High-Performing Dry Powder Inhalers of Paclitaxel DPPC/DPPG Lung Surfactant-Mimic Multifunctional Particles in Lung Cancer: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies

Abstract

Inhalable lung surfactant-based carriers composed of synthetic phospholipids, dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG), along with paclitaxel (PTX), were designed and optimized as respirable dry powders using organic solution co-spray-drying particle engineering design. These materials can be used to deliver and treat a wide variety of pulmonary diseases with this current work focusing on lung cancer. In particular, this is the first time dry powder lung surfactant-based particles have been developed and characterized for this purpose. Comprehensive physicochemical characterization was carried out to analyze the particle morphology, surface structure, solid-state transitions, amorphous character, residual water content, and phospholipid bilayer structure. The particle chemical composition was confirmed using attenuated total reflectance-Fourier-transform infrared (ATR-FTIR) spectroscopy. PTX loading was high, as quantified using UV-VIS spectroscopy, and sustained PTX release was measured over weeks. In vitro cellular characterization on lung cancer cells demonstrated the enhanced chemotherapeutic cytotoxic activity of paclitaxel from co-spray-dried DPPC/DPPG (co-SD DPPC/DPPG) lung surfactant-based carrier particles and the cytotoxicity of the particles via pulmonary cell viability analysis, fluorescent microscopy imaging, and transepithelial electrical resistance (TEER) testing at air-interface conditions. In vitro aerosol performance using a Next Generation Impactor™ (NGI™) showed measurable powder deposition on all stages of the NGI and was relatively high on the lower stages (nanometer aerodynamic size). Aerosol dispersion analysis of these high-performing DPIs showed mass median diameters (MMADs) that ranged from 1.9 to 2.3 μm with excellent aerosol dispersion performance as exemplified by high values of emitted dose, fine particle fractions, and respirable fractions.

Microparticulate/nanoparticulate powders of a novel Nrf2 activator and an aerosol performance enhancer for pulmonary delivery targeting the lung Nrf2/Keap-1 pathway

“…The mean size, standard deviation and size range of the particles were determined digitally using SigmaScan Pro 5.0.0 (Systat, San Jose, CA, USA), using similar conditions that have been previously reported 48 . Representative micrographs for each particle sample at 15,000× magnification was analyzed by measuring the diameter of at least 100 particles per sample.…”

Assessment of genetic toxicity with major inhalable mineral granules in A549 cells

“…In addition, an increase in the number of dead cells was observed in these treatment groups. The different mineral granule treatments caused varying degrees of morphological damage (Esposito et al, 2012;Al-Hallak et al, 2012;Meenach et al, 2014). Montmorillonite and quartz treatment caused the most widespread destruction of the cell morphology (Xia et al, 2014;Sharma et al, 2014), whereas albite and sericite treatment caused the least amount of cell damage (Discoll et al, 1998;Ghio et al, 2014;Ziemann et al, 2014).…”

POxylated Dendrimer‐Based Nano‐in‐Micro Dry Powder Formulations for Inhalation Chemotherapy

“…In this case, the FPFs reached stagest hree and four very efficiently (up to 87 %). [22] Our PTX and DOX formulations reached stage five with an acceptable FPF (up to 31 %). Regarding DOX formulations, polyethyleneg lycol (PEG)ylated poly(amidoamine) (PAMAM)-DOX conjugates, ad endrimer-based system, was reported to show adequate MMAD values (1.2-3.3 mm) and a high FPF (up to 78 %), reaching stage five.…”

“…However, surfactant‐based dry powder formulations show MMAD values (1.5–3.1 μm) that are similar to the MMAD values obtained for our system (1.9–2.3 μm). In this case, the FPFs reached stages three and four very efficiently (up to 87 %) . Our PTX and DOX formulations reached stage five with an acceptable FPF (up to 31 %).…”