Aerosol Delivery of Paclitaxel-Containing Self-Assembled Nanocochleates for Treating Pulmonary Metastasis: An Approach Supporting Pulmonary Mechanics

Abstract

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.