Development and evaluation of well-tolerated and tumor-penetrating polymeric micelle-based dry powders for inhaled anti-cancer chemotherapy.

Despite the direct access to the lung offered by the inhalation route, drug penetration into lung tumors could remain an important issue. In this study, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD) micelles were developed as an effective pulmonary drug delivery system to reach and penetrate lung tumors and cancer cells. The F-PEG-HMD micelles were able to enter HeLa and M109-HiFR, two folate receptor-expressing cancer cell lines, in vitro, and in vivo after administration by inhalation to orthotopic M109-HiFR lung tumor grafted mice. Paclitaxel-loaded F-PEG-HMD micelles characterized in PBS by a Z-average diameter of ∼50 nm and a zeta potential of ∼-4 mV were prepared with an encapsulation efficiency of ∼100%. The loaded micelles reduced HeLa and M109-HiFR cell growth, with half maximal inhibitory concentrations of 37 and 150 nM, respectively. Dry powders embedding the paclitaxel-loaded F-PEG-HMD micelles were developed by spray-drying. In vitro, good deposition profiles were obtained, with a fine particle fraction of up to 50% and good ability to re-disperse the micelles in physiological buffer. A polymeric micelle-based dry powder without paclitaxel was well-tolerated in vivo, as assessed in healthy mice by determination of total protein content, cell count, and cytokine IL-1β, IL-6, and TNF-α concentrations in bronchoalveolar lavage fluids.