Deep Lung Tissue Research Articles

Design, infectability, and transcriptomic analysis of transregionally differentiated and scalable lung organoids derived from adult bronchial cells.

The lung is a primary target for many lethal respiratory viruses, leading to significant global mortality. Current organoid models fail to completely mimic the cellular diversity and intricate tubular and branching structures of the human lung. Lung organoids derived from adult primary cells have so far only included cells from the input cell region, proximal or distal. Existing models are expensive. They often require cells from invasive deep lung tissue biopsies. The present study aimed to address these limitations. The lung organoids obtained using an original protocol exhibited transregional differentiation and were derived from relatively more accessible primary cells from the trachea/bronchi. Immortal bronchial cell lines were also used to simplify organoid fabrication and improve its scalability. The lung organoids are formed starting from bronchial cells with fibroblasts feeder cells in an alginate hydrogel coated with base membrane zone proteins. Characterizations were performed using bulk RNA sequencing and tandem mass tags. The resulting organoids express markers of different lung regions and mimic to some extent the tubular and branching morphology of the lung. The proteomic profile of organoid from primary cells and from cell lines was found to evolve towards that of mature lung tissue. Upregulated genes were mostly related to the respiratory system, tube development, and various aspects of respiratory viral infections. Infection with SARS-CoV-2 and influenza H1N1 was successful and did not require organoid disassembly. The organoids matured within 21 days and did not require complex or expensive culture methods. Transregionally differentiated lung organoid may find applications for the study of emerging or re-emerging viral infections and fostering the development of novel in-vitro therapeutic strategies.

Inhalable Polymeric Microparticles for Phage and Photothermal Synergistic Therapy of Methicillin-Resistant Staphylococcus aureus Pneumonia.

Acute methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is a common and serious lung infection with high morbidity and mortality rates. Due to the increasing antibiotic resistance, toxicity, and pathogenicity of MRSA, there is an urgent need to explore effective antibacterial strategies. In this study, we developed a dry powder inhalable formulation which is composed of porous microspheres prepared from poly(lactic-co-glycolic acid) (PLGA), internally loaded with indocyanine green (ICG)-modified, heat-resistant phages that we screened for their high efficacy against MRSA. This formulation can deliver therapeutic doses of ICG-modified active phages to the deep lung tissue infection sites, avoiding rapid clearance by alveolar macrophages. Combined with the synergistic treatment of phage therapy and photothermal therapy, the formulation demonstrates potent bactericidal effects in acute MRSA pneumonia. With its long-term stability at room temperature and inhalable characteristics, this formulation has the potential to be a promising drug for the clinical treatment of MRSA pneumonia.

Natural Products-Based Inhaled Formulations for Treating Pulmonary Diseases.

Given the unique physiological and pathological characteristics of the lung, the direct, inhalable route is more conducive to pulmonary drug delivery and disease control than traditional systemic drug delivery, significantly circumventing drug loss, off-target effects, systemic and organ toxicity, etc., and is widely regarded as the preferred regimen for pulmonary drug delivery. However, very few lung diseases are currently treated with the preferred inhaled formulations, such as asthma, chronic obstructive pulmonary disease and pulmonary hypertension. And there is a lack of appropriate inhaled formulations for other critical lung diseases, such as lung cancer and pulmonary fibrosis, due to the fact that the physicochemical properties of the drugs and their pharmacokinetic profiles do not match the physiology of the lung, and conventional inhalation devices are unable to deliver them to the specific parts of the lung. Phytochemicals of natural origin, due to their wide availability and clear safety profile, hold great promise for the preparation of inhalable formulations to improve the current dilemma in the treatment of lung diseases. In particular, the preparation of inhalable formulations based on nano- and microparticulate carriers for drug delivery to deep lung tissues, which overcome the shortcomings of conventional inhalation therapies while targeting the drug activity directly to a specific part of the lung, may be the best approach to change the current dilemma of lung disease treatment. In this review, we discuss recent advances in nano- and micron-carrier-based inhalation formulations for the delivery of natural products for the treatment of pulmonary diseases, which may represent an opportunity for practical clinical translation of natural products.

In Situ Noninvasive Observation of Nitric Oxide Fluctuation in SARS-CoV-2 Infection In Vivo by Organic Near-Infrared-II Fluorescent Molecular Nanoprobes.

The pathogenesis understanding of SARS-CoV-2 infection is crucial to prevent the rampant spread of COVID-19 and its contribution to deterioration in health, even death. Nitric oxide (NO), a crucial molecule involved in signal transduction and cytotoxicity, is a possible key regulator in the occurrence and development of COVID-19. However, understanding the pathogenesis of NO in SARS-CoV-2 infection is still in its infancy due to the lack of suitable in situ monitoring probes of NO fluctuation in the complex SARS-CoV-2 infection environment in deep lung tissues. Herein, we developed an activatable near-infrared-II fluorescent molecular nanoprobe (OSNP) that uncages high-resolution and deep-tissue-penetrating near-infrared-II fluorescence signal in specific response to NO for in situ and noninvasive visualization of NO fluctuation in a SARS-CoV-2 infection mouse model in lung tissues. In vivo visualization revealed that the NO level is a positive relationship with SARS-CoV-2 infection progress. With the assistance of immuno-histochemical analyses, we uncovered the NO-involved pathological mechanism, that being the improved NO level is associated with an increase in inducible NO synthase rather than endothelial NO synthase. Our study not only provides the example of a near-infrared-II fluorescent imaging of NO in SARS-CoV-2 infection but also provides opportunities to uncover tunderlying pathomechanism of NO for SARS-Cov-2 infections.

The impact ofvaping ethanol-containing electronic cigarette liquids onroadside impairment investigations.

Legal professionals and others have suggested that vaping electronic cigarettes (e-cigs) prior to or during ethanol breath testing may produce false positives. Preliminary breath tests (PBTs) and evidentiary breath tests (EBTs) measure ethanol in exhaled breath and standardized field sobriety tests (SFSTs) are used to assess impairment. Ethanol has been identified in e-cig liquids (e-liquids). Presented are a series of experiments designed to determine the mechanics of vaping ethanol using an e-cig and the effects of vaping ethanol on the SFSTs and breath tests used by law enforcement officers (LEO). Twelve participants (five females, age: 21-32 and seven males, age: 21-55), vaped either one or ten puffs of an e-liquid (0% or 20% ethanol). LEOs assessed impairment using SFSTs (12 and 42 min), PBTs (<1, 27, 32, 37 and 57 min) and EBTs (2, 29, 34, 39 and 59 min) post-vaping. A self-assessment test was administered post-vaping (22 and 52 min). Baseline responses for all measures were collected prior to vaping. Results demonstrated that ethanol in the e-liquids was aerosolized by e-cigs and produced particles that could reach the deep lung tissue based on mean-mass diameter. Ethanol was detected by PBT <3 min after participants vaped one (0.007-0.030 g/210 L) or ten puffs (013-0.074 g/210 L) of a 20% ethanol e-liquid. Ethanol was not detected by PBT at any subsequent time point. Ethanol was not detected by the EBT under any condition. Impairment was not indicated by the SFST. Some subjective effects were reported, but few statistically significant differences between conditions were indicated. A wait period prior to ethanol breath testing is not always mandated, depending on jurisdiction, or observed in all applications, such as workplace testing. The results demonstrate that a wait period must be employed to prevent vaping-related false-positive breath ethanol results.

Quantification and persistence of COVID-19 virus in recently deceased individuals before and after embalming.

The COVID-19 pandemic severely affected the medical education worldwide. The infection risk for medical students and healthcare personnel who work with COVID-19 positive cadavers or tissues remains unclear. Moreover, COVID-19 positive cadavers have been rejected by medical schools, adversely impacting the continuum of medical education. Herein, the viral genome abundance in tissues from four COVID-19 positive donors before and after embalming were compared. Tissue samples were collected from the lungs, liver, spleen, and brain both pre- and postembalming. The possible presence of infectious COVID-19 was determined by inoculating human tissue homogenates onto a monolayer of human A549-hACE2 cells and observing for cytopathic effects up to 72 h postinoculation. A real- time quantitative reverse transcription polymerase chain reaction was performed to quantify COVID-19 present in culture supernatants. Fully intact viral genome sequence was possible to obtain in samples with higher levels of virus, even several days postmortem. The embalming procedure described above substantially reduces the abundance of viable COVID-19 genomes in all tissues, sometimes even to undetectable levels. However, in some cases, COVID-19 RNA can still be detected, and a cytopathic effect can be seen both pre- and postembalmed tissues. This study suggests that embalmed COVID-19 positive cadavers might be used safely with appropriate precautions followed in gross anatomy laboratories and in clinical and scientific research. Deep lung tissue is the best specimen to test for the virus. If the tests on the lung tissues are negative, there is a very low likelihood that other tissues will show positive results.

Inhalable Solubilized Zileuton for Improved Lung Targeting in vitro and in vivo Analysis

Abstract: Background: Pulmonary diseases that affect the normal functioning of the lungs show airway symptoms ranging from change in airflow to bronchiectasis. Zileuton is an inhibitor of 5-lipoxygenase enzyme that catalyzes the synthesis of leukotrienes. Zileuton is used in the management of inflammatory conditions of the upper airways like obstructive pulmonary conditions and acute lung inflammation. Although a promising therapeutic, zileuton is poorly water-soluble and requires frequent administration to overcome bioavailability issues and maintain therapeutic levels that often lead to adverse reactions, especially to the non-targeted organs. Materials and Methods: Therefore, we designed a rapidly nanoemulsifying formulation of zileuton using Acrysol K150 as an oil, Cremophor EL as a surfactant, and Transcutol HP as a cosolvent. Results: This self-emulsifying composition exhibited showed a mean globule size of 133 ± 3.6 nm with a polydispersity index of 0.38. Scanning electron microscopy (SEM) images revealed the spherical shape of emulsion globules. In vitro lung deposition showed >80% delivery to the deep lung tissue. Mass median aerodynamic diameter of 2.05±0.98 μm for the aerosolized formulation. In vivo, pharmacokinetic studies in Wistar rats by inhalation route showed that the zileuton-loaded nanoemulsifying formulation had a significantly higher concentration in the lung compared to other non-target organs. The in vivo efficacy in the lipopolysaccharide-induced acute lung inflammation model in rats significantly impeded the protein accumulation and neutrophil infiltration in the lungs. Conclusion: The zileuton-loaded nanoemulsifying inhalable formulation successfully improved the therapeutic efficacy of zileuton specifically to the lung thereby minimizing the off-target organ side effects. Keywords: Self-emulsifying, Zileuton, Aerosols, Pharmacodynamics, in vivo, Lung targeting.

Nanoparticle-modified microrobots for in vivo antibiotic delivery to treat acute bacterial pneumonia.

Bioinspired microrobots capable of actively moving in biological fluids have attracted considerable attention for biomedical applications because of their unique dynamic features that are otherwise difficult to achieve by their static counterparts. Here we use click chemistry to attach antibiotic-loaded neutrophil membrane-coated polymeric nanoparticles to natural microalgae, thus creating hybrid microrobots for the active delivery of antibiotics in the lungs in vivo. The microrobots show fast speed (>110 µm s-1) in simulated lung fluid and uniform distribution into deep lung tissues, low clearance by alveolar macrophages and superb tissue retention time (>2 days) after intratracheal administration to test animals. In a mouse model of acute Pseudomonas aeruginosa pneumonia, the microrobots effectively reduce bacterial burden and substantially lessen animal mortality, with negligible toxicity. Overall, these findings highlight the attractive functions of algae-nanoparticle hybrid microrobots for the active in vivo delivery of therapeutics to the lungs in intensive care unit settings.

Impact of vaping ethanol on the roadside field sobriety test in a clinical setting

Recent studies have shown that electronic cigarette (e-cig) liquid formulations (e-liquids) can contain ethanol, sometimes in concentrations greater than 20%. Ethanol, rarely listed as an ingredient in e-liquids, is often used as a thinning agent, to dissolve insoluble substances, or added intentionally for consumption. Ethanol in e-liquids has been demonstrated to be aerosolized by e-cigs. Ethanol within the aerosol can be absorbed across mucosal membranes in the mouth, and also within deep lung tissue based on mean-mass particle size diameter. Preliminary Breath Tests (PBT) and Evidentiary Breath Tests (EBT) are conducted to measure ethanol in exhaled breath, with a 15–20 minute wait period, and Standardized Field Sobriety Tests (SFST) evaluate several operant conditions to assess ethanol impairment. Literature on impacts of vaping ethanol is limited. An evaluation to assess the impact of vaping ethanol from e-liquids is essential for law enforcement officers (LEO), medical review officers, ethanol treatment and recovery providers, workplace drug testing, and court mandated drug testing. This study evaluated the impact of inhaled ethanol via vaping on the SFST, PBT, and EBT for thirteen participants using a blind two-by-two experimental design under Virginia Commonwealth University (VCU) IRB HM20015064 and in collaboration with the Virginia Department of Forensic Science, the Center for the Study of Tobacco Products at VCU, VCU Police Department, and City of Richmond Police Department. E-liquids were made by a commercial manufacturer at concentrations of 0% and 20% ethanol. Ethanol concentrations were verified in-house using a Shimadzu HS-20 headspace attached to a Nexis GC-2030 gas chromatograph with dual flame ionization detectors. Stability studies were performed monthly to ensure sample suitability prior to clinical use. Thirteen participants were enrolled into the study based on inclusion and exclusion criteria. They vaped either one or ten puffs of an e-liquid (0% or 20% ethanol). LEOs assessed indicators of impairment by following a study design incorporating SFSTs, PBTs, and EBTs at predetermined intervals. Ethanol concentrations within the e-liquids were determined to be stable at −20 °C for the duration of the study. Positive breath ethanol results ranged from 0.007–0.030 and 0.013–0.043 g/210 dL by PBT immediately after using a 20% ethanol e-liquid when vaping one-puff and ten-puffs, respectively. All subsequent PBTs were negative for ethanol. No ethanol or instrument error was detected by EBT for any vaping scenario, at any timepoint. Impairment was not indicated by SFST. A well-designed human clinical study with robust and relevant collaborations between a crime lab, police departments, and a research university is important to address pertinent questions to forensic science. Breath ethanol concentrations were detectable by PBT immediately after vaping an e-liquid containing 20% ethanol. The results demonstrated the standard wait period of 15–20 minutes employed by LEO before administering a PBT for roadside stops was effective in negating vaping-related false positive breath ethanol results. Vaping ethanol also did not impact SFST results. Results should be considered for other contexts of ethanol testing, such as workplace testing and vehicle ignition interlock systems.

Omicron Variant (B.1.1.529) of SARS-CoV-2, A Worldwide Public Health Emergency!

B.1.1.529 is the newest form of SARS- CoV-2. It was initially reported to the World Health Organization (WHO) on November 24, 2021, by South Africa. WHO recognized it as a variant of concern on November 26, 2021, and named it "Omicron.” The Omicron variant features an exceptionally large number of mutations, many of which are unique, and a substantial number of which impair the spike protein targeted by most COVID-19 vaccines at the time of its discovery. Despite initial studies showing that the variant caused less serious disease than prior strains, this amount of miscellany has raised worries about its transmissibility, immune system evasion, and vaccine resistance. Omicron is suspected to be much more infectious than previous variants of concerns, spreading around 70 times faster in the bronchi, but it is less able to penetrate deep lung tissue, which may explain why there is a significant reduction in the risk of severe disease requiring hospitalization. Nonetheless, because of the virus's fast rate of transmission and capacity to resist both two-dose vaccination and the immune system, the overall number of patients requiring medical care at present remains a major worry. In this article, the current state of the art for Omicron variant has been discussed to provide a strong framework for future research. The evolution, mutation, epidemiology, infectivity, vaccine breakthrough, and antibody resistance of the Omicron variant are investigated and discussed.

On the Treatment of SARS-COV-2 Including Omicron Type

Objective: The aim of this research is to introduce new method of the treatment/control of Omicron Virus and answer some major questions regarding the cure of COVID-19 and the new type: Omicron. Background: We have selected 24 patients (12 females plus 12 males) aged from 15-64 years of old contaminated severe Omicron virus and used the novel methods on the treatment of these patients. Introduction: The Omicron variant (B.1.1.529) is a variant of SARS-CoV-2 which was first reported to the World Health Organization (WHO) from South Africa on 24 November 2021. Omicron multiplies around 70 times faster than the Delta variant in the bronchi but some evidence suggests that it is less severe than previous strains, specifically compared to the Delta variant. Omicron might be less able to penetrate deep lung tissue. Omicron infections are 91 percent less fatal than the delta variant, with 51 percent less risk of hospitalization. Materials and Methods: The Omicron virus has strongly high rate of mutation compared with other kinds of Coronaviruses and therefore; cause severe symptoms of inflammation in the patients including lungs. In our research, all the patients were under unique control. They received HBO2T with 2% Ozone mixture with Oxygen in special cube. Also they had an injection of liquid ozone which dramatically declines the inflammation in all tissues. They had under strict diet of special Ketogenic diet to maintain their mitochondria to remain high metabolism to hamper the fatigue and tiredness. The had also gain supplements necessary for the disease. Results: The entire patient showed full recovery in 3 days, but they had fatigue and tiredness which we had to give them MTC oil 30 grams/day and coconut oil 30 grams/day as well which reduced the tiredness of the patients dramatically and remain their metabolism in a normal state. As a whole, all the patients recovered in 7 days without any symptoms including coughing, tiredness, fever and etc. Conclusion: Using the novel methodology of the treatment of SARS-CoV including Omicron had positive results on the patients. HBO2T plus specific Ozone therapy dramatically reduced the inflammation in all tissues of the patients. This novel method is a breakthrough in the science of Infectious Diseases including Omicron virus.

Design and Characterization of Spray-Dried Proliposomes for the Pulmonary Delivery of Curcumin.

PurposeThe goal was to directly deliver curcumin, a natural polyphenolic anticancer and anti-inflammatory compound, to the lung tissues with minimal systemic exposure through the fabrication of proliposomes, overcoming its poor aqueous solubility and oral bioavailability.MethodsNano-spray drying was employed to prepare proliposomes using hydroxypropyl beta-cyclodextrin as a carrier. Lecithin and cholesterol were used as lipids, stearylamine and Poloxamer 188 were added as positive charge inducer and a surfactant, respectively. Different characterization parameters were evaluated like percentage yield, entrapment efficiency, drug loading, aerodynamic particle size, in vitro release besides morphological examination. Cytotoxicity studies on cell line A549 lung tumor cells as well as in vivo lung pharmacokinetic studies were also carried.ResultsThe optimized formulations showed superior aerosolization properties coupled their enhanced ability to reach deep lung tissues with a high % of fine particle fraction. Cytotoxicity studies using MTT assay demonstrated enhanced growth inhibitory effect on lung tumor cells A549 and significant reduction of proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6 and interleukin-10 compared to the pure drug. Results of lung pharmacokinetic tests confirmed the superiority of proliposomal curcumin over curcumin powder in both, the rate and extent of lung tissue absorption, as well as the mean residence time within the lung tissues.ConclusionThe pulmonary delivery of curcumin-loaded proliposomes as dry powder provides a direct approach to lung tissues targeting while avoiding the limitations of the oral route and offering a non-invasive alternative to the parenteral one.

Introduction of lung ultrasound surface wave elastography

Ultrasonography is not widely used for lung assessment because ultrasound cannot image deep lung tissue. Many lung diseases including interstitial lung disease (ILD) are associated with changes in lung's elastic properties. ILD includes multiple serious lung disorders associated with lung fibrosis and can lead to respiratory failure and pulmonary hypertension. High-resolution CT (HRCT) is the clinical standard for diagnosing lung fibrosis, but it results in increased radiation exposure for patients. Lung fibrosis is associated with stiffened lung parenchyma. Current clinical techniques including HRCT cannot measure lung elastic properties. Most ILDs are typically distributed in the lung's peripheral and subpleural regions. We developed noninvasive lung ultrasound surface wave elastography (LUSWE) to measure lung surface wave speed safely and quickly. In this abstract, we will present some basics for LUSWE. We will also present its clinic application for assessing ILD. We studied 30 healthy controls, 16 mild ILD patients, 45 moderate ILD patients, and 27 severe ILD patients. Lung surface wave speed has good sensitivity and specificity for separating ILD patients from healthy subjects as well as for separating mild ILD patients from healthy subjects. LUSWE is useful for other lung disorders such as pulmonary edema.

Analytical modeling of depth-dose degradation in heterogeneous lung tissue for intensity-modulated proton therapy planning.

Proton therapy may be promising for treating non-small-cell lung cancer due to lower doses to the lung and heart, as compared to photon therapy. A reported challenge is degradation, i.e., a smoothing of the depth-dose distribution due to heterogeneous lung tissue. For pencil beams, this causes a distal falloff widening and a peak-to-plateau ratio decrease, not considered in clinical treatment planning systems. We present a degradation model implemented into an analytical dose calculation, fully integrated into a treatment planning workflow. Degradation effects were investigated on target dose, distal dose falloffs, and mean lung dose for ten patient cases with varying anatomical characteristics. For patients with pronounced range straggling (in our study large tumors, or lesions close to the mediastinum), degradation effects were restricted to a maximum decrease in target coverage (D 95 of the planning target volume) of 1.4%. The median broadening of the distal 80-20% dose falloffs was 0.5mm at the maximum. For small target volumes deep inside lung tissue, however, the target underdose increased considerably by up to 26%. The mean lung dose was not negatively affected by degradation in any of the investigated cases. For most cases, dose degradation due to heterogeneous lung tissue did not yield critical organ at risk overdosing or overall target underdosing. However, for small and deep-seated tumors which can only be reached by penetrating lung tissue, we have seen substantial local underdose, which deserves further investigation, also considering other prevalent sources of uncertainty.

COVID-19 Patient with Multifocal Pneumonia and Respiratory Difficulty Resolved Quickly: Possible Antiviral and Anti-Inflammatory Benefits of Quercinex (Nebulized Quercetin-NAC) as Adjuvant

Background: SARS-CoV-2 (COVID-19) is a viral pandemic with no current vaccine or effective treatment. Hydroxychloroquine and azithromycin are not without cardiovascular risk or complications, and these treatments can fail to aid in full recovery from COVID-19. As new treatments become approved for the pandemic, an inexpensive, non-toxic, and safe adjunctive therapy is needed. Case Presentation: A 59-year-old male presented with respiratory symptoms. Chest X-ray revealed classic indications of COVID-19 pneumonia. A PCR nasopharyngeal swab test confirmed a COVID-19 infection and hospital doctors prescribed Rocephin, azithromycin, and hydroxychloroquine. The patient was then prescribed Quercinex, a nebulized formula of quercetin-(cyclodextrin) (20 mg/mL) and N-acetylcysteine (100 mg/mL) three times daily for 14 days by physicians at Envita Medical Center for continued COVID-19 respiratory symptoms. Following 30 minutes after each nebulization treatment, the patient experienced immediate deep breathing relief that lasted for multiple hours. Within the following 48 hours after the first treatment, respiratory symptoms continued to diminish and resolve quickly. Finally, post-treatment follow-up chest X-rays revealed no pulmonary fibrosis (scarring) and clear lung fields. Conclusion: The Quercinex formula appeared to greatly alleviate the unresolved respiratory symptoms rapidly. Several mechanisms of the formula, namely antiviral and anti-inflammatory action, with direct administration via nebulizer to the deep lung tissue, could potentially explain the fast and complete recovery. We recommend that the Quercinex formula be considered for further clinical study as an adjuvant or on its own for COVID-19 and possibly other viral pulmonary conditions.

A multilayer hollow nanocarrier for pulmonary co-drug delivery of methotrexate and doxorubicin in the form of dry powder inhalation formulation

Lung cancer is the number one cause of cancer deaths in the global population and remains difficult to treat mainly because of the absence of targeted drug delivery stages and restrictions related with delivery of drugs to deep lung tissues. The aim of the present study was to develop a noninvasive, patient-convenient formulation for the targeted delivery of chemotherapeutics to cancer cells located in the deep lung tissue. A PEGylated paramagnetic hollow-nanosphere was fabricated, fully characterized and used as a nanocarrier for pulmonary co-delivery of Doxorubicin (DOX) and Methotrexate (MTX). In first step, magnetic-silica nanoparticles were synthesized and then coated with amino/acrylate groups and derivatized with polyethylene glycol (PEG). Finally, silica was removed to provide hollow structured nanoparticles. The biocompatibility of blank carriers and the efficiency of MTX-DOX-loaded carriers were also approved by MTT assay and DAPI staining. The aerosolization performance of nanoparticles embedded microspheres were assessed by next generation impactor. The almost natural zeta potential and obvious decrease in silica content observed by EDX and removal of intense silica characteristic peak at FTIR analyses approved the successful removal of silica layer and preparation of hollow-nanospheres. The successful PEGylation of multilayer magnetic hollow-nanospheres catalyzed by boric acid was confirmed by presence of amide groups in FTIR spectra. The developed polymeric nanoparticle showed quite appropriate loading capacity for both DOX and MTX (48%) because of designing adequate negatively and positively charged sites for both drugs. The cytotoxicity assays proved the safety of blank nanoparticles and efficacy of drugs-loaded nanoparticles on lung cancer A549 cell lines. The developed dry powder inhalation formulation of nanoparticles showed appropriate aerosolization performance (fine particle fraction around 22%). It was concluded that these outcomes may open the potentials for efficient pulmonary co-delivery of MTX and DOX to the carcinogenic tissues.

Targeting oxidative stress using tri-needle electrospray engineered Ganoderma lucidum polysaccharide-loaded porous yolk-shell particles

Chronic lung diseases (e.g. chronic obstructive pulmonary disease and asthma) are associated with oxidative stress and common treatments include various types of inhalation therapies. In this work Ganoderma lucidum polysaccharide (GLP), a naturally occurring antioxidant is loaded into porous Poly (ε-caprolactone) (PCL) particles using a single step tri-needle coaxial electrospray process (Tri-needle CES); with a view to develop therapies to combat oxidative stress. Based on the core-shell structure of porous yolk shell particles (YSPs), GLP-loaded YSPs displayed a bi-phasic release pattern. In vitro cell studies indicate GLP-loaded porous YSPs display good biocompatibility and positive attributes towards H2O2-induced oxidative stress in MRC-5 cells and dramatically attenuate intracellular reactive oxygen species (ROS) levels as well as significantly increase cell viability. In vivo inhalation studies indicate that GLP-loaded porous YSPs can be delivered to deep lung tissue and remain deposited for over 48 h and are subsequently removed by natural clearance mechanisms. Based on current findings GLP-loaded porous YSPs are suitable for pulmonary delivery and display good inhalation therapy potential to treat chronic lung diseases.

Lung ultrasound surface wave elastography for assessing interstitial lung disease

Many lung diseases including interstitial lung disease (ILD) are associated with changes in the lung’s biomechanical properties. ILD comprises a number of serious diseases in which fibrosis stiffens and damages lung tissue. Most ILDs are typically distributed in the lung’s peripheral and subpleural regions. Pulmonary function test (PFT) and high-resolution computed tomography (HRCT) are used to assess ILD. Ultrasonography is not widely used for lung assessment because ultrasound cannot image deep lung tissue. We have developed lung ultrasound surface wave elastography (LUSWE) for measuring superficial lung wave speed. In LUSWE, a 0.1-s harmonic vibration is generated on the chest wall of a subject using a handheld vibrator. An ultrasound probe is aligned with the vibration excitation in the same intercostal space to measure the generated surface wave propagation on the lung. A human subject is examined in a sitting position. The lung is tested at the total lung volume and through six intercostal spaces. Significant differences of surface wave speed between patients and controls were found in 6 lung regions and for 3 excitation frequencies. A positive correlation between LUSWE and clinical tests including HRCT and PTF was found. LUSWE may complement the clinical standard HRCT for assessing ILD.

An ultrasound surface wave elastography technique for noninvasive measurement of surface lung tissue

Ultrasonography is not widely used in clinic for lung assessment because ultrasound cannot image deep lung tissue. In this abstract, we present a novel technique, lung ultrasound surface wave elastography (LUSWE), for measuring the elastic properties of superficial lung tissue. In LUSWE, a small, local, and 0.1 second harmonic vibration is generated on the chest of a subject. The speed of surface wave on the lung is measured by using an ultrasound probe. We are evaluating LUSWE for assessing patients with interstitial lung disease (ILD). LUSWE may be useful for assessing ILD because most ILD patients have typical fibrotic scars in the peripheral and subpleural regions of the lung. In a large clinical study of ILD patients, we measure both lungs through six intercostal spaces for patients and controls. The surface wave speed is measured at 100 Hz, 150 Hz, and 200 Hz. In an example, the surface wave speed is 1.88 ± 0.11 m/s and 3.3 ± 0.37 m/s, respectively, for a healthy subject and an ILD patient at 100 Hz and in the same intercostal space. LUSWE may compliment the clinical standard high-resolution computed tomography for assessing ILD. LUSWE may be useful for assessing other lung disorders.

Development of an inhalable, stimuli-responsive particulate system for delivery to deep lung tissue

Lung cancer, the deadliest solid tumor among all types of cancer, remains difficult to treat. This is a result of unavoidable exposure to carcinogens, poor diagnosis, the lack of targeted drug delivery platforms and limitations associated with delivery of drug to deep lung tissues. Development of a non-invasive, patient-convenient formula for the targeted delivery of chemotherapeutics to cancer in deep lung tissue is the aim of this study. The formulation consisted of inhalable polyvinylpyrrolidone (PVP)/maltodextrin (MD)-based microparticles (MPs) encapsulating chitosan (CS) nanoparticles (NPs) loaded with either drug only or drug and magnetic nanoparticles (MNPs). Drug release from CS NPs was enhanced with the aid of MNPs by a factor of 1.7 in response to external magnetic field. Preferential toxicity by CS NPs was shown towards tumor cells (A549) in comparison to cultured fibroblasts (L929). The prepared spray freeze dried (SFD) powders for CS NPs and CS MNPs were of the same size at ⿼6μm. They had a fine particle fraction (FPF⿤5.2μm) of 40⿿42% w/w and mass median aerodynamic diameter (MMAD) of 5⿿6μm as determined by the Next Generation Impactor (NGI). SFD-MPs of CS MNPs possess higher MMAD due to the high density associated with encapsulated MNPs. The developed formulation demonstrates several capabilities including tissue targeting, controlled drug release, and the possible imaging and diagnostic values (due to its MNPs content) and therefore represents an improved therapeutic platform for drug delivery to cancer in deep lung tissue.