| The human lung has a large surface area and a specific interface with the external environment.Lung tissue is composed of multiple types of cells that are constantly exposed to chemical,physical,hormonal,immune and exogenous stressors throughout their lives.Bacterial infections of the lungs type lung diseases are common public health problems that place a heavy burden on national or urban health care systems.Respiratory tract infections are the infectious diseases that cause the most deaths worldwide.Inhaled antimicrobials are gradually gaining interest in the treatment of lung infections,especially for drug-resistant bacterial lung infections.Indeed,nebulized antibiotics provide a superior method of delivering large doses of antimicrobial drugs directly to infected cells and around bacteria without having to pass through the systemic circulation,thereby reducing drug toxicity and increasing the bioavailability of available antimicrobial drugs.However,important determinants affecting clinical outcomes are the concentration/persistence of the antibiotic at the site of bacterial infection and the extent to which the drug can penetrate into the alveolar ducts and bronchioles.In this paper,we first analyzed real respiratory pathological mucus samples;investigated the suitability of respiratory mucus penetration and particle surface properties;revealed the property patterns of a series of polyelectrolyte materials with mucus diffusion advantages;designed and synthesized nebulized delivery nanosystems that can be used to treat different lung bacterial infections,and also validated the functional advantages of nebulized delivery nanosystems and their in vivo lung The functional advantages of the nebulized delivery nanosystems and their therapeutic effects in lung infections in vivo were also verified.1.Based on the analysis of pathological mucus,the effect of variables of particle surface charge and particle size on the diffusion kinetics of nanoparticles in mucus was investigated by means of multi-particle tracking.A series of polyelectrolyte materials with mucus diffusion advantages are revealed,i.e.,particles with neutral or negative charge,particle size <400 nm and hydrophilic surface have better mucus diffusion ability.It is useful to clarify the design criteria for inhaled therapeutic nanoparticles.2.Three nano-delivery systems for nebulization were designed and synthesized(where the polymeric materials used include sodium hyaluronate-HA,poly(lactic acid)-hydroxyacetic acid copolymer-PLGA,and poly(β-amino ester)-PAE;the antibiotic drugs were polymyxin-B(PMB)and vancomycin(Van),namely HA@PLGA-PMB NPs,HA@PLGA-Van NPs,and Their advantages in terms of in vitro mucus penetration,in vitro antimicrobial efficacy,cell safety,cellular uptake function and in vivo aerosol deposition were verified.The HA@PLGA-PMB/Van NPs had better mucus penetration efficiency,2.9times that of the free drug,and also maintained good in vitro antimicrobial activity and alveolar cellular uptake.HA-PAE/PMB NPs had better motor diffusion properties in mucus(<MSD> value 1000 times that of the free drug)and responded to rapid drug release at low p H The function of the drug in low p H.The excellent in vivo therapeutic efficacy of the nebulized delivery system was verified by constructing mouse models of different bacterial infections and performing nebulized drug delivery treatment in different infection models.HA@PLGA-PMB/Van NPs significantly reduced the lung bacterial load after nebulized drug delivery treatment,and the in vivo antimicrobial treatment was 1.5 times more efficient than free drug,while effectively alleviating lung inflammation and injury and modulating inflammatory factor levels.In the treatment of severe lung infections nebulized administration of HA-PAE/PMB NPs has better efficacy in restoring normal lung function than free drugs.This has laid the foundation for the clinical application of nebulized delivery of nanoparticles.The nanoparticles we designed and synthesized are of suitable electrical properties and size,which are in accordance with the requirements of mucus penetration during nebulized delivery.At the same time,the nanoparticles have excellent functions such as good mucus permeation or diffusion properties,good antibacterial activity,good cell biocompatibility and cellular uptake.HA@PLGA-PMB NPs,HA@PLGA-Van NPs and HA-PAE/PMB NPs have excellent results in nebulized delivery for the treatment of pulmonary infections with good safety profile,which provide The clinical application of nebulized delivery nanoparticles for the treatment of pulmonary infectious diseases has laid the foundation. |
PDF Full Text Request