| Pulmonary hypertension is a complex cardiopulmonary system disease that the pulmonary vascular pressure is beyond the average range.If not treated effectively in time,it will even lead to death.At present,the method for pulmonary hypertension is used prostacyclin or endothelin receptor analogues which have the specific target,but there are still disadvantages of poor prognosis and high cost.Hydrogen sulfide is a kind of endogenous gas transmitter found in humans.It has been found to have effects in the treatment of cardiopulmonary vascular disease.Pulmonary administration is specifically targeted and has no invasive.It is a preferred way to treat cardiopulmonary vascular disease.Microfluidic technology can be used as a new technology to control droplet formation at microscale which is able to prepare highly dispersible fine particles.Based on these,poly(lactic-co-glycolic acid)(PLGA)was chosen as carrier,and ammonium bicarbonate(AB)was chosen as porogen in this article.Porous microspheres used to delivery drugs to lungs(PLGA PMs)and porous microspheres loaded with ACS14(ACS14-PLGA PMs)were prepared by microfluidic technique and its biocompatibility and therapeutic effects were studied.The main study containing follows:1.Preparation and study of PLGA PMs:The Minitab full-factor experiments were used to investigate the indicators affecting the geometrical particle size of porous microspheres,including PLGA concentration,porogen concentration,water and oil phase ratio and two phases flow ratio.Porous microspheres having a geometric particle size(D_g)of about 27?m and aerodynamic diameter(D_a)approximate 4.4?m were prepared by selecting suitable preparation conditions.The results of Fourier transform infrared spectroscopy(FTIR),differential scanning calorimetry(DSC)and gas chromatography(GC)showed that the chemical composition of PLGA did not change before and after microfluidic technology process,and glass transition temperature was not changed,organic solvent have not been detected left.Rseults showed that PLGA PMs can be effectively deposited in the lungs and appeared good biocompatibility.2.Preparation and study of ACS14-PLGA PMs:Porous microspheres with different drug loading were prepared following the conditions of PLGA PMs.The Dg was less than 30?m,Da was less than 5?m and FPF was greater than 50%,FTIR,X-ray powder diffraction(XRD),DSC and GC results showed that the ACS14-PLGA PMs prepared by the microfluidic technique did not undergo chemical changes and no organic solvent remained.Liquid chromatography(HPLC)experiment showed high drug loading and encapsule efficiency of ACS14-PLGA PMs.Also,ACS14-PLGA PMs could realize slow release of ACS14 in vitro.Acute injure and inflammation experiments on rats showed that pulmonary delivery does not cause serious acute lung injury and immune inflammatory response and is non-toxic to alveolar epithelial cells,which is an avaliable way of drug delivery.3.Pharmacodynamic study of ACS14-PLGA PMs:Cell-level studies showed that ACS14-PLGA PMs can promote apoptosis of over-proliferated human pulmonary artery smooth muscle cells.Animal-level studies illustrated that after pulmonary administration for 14 days,index of pulmonary artery pressure,right ventricular hypertrophy and tricuspid systolic displacement value of pulmonary hypertension model rats were changed and have significant different from the untreated group.Pulmonary vascular hematoxylin-eosin test showed that the blood vessel wall thickness was significantly decreased.Concluding the related results,it can be said that pulmonary administration of ACS14-PLGA PMs has a certain therapeutic result to model rats.Comprehensive analysis of results showed that ACS14-PLGA PMs prepared by microfluidic technology can effectively achieve pulmonary deposition,have good individual safety,and have a certain therapeutic effect on pulmonary hypertension,which can provide another idea and direction for clinical application in the future. |
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