Microfluidic fabrication of inhalable large porous microspheres loaded with H2S-releasing aspirin derivative for pulmonary arterial hypertension therapy.

Hydrogen sulfide (H2S) has recently emerged as a novel gaseous mediator with protective actions in the treatment of pulmonary arterial hypertension (PAH). However, the therapeutic potential of H2S in PAH has been substantially hampered due to the lack of appropriate donors that could mimic the slow and continuous generation of H2S in vivo. Large porous microspheres (LPMs) have low density and large surface area leading to excellent absorption capabilities and aerodynamic properties. They are extensively studied as pulmonary delivery carriers for controlled and sustained release of drug molecules in the treatment of pulmonary disorders. Therefore, we hypothesized that LPMs containing H2S-releasing aspirin derivative (ACS14), a novel synthetic H2S donor may be a feasible option to facilitate the use of H2S in PAH treatment. LPMs were prepared with a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA) by a microfluidic technique. Surface morphology, lung deposition characteristics, safety and H2S release profiles of the formulation were evaluated. The resulting ACS14-containing LPMs (ACS14 MSs) displayed excellent aerodynamic properties (mass median aerodynamic diameter of 4.4 ± 0.4 µm), desirable drug loading and entrapment efficiency (25.8 ± 2.7% and 77.4 ± 6.9%, respectively) with slow and sustained H2S release for 24 h and negligible cytotoxicity (~95% cell viability). Daily intratracheally administered with ACS14 MSs elicited improvement in the severity of PAH in a rat model of monocrotaline-induced PAH, with comparable efficacy to oral administration with sildenafil, a conventional PAH treatment. It also inhibited the process of endothelial-to-mesenchymal transition (EndMT), an important process in vascular remodeling of PAH by suppressing the induction of NF-κB-Snail pathway. Moreover, ACS14 MSs dose-dependently inhibited TGF-ß1-induced EndMT and the activation of NF-κB-Snail pathway in human pulmonary artery endothelial cells. In conclusion, our findings demonstrated that the designed microfluidics-assisted ACS14-containing LPMs have shown great potential to be used as an inhalable and efficacious H2S donor in the treatment of PAH.

Supercritical Fluid-Assisted Porous Microspheres for Efficient Delivery of Insulin and Inhalation Therapy of Diabetes.

Pulmonary delivery of drugs has attracted increasing attention in healthcare, as the lungs are an easily accessible site for noninvasive systemic delivery of drugs. Although pulmonary inhalation of porous microparticles has been shown to sustain drug delivery, there are limited reports on efficient delivery of insulin and inhalation therapy of diabetes based on supercritical carbon dioxide (SC-CO2 ) technology. Herein, this study reports the fabrication of insulin-loaded poly-l-lactide porous microspheres (INS-PLLA PMs) by using the SC-CO2 technology, and their use as an inhalation delivery system potentially for diabetes therapy. Biocompatibility and delivery efficiency of the PLLA PMs in the lungs are investigated. The PLLA PMs show negligible toxicity to lung-derived cells, resulting in no significant reduction in cell viability, as well as levels of various inflammatory mediators such as interleukin (IL)-6, IL-8, and tumor necrosis factor-α, compared with the negative control group. INS-PLLA PMs are further efficiently deposited in the trachea and the bronchi of superior lobes of the lungs, which exhibit pronounced hypoglycemic activity in induced diabetic rats. Together, the results demonstrate that the INS-PLLA PMs have a strong potential as an effective strategy for inhalation treatment of diabetes.