| Allergic rhinitis(AR)is an inflammatory disease of the nasal mucosa and one of the most common allergic diseases.The symptoms of AR include sneezing,nasal congestion,and nasal itching,which seriously affect the quality of life and work efficiency of patients.Clinically,AR drug therapy includes the use of antihistamines,decongestants,glucocorticoids,mast cell stabilizers,and leukotriene receptor antagonists,and other therapies include surgery or specific immunotherapy.However,the efficacy of these strategies remains limited or patient compliance is poor,and their side effects have been reported clinically.As gene regulators,mi RNAs play an important role in regulating the pathogenesis of allergic inflammation.Previous studies have shown that mi R-146 a is involved in suppressing inflammation,regulating the immune system,and suppressing allergic inflammation.However,naked mi RNAs are difficult to penetrate the extracellular barrier and are easily degraded in vivo.Nanoparticles have good nucleic acid delivery capabilities and can maintain the stability of nucleic acids in the body.At present,nanoparticles have been widely used in drug and gene delivery platforms.In addition,nanoparticle delivery platforms are increasingly being combined with other biomaterials to form a hybrid system with new application prospects.Objective:To prevent the rapid removal of mucus and nasal cilia and improve the bioavailability,based on the unique p H and temperature of the nasal cavity,a binary preparation of chitosan hydrogel containing nucleic acid-containing nanoparticles was designed.The prepared binary preparation was characterized,and its pharmacodynamic effect in the treatment of allergic rhinitis was investigated,to evaluate the delivery system for nasal administration in the treatment of allergic rhinitis.Methods:(1)PEG-PLA nanoparticles carrying mi R-146 a were prepared by the double emulsion method,the morphology of the nanoparticles was observed by a transmission electron microscope,the size and potential of the nanoparticles were characterized by a Malvern particle sizer.The entrapment rate of mi RNA in nanoparticles was measured.(2)According to the gel strength,mucosal adhesion strength,and mucosal adhesion duration,the preparation of nanoparticle-loaded chitosan composite hydrogel was optimized.The binary preparation of gel/NPs/mi R-146 a carrying nucleic acid was prepared to base on the optimal process,and the in vitro penetration study of the nucleic acid contained in the binary preparation was carried out through the Franz diffusion cell.(3)The rat model of allergic rhinitis was established by using ovalbumin(OVA)as an allergen.After making the model,the model rats were randomly divided into 5 groups,and each group was given corresponding doses of normal saline,naked mi R-146 a,NPs/mi R-146 a,gel/mi R-146 a,gel/NPs/mi R-146 a,and nasal symptom scores were given respectively.Groups of rats by observing behavior,the effects of different preparations on the nasal mucosa cells were detected by TUNEL staining,and the pathological morphological changes of nasal mucosa were observed by hematoxylin-eosin staining.The changes of inflammatory factors in blood were detected by enzyme-linked immunoassay.the expressions of TLR4 and NF-κB in the nasal mucosa were detected by immunohistochemistry,and the expressions of mi R-146 a and related inflammatory factors were analyzed by PCR and Western blot,to further evaluate the efficacy of the prepared binary for nasal delivery nucleic acid in the treatment of rhinitis.Results:(1)The PEG-PLA nanoparticles containing nucleic acid were spherical with an average particle size of 551.5±53.2 nm,a potential of-22.6±1.3 m V,and a polydispersity coefficient of 0.217±0.105.The encapsulation efficiency was 82.8±9.9%.(2)The prepared binary formulation quickly formed gel at nasal temperature 34°C and had good mucosal adhesion.The permeability of the Gel/NPs/mi R-146 a binary formulation was 40%.After 48 h,the retention rate of NPs/mi R-146 a in the mucosa was about 29%,and that of gel/mi R-146 a was about 39%.The mucosal rejection rate of gel/NPs/mi R-146 a binary formulation was the highest,which was 51% of the initial dose.(3)After modeling,all AR rats showed typical symptoms of allergic rhinitis.There was no significant change in nasal symptoms in mi R-146 a group;the nasal symptoms of the gel/mi R-146 a and NPs/mi R-146 a groups had a certain improvement effect;while treated with gel/NPs/mi R-146 a delivery nucleic acid showed a good improvement.The results of the hematoxylin-eosin staining method and enzyme-linked immunosorbent assay showed that the binary formulations prepared by combining chitosan and nanoparticles had the better nasal nucleic acid delivery ability and produced better pharmacodynamic effect than the separate dosage form of gel and nanoparticles.Conclusions: Gel/NPs/mi R-146 a has appropriate nasal mucosal drug delivery ability after nasal administration,which makes the drug delivery in the nose last longer.And it has a good pharmacodynamics effect on rhinitis of rats sensitized by ovalbumin.The prepared gel/NPs/mi RNA binary formulation can be used as a nucleic acid delivery platform for nasal administration in the treatment of rhinitis. |
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