OBJECTIVE: In this study, pyrazinamide (PZA)-proliposome in a dry powder aerosol form was developed for delivering drugs to alveolar macrophages (AMs) infected with mycobacteria. MATERIALS AND METHODS: PZA-proliposomes consisting of pyrazinamide, soybean phosphatidylcholine, cholesterol and porous mannitol were prepared by a spray drying method. The PZA-proliposome physicochemical properties were determined using a cascade impactor, X-ray diffraction, differential scanning calorimetry and infrared spectroscopy. The toxicity of proliposomes to respiratory-associated cell lines (Calu-3, A549 and NR8383) and its potential to provoke immunological responses from AMs were determined. In vivo repeated dose toxicity in rats was evaluated. RESULTS AND DISCUSSION: PZA-proliposomes were successfully prepared. For the aerosolization properties of PZA-proliposomes at 60 l/min, the powders showed mass median aerodynamic diameters of 4.26-4.39 µm, with fine particle fractions (aerosolized particles less than 4.4 µm) of 20-30%. Encapsulation of PZA was 26-45%. PZA-proliposomes were less toxic to respiratory-associated cells, and did not activate AMs to produce inflammatory mediators, including interleukin-1β, tumor necrosis factor-α, and nitric oxide, at a toxic level. Renal and liver toxicity in rats were not observed. CONCLUSIONS: We suggest that PZA-proliposomes are potential candidates for pulmonary tuberculosis treatment.
OBJECTIVE: In this study, pyrazinamide (PZA)-proliposome in a dry powder aerosol form was developed for delivering drugs to alveolar macrophages (AMs) infected with mycobacteria. MATERIALS AND METHODS: PZA-proliposomes consisting of pyrazinamide, soybeanphosphatidylcholine, cholesterol and porous mannitol were prepared by a spray drying method. The PZA-proliposome physicochemical properties were determined using a cascade impactor, X-ray diffraction, differential scanning calorimetry and infrared spectroscopy. The toxicity of proliposomes to respiratory-associated cell lines (Calu-3, A549 and NR8383) and its potential to provoke immunological responses from AMs were determined. In vivo repeated dose toxicity in rats was evaluated. RESULTS AND DISCUSSION: PZA-proliposomes were successfully prepared. For the aerosolization properties of PZA-proliposomes at 60 l/min, the powders showed mass median aerodynamic diameters of 4.26-4.39 µm, with fine particle fractions (aerosolized particles less than 4.4 µm) of 20-30%. Encapsulation of PZA was 26-45%. PZA-proliposomes were less toxic to respiratory-associated cells, and did not activate AMs to produce inflammatory mediators, including interleukin-1β, tumor necrosis factor-α, and nitric oxide, at a toxic level. Renal and liver toxicity in rats were not observed. CONCLUSIONS: We suggest that PZA-proliposomes are potential candidates for pulmonary tuberculosis treatment.
Authors: Caleb F Anderson; Maria E Grimmett; Christopher J Domalewski; Honggang Cui Journal: Wiley Interdiscip Rev Nanomed Nanobiotechnol Date: 2019-10-10