Shanmugam Thanigaivel, Joshi Nitin, Kaviratna Anubhav, Ahamad Nadim, Bhatia Eshant, Banerjee Rinti
Nanomedicine Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology-Bombay, Mumbai 400076, India.
ACS Biomater Sci Eng. 2021 Jan 11;7(1):144-156. doi: 10.1021/acsbiomaterials.0c01126. Epub 2020 Dec 21.
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 ( < 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 ( < 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.
紫杉醇（PTX）是一种强效抗癌剂，临床上通过静脉输注给药以治疗不同癌症的肺转移。全身注射PTX在治疗各种癌症的肺转移方面很有前景，但同时会导致身体出现许多严重并发症。在本研究中，我们展示了一种通过可吸入的基于磷脂的纳米耳蜗平台将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肺转移方面的潜力。纳米耳蜗此前已被探索用于口服递送抗癌药物；迄今为止，其在基于气雾剂给药方面的应用在文献中尚未实现。我们的结果表明，与市售的紫杉醇制剂（已知含有大量聚氧乙烯蓖麻油EL）相比，携带PTX的气溶胶纳米耳蜗（PTX-CPT）具有优异的肺表面活性剂作用，其特征在于高表面活性，并在体外终末气道通畅性方面表现令人鼓舞。我们在体外双撞击器分析中观察到，PTX-CPT有很高的倾向沉积在II期（肺的肺泡区域），表明CPT能够到达深部肺泡区域。此外，当暴露于人肺腺癌细胞系（A549）时，PTX-CPT通过能量依赖性内吞作用增强细胞摄取，表现出优异的细胞毒性。与静脉注射紫杉醇剂量相比，在肺转移小鼠黑色素瘤模型（B16F10）中基于气雾剂给药的PTX-CPT导致显著（<0.05）的肿瘤生长抑制。与其他治疗组相比，基于气雾剂的PTX-CPT治疗的动物中肿瘤生长受到抑制，这在肺中肿瘤结节数量和黑色素瘤细胞覆盖的转移面积百分比显著（<0.05）降低中很明显。总体而言，我们的发现表明，使用新开发的CPT系统可以以气雾剂形式安全地给药PTX，该系统在治疗肺转移中兼具药物递送载体和肺表面活性剂的双重作用。
