Heterogenous Intrapulmonary Distribution of Aerosolized Model Compounds in Mice with Bleomycin-Induced Pulmonary Fibrosis.

A distinctive pathological feature of idiopathic pulmonary fibrosis (IPF) is the aberrant accumulation of extracellular matrix components in the alveoli in abnormal remodeling and reconstruction following scarring of the alveolar structure. The current antifibrotic agents used for IPF therapy frequently result in systemic side effects because these agents are distributed, through the blood, to many different tissues after oral administration. In contrast to oral administration, the intrapulmonary administration of aerosolized drugs is believed to be an efficient method for their direct delivery to the focus sites in the lungs.

Development of a Compensated Förster Resonance Energy Transfer Imaging for Improved Assessment of the Intrapulmonary Distribution of Polymeric Nanoparticles.

Inhalation-based drug delivery systems have gained attention as potential therapeutic options for various respiratory diseases. Among these systems, nanoparticles are being explored as drug carriers because of their ability to deliver therapeutic agents directly to the lungs. It is essential to accurately evaluate the intrapulmonary behavior of nanoparticles to optimize drug delivery and achieve selective targeting of lung lesions.

Development of visualization and analysis methods for evaluating intratumoral nanoparticle kinetics for tumor-targeted drug delivery using Förster resonance energy transfer in vivo live imaging and tissue clearing techniques.

In this study, the imaging methods for evaluating the kinetics of nanoparticles as drug delivery systems in tumor tissues were improved in BxPC3 tumor-bearing mice. First, Förster resonance energy transfer (FRET) live imaging was selected to quantitatively evaluate nanoparticle kinetics in the tumor tissue of mice. Briefly, and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine iodide (as an acceptor)-and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt (as a donor)-coloaded nanoparticles were administered intravenously to the mice, and imaging was performed using a fluorescence in vivo imager.

Improvement of the pharmacokinetics and antifibrotic effects of nintedanib by intrapulmonary administration of a nintedanib-hydroxypropyl-γ-cyclodextrin inclusion complex in mice with bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a chronic lung disease that is characterized by progressive abnormal reprogramming following injury of the pulmonary structure. In this study, we prepared a nintedanib (antifibrotic agent) and cyclodextrin (CyD) inclusion complex to improve the pharmacokinetics and antifibrotic effects of nintedanib following intrapulmonary administration. Hydroxypropyl-γ-CyD (HP-γ-CyD) enhanced the solubility of nintedanib without cytotoxic effects on WI-38 cells (lung fibroblasts) and NCI-H441 cells (alveolar epithelium model).

Three-Dimensional Imaging of Pulmonary Fibrotic Foci at the Alveolar Scale Using Tissue-Clearing Treatment with Staining Techniques of Extracellular Matrix.

Idiopathic pulmonary fibrosis is a progressive, chronic lung disease characterized by the accumulation of extracellular matrix proteins, including collagen and elastin. Imaging of extracellular matrix in fibrotic lungs is important for evaluating its pathological condition as well as the distribution of drugs to pulmonary focus sites and their therapeutic effects. In this study, we compared techniques of staining the extracellular matrix with optical tissue-clearing treatment for developing three-dimensional imaging methods for focus sites in pulmonary fibrosis.

Aerosolized Liposomal Formulation Prevents Enhanced Drug Transfer from Fibrotic Lungs to the Systemic Circulation.

Background: Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive respiratory disease characterized by the destruction of the alveolar structure. In pulmonary fibrosis, aerosolized drugs are easily transferred to the systemic circulation via leakage through the injured alveolar epithelium. Therefore, pulmonary drug delivery systems for sustained distribution in fibrotic lungs are needed.

Evaluation of tissue-clearing techniques for intraorgan imaging of distribution of polymeric nanoparticles as drug carriers.

Objective: The development of drug delivery systems using nanocarriers requires intraorgan imaging techniques for evaluating the distribution of nanocarriers. In this study, we evaluated the tissue-clearing techniques for the imaging of polymeric nanoparticles, a nanocarrier, in the liver used as a model of pigment-rich organ in mice.

Significance: The intraorgan imaging method of polymeric nanoparticles was examined without sectioning of organ samples for evaluating the delivery efficiency in preclinical studies.

Prolonged distribution of aerosolized PEGylated liposomes in the lungs of mice with bleomycin-induced pulmonary fibrosis.

Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic lung disease characterized by abnormal remodeling of the lung parenchyma with subsequent scarring of the alveolar structure. In this study, we examined the distribution characteristics of aerosolized polyethylene glycol (PEG)ylated liposomes in the lungs of mice with bleomycin-induced pulmonary fibrosis.

Significance: The present study details the utility of aerosolized PEGylated liposomes for improving intrapulmonary pharmacokinetics in fibrotic lungs.

Multiscale Live Imaging Using Förster Resonance Energy Transfer (FRET) for Evaluating the Biological Behavior of Nanoparticles as Drug Carriers.

To develop targeted drug delivery systems using nanoparticles for treating various diseases, the evaluation of nanoparticle behavior in biological environments is necessary. In the present study, the biological behavior of polymeric nanoparticles was directly traced in living mice and cells. The dissociation of nanoparticles was detected by Förster resonance energy transfer (FRET) imaging.

Intratumoral delivery and therapeutic efficacy of nanoparticle-encapsulated anti-tumor siRNA following intrapulmonary administration for potential treatment of lung cancer.

This study evaluated the delivery efficiency and antitumor effects of the intrapulmonary administration of antitumor small interfering ribonucleic acid (siRNA)-containing nanoparticles to mice with metastatic lung tumor. Fluorescence-labeled, siRNA-containing nanoparticles were administered using Liquid MicroSprayer to mice with metastatic lung tumors induced by the murine melanoma cell line B16F10. Fluorescent signals in the whole lung and in the tumor region following the intrapulmonary administration of siRNA-containing nanoparticles were stronger than those following intravenous administration.

Evaluation of various tissue-clearing techniques for the three-dimensional visualization of liposome distribution in mouse lungs at the alveolar scale.

Purpose: To develop a three-dimensional visualization method for evaluating the distribution of pulmonary drug delivery systems and compare four tissue-clearing techniques (Clear, CUBIC, ScaleS, and SeeDB2) using intrapulmonary liposomes as drug carriers.

Methods: Rhodamine B-labeled liposomes were administered intrapulmonarily to mice using a MicroSprayer, and then fluorescent-labeled tomato lectin was administered intravenously to visualize the general lung structure. Tissue-clearing treatment of the mouse lungs was performed using the standard protocols of the Clear, CUBIC, ScaleS, and SeeDB2 techniques.

Tissue-Clearing Techniques Enable Three-Dimensional Visualization of Aerosolized Model Compound and Lung Structure at the Alveolar Scale.

In this study, we examined the usefulness of a tissue-clearing technique for the evaluation of the lung distribution of aerosolized drugs. An aerosol formulation of TexasRed dextran (70 kDa), a model compound of drug carrier for aerosolized drugs, was administered intrapulmonarily to mice using a MicroSprayer, and then DyLight 488-conjugated tomato lectin was administered intravenously to visualize general lung structure via the fluorescent labeling of alveolar and bronchial epithelial cells. Tissue clearing followed by laser scanning confocal microscopy enabled the three-dimensional visualization of intrapulmonary TexasRed dextran and the evaluation of its distribution at the alveolar scale without the preparation of thin tissue sections.

Aerosolized liposomes with dipalmitoyl phosphatidylcholine enhance pulmonary absorption of encapsulated insulin compared with co-administered insulin.

Objective: We have previously shown that aerosolized liposomes with dipalmitoyl phosphatidylcholine (DPPC) enhance the pulmonary absorption of encapsulated insulin. In this study, we aimed to compare insulin encapsulated into the liposomes versus co-administration of empty liposomes and unencapsulated free insulin, where the DPCC liposomes would serve as absorption enhancer.

Significance: The present study provides the useful information for development of noninvasive treatment of diabetes.

Evaluation of permeability alteration and epithelial-mesenchymal transition induced by transforming growth factor-β in A549, NCI-H441, and Calu-3 cells: Development of an in vitro model of respiratory epithelial cells in idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease, which is accompanied by changes in lung structure. With regard to treatment, aerosolized drugs administered intrapulmonarily are rapidly distributed into the plasma and do not remain in the lungs due to damage to the alveolar epithelium that occurs from pulmonary fibrosis. In this study, we sought to develop an in vitro model of respiratory epithelial cells in IPF for the evaluation of the intrapulmonary distribution of aerosolized drugs.

Ingestibility and Formulation Quality of Lansoprazole Orally Disintegrating Tablets.

. We evaluated the ingestibility and formulation quality of one branded (formulation A) and five generic (formulations B, C, D, E, and F) lansoprazole orally disintegrating (OD) tablets. .

Sustained distribution of aerosolized PEGylated liposomes in epithelial lining fluids on alveolar surfaces.

The distribution characteristics of aerosolized PEGylated liposomes in alveolar epithelial lining fluid (ELF) were examined in rats, and the ensuing mechanisms were investigated in the in vitro uptake and protein adsorption experiments. Nonmodified or PEGylated liposomes (particle size 100 nm) were aerosolized into rat lungs. PEGylated liposomes were distributed more sustainably in ELFs than nonmodified liposomes.

Alteration in Intrapulmonary Pharmacokinetics of Aerosolized Model Compounds Due to Disruption of the Alveolar Epithelial Barriers Following Bleomycin-Induced Pulmonary Fibrosis in Rats.

Idiopathic pulmonary fibrosis is a lethal lung disease that is characterized by the accumulation of extracellular matrix and a change in lung structure. In this study, intrapulmonary pharmacokinetics of aerosolized model compounds were evaluated using rats with bleomycin-induced pulmonary fibrosis. Aerosol formulations of indocyanine green, 6-carboxyfluorescein (6-CF), and fluorescein isothiocyanate dextrans (FD; 4.

Efficient delivery to human lung fibroblasts (WI-38) of pirfenidone incorporated into liposomes modified with truncated basic fibroblast growth factor and its inhibitory effect on collagen synthesis in idiopathic pulmonary fibrosis.

In the present in vitro study, we assessed the delivery of pirfenidone incorporated into liposomes modified with truncated basic fibroblast growth factor (tbFGF) to lung fibroblasts and investigated the anti-fibrotic effect of the drug. The tbFGF peptide, KRTGQYKLC, was used to modify the surface of liposomes (tbFGF-liposomes). We used the thin-layer evaporation method, followed by sonication, to prepare tbFGF-liposomes containing pirfenidone.

Involvement of intestinal permeability in the oral absorption of clarithromycin and telithromycin.

The involvement of intestinal permeability in the oral absorption of clarithromycin (CAM), a macrolide antibiotic, and telithromycin (TEL), a ketolide antibiotic, in the presence of efflux transporters was examined. In order independently to examine the intestinal and hepatic availability, CAM and TEL (10 mg/kg) were administered orally, intraportally and intravenously to rats. The intestinal and hepatic availability was calculated from the area under the plasma concentration-time curve (AUC) after administration of CAM and TEL via different routes.

Subcellular distribution of azithromycin and clarithromycin in rat alveolar macrophages (NR8383) in vitro.

Azithromycin (AZM), a 15-membered ring macrolide antimicrobial agent, has an antibacterial spectrum that includes intracellular parasitic pathogens that survive or intracellularly multiply in alveolar macrophages (AMs). The subcellular distribution of AZM in AMs was evaluated in vitro in comparison with clarithromycin (CAM). AZM and CAM (50 µM) were applied to the NR8383 cells, used as an in vitro model of AMs, followed by incubation at 37°C or 4°C.

Enantioselective uptake of fexofenadine by Caco-2 cells as model intestinal epithelial cells.

Objectives: Fexofenadine contains a chiral carbon in its chemical structure and is orally administered as a racemic mixture. This study evaluated the selective uptake of fexofenadine enantiomers by Caco-2 cells as a model of intestinal epithelial cells.

Methods: R(+)-fexofenadine or S(-)-fexofenadine was applied to Caco-2 cells, followed by incubation.

Aerosol-based efficient delivery of azithromycin to alveolar macrophages for treatment of respiratory infections.

The efficacy of aerosol-based delivery of azithromycin (AZM) for the treatment of respiratory infections caused by pathogenic microorganisms infected in alveolar macrophages (AMs) was evaluated by comparison with oral administration. The aerosol formulation of AZM (0.2 mg/kg) was administered to rat lungs using a Liquid MicroSprayer(®).

Aerosol-based efficient delivery of clarithromycin, a macrolide antimicrobial agent, to lung epithelial lining fluid and alveolar macrophages for treatment of respiratory infections.

Background: Macrolide antimicrobial agents are generally given by the oral route for the treatment of respiratory infections caused by pathogenic microorganisms infected in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs). However, because macrolides distribute to many different tissues via the blood after oral administration, systemic side effects are frequently induced. In contrast with oral administration, aerosolization may be an efficient method for delivering macrolides directly to ELF and AMs.

Distribution characteristics of clarithromycin and azithromycin, macrolide antimicrobial agents used for treatment of respiratory infections, in lung epithelial lining fluid and alveolar macrophages.

The distribution characteristics of clarithromycin (CAM) and azithromycin (AZM), macrolide antimicrobial agents, in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs) were evaluated. In the in vivo animal experiments, the time-courses of the concentrations of CAM and AZM in ELF and AMs following oral administration (50 mg/kg) to rats were markedly higher than those in plasma, and the area under the drug concentration-time curve (AUC) ratios of ELF/plasma of CAM and AZM were 12 and 2.2, and the AUC ratios of AMs/ELF were 37 and 291, respectively.

[Effects of sperminated pullulans on the pulmonary absorption of insulin].

Sperminated pullulans (SP) having different molecular weights (MWs) were prepared, and the enhancing effect on the pulmonary absorption of insulin in rats was examined. SP acted as enhancers of insulin absorption when a 0.1% solution was applied with insulin simultaneously and their enhancing effects depended on the MW of the SP; the same solutions exhibited low toxicity in the in vivo LDH leaching test.