PTX-CPT有很高的沉积在II期阶段（肺泡区域）的趋势，表明CPT能够到达深部的肺泡区域。此外，PTX-CPT暴露于人肺腺癌细胞系（A549）时，表现出优异的细胞毒性，该毒性是通过能量依赖性内吞作用增强的细胞摄取介导的。在肺转移性鼠黑色素瘤模型（B16F10）中以气雾剂形式施用PTX-CPT导致显着（当暴露于人肺腺癌细胞系（A549）时，PTX-CPT表现出优异的细胞毒性，该毒性是通过能量依赖性内吞作用增强的细胞摄取介导的。在肺转移性鼠黑色素瘤模型（B16F10）中以气雾剂形式施用PTX-CPT导致显着（当暴露于人肺腺癌细胞系（A549）时，PTX-CPT表现出优异的细胞毒性，该毒性是通过能量依赖性内吞作用增强的细胞摄取介导的。在肺转移性鼠黑色素瘤模型（B16F10）中以气雾剂形式施用PTX-CPT导致显着（与静脉注射紫杉醇相比，p <0.05）抑制肿瘤生长。与其他治疗组相比，经肺部黑色素瘤细胞覆盖的肿瘤结节数量和转移面积百分比显着减少（p <0.05），明显证明了以气雾剂为基础的PTX-CPT处理动物的肿瘤生长得到抑制。总体而言，我们的发现表明，可以使用新开发的CPT系统以气雾剂形式安全地施用PTX，该系统既可以作为药物输送载体，又可以作为肺表面活性剂来治疗肺转移。