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1.
Drug Deliv Transl Res ; 11(4): 1752-1765, 2021 08.
Article in English | MEDLINE | ID: mdl-34047967

ABSTRACT

The major pathogen found in the lungs of adult cystic fibrosis (CF) patients is Pseudomonas aeruginosa, which builds antibiotic-resistant biofilms. Pulmonary delivery of antibiotics by inhalation has already been proved advantageous in the clinic, but the development of novel anti-infective aerosol medicines is complex and could benefit from adequate in vitro test systems. This work describes the first in vitro model of human bronchial epithelial cells cultivated at the air-liquid interface (ALI) and infected with P. aeruginosa biofilm and its application to demonstrate the safety and efficacy of aerosolized anti-infective nanocarriers. Such a model may facilitate the translation of novel therapeutic modalities into the clinic, reducing animal experiments and the associated problems of species differences. A preformed biofilm of P. aeruginosa PAO1 was transferred to filter-grown monolayers of the human CF cell line (CFBE41o-) at ALI and additionally supplemented with human tracheobronchial mucus. This experimental protocol provides an appropriate time window to deposit aerosolized ciprofloxacin-loaded nanocarriers at the ALI. When applied 1 h post-infection, the nanocarriers eradicated all planktonic bacteria and reduced the biofilm fraction of the pathogen by log 6, while CFBE41o- viability and barrier properties were maintained. The here described complex in vitro model approach may open new avenues for preclinical safety and efficacy testing of aerosol medicines against P. aeruginosa lung infection.


Subject(s)
Cystic Fibrosis , Pseudomonas aeruginosa , Animals , Anti-Bacterial Agents , Biofilms , Ciprofloxacin , Cystic Fibrosis/drug therapy , Cystic Fibrosis/microbiology , Humans
2.
Eur J Pharm Biopharm ; 117: 363-371, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28476373

ABSTRACT

Current pulmonary treatments against Pseudomonas aeruginosa infections in cystic fibrosis (CF) lung suffer from deactivation of the drug and immobilization in thick and viscous biofilm/mucus blend, along with the general antibiotic resistance. Administration of nanoparticles (NPs) with high antibiotic load capable of penetrating the tight mesh of biofilm/mucus can be an advent to overcome the treatment bottlenecks. Biodegradable and biocompatible polymer nanoparticles efficiently loaded with ciprofloxacin complex offer a solution for emerging treatment strategies. NPs were prepared under controlled conditions by utilizing MicroJet Reactor (MJR) to yield a particle size of 190.4±28.6nm with 0.089 PDI. Encapsulation efficiency of the drug was 79% resulting in a loading of 14%. Release was determined to be controlled and medium-independent in PBS, PBS+0.2% Tween 80 and simulated lung fluid. Cytotoxicity assays with Calu-3 cells and CF bronchial epithelial cells (CFBE41o-) indicated that complex-loaded PLGA NPs were non-toxic at concentrations ≫ MICcipro against lab strains of the bacteria. Antibacterial activity tests revealed enhanced activity when applied as nanoparticles. NPs' colloidal stability in mucus was proven. Notably, a decrease in mucus turbidity was observed upon incubation with NPs. Herewith, ciprofloxacin complex-loaded PLGA NPs are introduced as promising pulmonary nano drug delivery systems against P.aeruginosa infections in CF lung.


Subject(s)
Ciprofloxacin/administration & dosage , Cystic Fibrosis , Lactic Acid/administration & dosage , Nanoparticles/administration & dosage , Polyglycolic Acid/administration & dosage , Pseudomonas aeruginosa/drug effects , Respiratory Tract Infections , Animals , Cell Line , Ciprofloxacin/metabolism , Cystic Fibrosis/drug therapy , Cystic Fibrosis/metabolism , Drug Carriers/administration & dosage , Drug Carriers/metabolism , Horses , Humans , Lactic Acid/metabolism , Mucus/drug effects , Mucus/metabolism , Mucus/microbiology , Nanoparticles/metabolism , Polyglycolic Acid/metabolism , Polylactic Acid-Polyglycolic Acid Copolymer , Pseudomonas aeruginosa/metabolism , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Respiratory Mucosa/microbiology , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/metabolism
3.
Adv Drug Deliv Rev ; 85: 44-56, 2015 May.
Article in English | MEDLINE | ID: mdl-25453270

ABSTRACT

New pharmaceutical formulations must be proven as safe and effective before entering clinical trials. Also in the context of pulmonary drug delivery, preclinical models allow testing of novel antimicrobials, reducing risks and costs during their development. Such models allow reducing the complexity of the human lung, but still need to reflect relevant (patho-) physiological features. This review focuses on preclinical pulmonary models, mainly in vitro models, to assess drug safety and efficacy of antimicrobials. Furthermore, approaches to investigate common infectious diseases of the respiratory tract, are emphasized. Pneumonia, tuberculosis and infections occurring due to cystic fibrosis are in focus of this review. We conclude that especially in vitro models offer the chance of an efficient and detailed analysis of new antimicrobials, but also draw attention to the advantages and limitations of such currently available models and critically discuss the necessary steps for their future development.


Subject(s)
Animal Use Alternatives , Anti-Bacterial Agents/administration & dosage , Cystic Fibrosis/drug therapy , Drug Delivery Systems/methods , Pneumonia, Bacterial/drug therapy , Tuberculosis, Pulmonary/drug therapy , Animals , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/therapeutic use , Cystic Fibrosis/microbiology , Disease Models, Animal , Drug Delivery Systems/adverse effects , Drug Evaluation, Preclinical , Humans , In Vitro Techniques , Pneumonia, Bacterial/microbiology , Tuberculosis, Pulmonary/microbiology
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