Target Lung Tissue Research Articles

Precise antibiotic delivery to the lung infection microenvironment boosts the treatment of pneumonia with decreased gut dysbiosis

Bacterial pneumonia is a common disease with significant health risks. However, the overuse antibiotics in clinics face challenges such as inadequate targeting and limited drug utilization, leading to drug resistance and gut dysbiosis. Herein, a dual-responsive lung inflammatory tissue targeted nanoparticle (LITTN), designed for targeting lung tissue and bacteria, is screened from a series of prepared nanoparticles consisting of permanent cationic lipids, acid-responsive lipids, and reactive oxygen species-responsive and phenylboronic acid-modified lipids with different surface properties. Such nanoparticle is further verified to enhance the adsorption of vitronectin in serum. Additionally, the optimized nanoparticle exhibits more positive charge and coordination of boric acid with cis-diol in the infected microenvironment, facilitating electrostatic interactions with bacteria and biofilm penetration. Importantly, the antibacterial efficiency of dual-responsive rifampicin-loaded LITTN (Rif@LITTN) against methicillin-resistant staphylococcus aureus is 10 times higher than that of free rifampicin. In a mouse model of bacterial pneumonia, the intravenous administration of Rif@LITTN could precisely target the lungs, localize in the lung infection microenvironment, and trigger the responsive release of rifampicin, thereby effectively alleviating lung inflammation and reducing damage. Notably, the targeted delivery of rifampicin helps protect against antibiotic-induced changes in the gut microbiota. This study establishes a new strategy for precise delivery to the lung-infected microenvironment, promoting treatment efficacy while minimizing the impact on gut microbiota. Statement of significanceIntravenous antibiotics play a critical role in clinical care, particularly for severe bacterial pneumonia. However, the inability of antibiotics to reach target tissues causes serious side effects, including liver and kidney damage and intestinal dysbiosis. Therefore, achieving precise delivery of antibiotics is of great significance. In this study, we developed a novel lung inflammatory tissue-targeted nanoparticle that could target lung tissue after intravenous administration and then target the inflammatory microenvironment to trigger dual-responsive antibiotics release to synergistically treat pneumonia while maintaining the balance of gut microbiota and reducing the adverse effects of antibiotics. This study provides new ideas for targeted drug delivery and reference for clinical treatment of pneumonia.

Tuberostemonine may alleviates proliferation of lung fibroblasts caused by pulmonary fibrosis.

Tuberostemonine has several biological activity, the aim of study examined the impact of tuberostemonine on the proliferation of TGF-β1 induced cell model, and its ability to alleviate pulmonary fibrosis stimulated by bleomycin in mice. In vitro, we assessed the effect of tuberostemonine (350, 550 and 750µM) on the proliferation of cells stimulated by TGF-β1 (10μg/L), as well as on parameters such as α-SMA vitality, human fibronectin, collagen, and hydroxyproline levels in cells. In vivo, we analyzed inflammation, hydroxyproline, collagen activity and metabolomics in the lungs of mice. Additionally, a comprehensive investigation into the TGF-β/smad signaling pathway was undertaken, targeting lung tissue as well as HFL cells. Within the confines of an in vitro setup, the tuberostemonine manifested a discerned IC50 of 1.9mM. Furthermore, a significant reduction of over fifty percent was ascertained in the secretion levels of hydroxyproline, fibronectin, collagen type I, collagen type III and α-SMA. In vivo, tuberostemonine obviously improved the respiratory function percentage over 50% of animal model and decreased the hydroxyproline, lung inflammation and collagen deposition. A prominent decline in TGF-β/smad pathway functioning was identified within both the internal and external cellular contexts. Tuberostemonine is considered as a modulator to alleviate fibrosis and may become a new renovation for pulmonary fibrosis.

Watershed analysis in wedge resection of pulmonary pure ground-glass nodules hardly localized by CT-guided puncture

BackgroundTo investigate the feasibility and safety of watershed analysis after target pulmonary vascular occlusion for the wedge resection in patients with non-palpable and non-localizable pure ground-glass nodules during uniport thoracoscopic surgery.MethodsA total of 30 patients with pure ground-glass nodules < 1 cm in diameter, localized in the lateral third of the lung parenchyma, were enrolled. Three-dimensional reconstruction of thin-section computed tomography (CT) data was performed using Mimics software before surgery to observe and identify the target pulmonary vessels supplying the lung tissue in the area where the pulmonary nodules were localized and to temporarily block the target pulmonary vessels during surgery. Next, the extent of the watershed was determined with the expansion-collapse method, and finally, wedge resection was performed. After wedge resection of the target lung tissue, the blocked pulmonary vessel was released, thus allowing operators to complete the procedure without damaging pulmonary vessels.ResultsNone of the patients experienced postoperative complications. The chest CT of all patients was reviewed six months after the operation, revealing no tumor recurrence.ConclusionsOur results suggest that watershed analysis following target pulmonary vascular occlusion for wedge resection in pulmonary pure ground-glass nodules is a safe and feasible approach.

Three Zone Scanning Protocol For Lung Ultrasound: An Anatomical Basis.

Lung ultrasound is rapidly gaining popularity based on point of care ease of use, diagnostic fidelity and lack of ionizing radiation. This was particularly notable at the beginning of the COVID-19 pandemic, where concerns of contamination of the x-ray department led to a reluctance to order frequent chest x-rays. Early COVID-19 lung involvement is of a bronchopneumonia, and patches of consolidation adjacent to the chest wall were easily detectable by ultrasound. A large number of proposed scanning protocols were advocated and are often complex and largely based on traditional stethoscope examination or access points on the chest wall rather than the underlying lung anatomy. A surgical understanding of lung anatomy and related surface anatomy has led us to develop a simplified three zone scanning protocol in 2013. The anterior zone corresponds to the upper lobe, and the posterior zone is divided between upper lobe and lower lobe. The relationship between lung lobes and the surface of the chest wall provides the anatomical basis for a simple three scanning zone lung ultrasound protocol.

Cyanidin-3-O-glucoside and Peonidin-3-O-glucoside-Rich Fraction of Black Rice Germ and Bran Suppresses Inflammatory Responses from SARS-CoV-2 Spike Glycoprotein S1-Induction In Vitro in A549 Lung Cells and THP-1 Macrophages via Inhibition of the NLRP3 Inflammasome Pathway.

Black rice is a functional food that is high in anthocyanin content, primarily C3G and P3G. It possesses nutraceutical properties that exhibit a range of beneficial effects on human health. Currently, the spike glycoprotein S1 subunit of SARS-CoV-2 (SP) has been reported for its contribution to pathological inflammatory responses in targeting lung tissue and innate immune cells during COVID-19 infection and in the long-COVID phenomenon. Our objectives focused on the health benefits of the C3G and P3G-rich fraction of black rice germ and bran (BR extract) on the inhibition of inflammatory responses induced by SP, as well as the inhibition of NF-kB activation and the NLRP3 inflammasome pathway in an in vitro model. In this study, BR extract was identified for its active anthocyanins, C3G and P3G, using the HPLC technique. A549-lung cells and differentiated THP-1 macrophages were treated with BR extract, C3G, or P3G prior to exposure to 100 ng/mL of SP. Their anti-inflammatory properties were then determined. BR extract at concentrations of 12.5–100 μg/mL exhibited anti-inflammation activity for both A549 and THP-1 cells through the significant suppression of NLRP3, IL-1β, and IL-18 inflammatory gene expressions and IL-6, IL-1β, and IL-18 cytokine secretions in a dose-dependent manner (p < 0.05). It was determined that both cell lines, C3G and P3G (at 1.25–10 μg/mL), were compatibly responsible for the significant inhibition of SP-induced inflammatory responses for both gene and protein levels (p < 0.05). With regard to the anti-inflammation mechanism, BR extract, C3G, and P3G could attenuate SP-induced inflammation via counteraction with NF-kB activation and downregulation of the inflammasome-dependent inflammatory pathway proteins (NLRP3, ASC, and capase-1). Overall, the protective effects of anthocyanins obtained from black rice germ and bran can be employed in potentially preventive strategies that use pigmented rice against the long-term sequelae of COVID-19 infection.

Non-invasive administration of AAV to target lung parenchymal cells and develop SARS-CoV-2-susceptible mice

Adeno-associated virus (AAV)-mediated gene delivery holds great promise for gene therapy. However, the non-invasive delivery of AAV for lung tissues has not been adequately established. Here, we revealed that the intratracheal administration of an appropriate amount of AAV2/8 predominantly targets lung tissue. AAV-mediated gene delivery that we used in this study induced the expression of the desired protein in lung parenchymal cells, including alveolar type II cells. We harnessed the technique to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-susceptible mice. Three kinds of immune function-relevant gene knockout (KO) mice were transduced with AAV encoding human angiotensin-converting enzyme 2 (hACE2) and then injected with SARS-CoV-2. Among these mice, type I interferon receptor (IFNAR) KO mice showed increased viral titer in the lungs compared to that in the other KO mice. Moreover, nucleocapsid protein of SARS-CoV-2 and multiple lesions in the trachea and lung were observed in AAV-hACE2-transduced, SARS-CoV-2-infected IFNAR KO mice, indicating the involvement of type I interferon signaling in the protection of SARS-CoV-2. In this study, we demonstrate the ease and rapidness of the intratracheal administration of AAV for targeting lung tissue in mice, and this can be used to study diverse pulmonary diseases.

The potential use of microRNAs as a therapeutic strategy for SARS-CoV-2 infection.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, there is no effective therapeutic approach for treating SARS-CoV-2 infections. MicroRNAs (miRNAs) have been recognized to target the viral genome directly or indirectly, thereby inhibiting viral replication. Several studies have demonstrated that host miRNAs target different sites in SARS-CoV-2 RNA and constrain the production of essential viral proteins. Furthermore, miRNAs have lower toxicity, are more immunogenic, and are more diverse than protein-based and even plasmid-DNA-based therapeutic agents. In this review, we emphasize the role of miRNAs in viral infection and their potential use as therapeutic agents against COVID-19 disease. The potential of novel miRNA delivery strategies, especially EDV™ nanocells, for targeting lung tissue for treatment of SARS-CoV-2 infection is also discussed.

Comprehensive Evaluation of Multimodality Imaging in SARS-CoV-2 Patients: A Review

Coronavirus disease 2019 (COVID-19) with its different symptoms has been widespread throughout the world for about two years and it has brought many deaths in different countries. Although the disease has been reported to target lung tissue as the first option but it can also cause damages in the heart and other tissues of the body. Many researches have been done on how to control and manage this pandemic to prevent further spread of this virus. There is always a percentage chance of error with RT-PCR test, when identifying the COVID-19, which was used as the first method of diagnosing the disease. In emergencies, low sensitivity of RT-PCR could lead to misdiagnosis of this virus. So, different imaging modalities can provide aid to detect the virus more precisely. So far, Radiology imaging especially Chest CT has played an important role in the process of recognizing the disease and in many cases, it has rushed to the aid of the healthcare staff for determining the stages and controlling of the disease. Although a number of countries have made good progress in the field of vaccines, it is very important for staff to know the advantages and disadvantages of each imaging modality in the disease assessment procedures, so that they can use them wisely to accelerate the elimination process of the disease. With this approach, this paper is an overview of various capabilities of different imaging modalities in the field of better management of SARS-CoV-2 disease.

Mesenchymal stem cells and exosome therapy for COVID-19: current status and future perspective.

Acute respiratory distress syndrome (ARDS) is the main cause for the COVID-19 infection-related morbidity and mortality. Recent clinical evidences suggest increased level of cytokines and chemokines targeting lung tissue as a prominent etiological factor. The immunomodulatory effect of mesenchymal stem cells (MSCs) as the alternative therapy for the treatment of inflammatory and autoimmune diseases is well known. Several studies have also revealed that similar therapeutic impacts of parent MSCs are also exhibited by MSCs-derived extracellular vesicles (EVs) including exosomes. In this review, we explored the therapeutic potential of both MSCs and exosomes in mitigating the COVID-19 induced cytokine storm as well as promoting the regeneration of alveolar tissue, attributed to the intrinsic cytokines and growth factor present in the secretome. The preliminary studies have demonstrated the safety and efficacy of MSCs and exosomes in mitigating symptoms associated with COVID-19. Thus, they can be used on compassionate basis, owing to their ability to endogenously repair and decrease the inflammatory reactions involved in the morbidity and mortality of COVID-19. However, more preclinical and clinical studies are warranted to understand their mechanism of action and further establish their safety and efficacy.

Oral Dosing of Dihydromethysticin Ahead of Tobacco Carcinogen NNK Effectively Prevents Lung Tumorigenesis in A/J Mice.

Our early studies demonstrated an impressive chemopreventive efficacy of dihydromethysticin (DHM), unique in kava, against tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice in which DHM was supplemented in the diet. The current work was carried out to validate the efficacy, optimize the dosing schedule, and further elucidate the mechanisms using oral bolus dosing of DHM. The results demonstrated a dose-dependent chemopreventive efficacy of DHM (orally administered 1 h before each of the two NNK intraperitoneal injections, 1 week apart) against NNK-induced lung adenoma formation. Temporally, DHM at 0.8 mg per dose (∼32 mg per kg body weight) exhibited 100% lung adenoma inhibition when given 3 and 8 h before each NNK injection and attained >93% inhibition when dosed at either 1 or 16 h before each NNK injection. The simultaneous treatment (0 h) or 40 h pretreatment (-40 h) decreased lung adenoma burden by 49.8% and 52.1%, respectively. However, post-NNK administration of DHM (1-8 h after each NNK injection) was ineffective against lung tumor formation. In short-term experiments for mechanistic exploration, DHM treatment reduced the formation of NNK-induced O6-methylguanine (O6-mG, a carcinogenic DNA adduct in A/J mice) in the target lung tissue and increased the urinary excretion of NNK detoxification metabolites as judged by the ratio of urinary NNAL-O-gluc to free NNAL, generally in synchrony with the tumor prevention efficacy outcomes in the dose scheduling time-course experiment. Overall, these results suggest DHM as a potential chemopreventive agent against lung tumorigenesis in smokers, with O6-mG and NNAL detoxification as possible surrogate biomarkers.

Engineering Caveolae-Targeted Lipid Nanoparticles To Deliver mRNA to the Lungs

Efficacious use of therapeutic gene delivery via nanoparticles is hampered by the challenges associated with targeted delivery to tissues of interest. Systemic administration of lipid nanoparticle (LNP)-encapsulated mRNA leads to a protein expressed predominantly in the liver and spleen. Here, LNP encapsulating mRNA was covalently conjugated to an antibody, specifically binding plasmalemma vesicle-associated protein (PV1) as a means to target lung tissue. Systemic administration of PV1-targeted LNPs demonstrated significantly increased delivery of mRNA to the lungs and a 40-fold improvement in protein expression in the lungs, compared with control LNPs. We also investigated the effect of LNP size to determine optimal tissue distribution and transfection. Larger-size PV1-targeted LNPs not only have the elasticity to target the PV1 expressed in the caveolae but also enable robust mRNA expression in the lungs. Targeted delivery of mRNA to the lungs is a promising approach in the treatment of lung diseases.

Predictive Modelling of Lung Function using Emphysematous Density Distribution

Target lung tissue selection remains a challenging task to perform for treating severe emphysema with lung volume reduction (LVR). In order to target the treatment candidate, the percentage of low attenuation volume (LAV%) representing the proportion of emphysema volume to whole lung volume is measured using computed tomography (CT) images. Although LAV% have shown to have a correlation with lung function in patients with chronic obstructive pulmonary disease (COPD), similar measurements of LAV% in whole lung or lobes may have large variations in lung function due to emphysema heterogeneity. The functional information of regional emphysema destruction is required for supporting the choice of optimal target. The purpose of this study is to develop an emphysema heterogeneity descriptor for the three-dimensional emphysematous bullae according to the size variations of emphysematous density (ED) and their spatial distribution. The second purpose is to derive a predictive model of airflow limitation based on the regional emphysema heterogeneity. Deriving the bullous representation and grouping them into four scales in the upper and lower lobes, a predictive model is computed using the linear model fitting to estimate the severity of lung function. A total of 99 subjects, 87 patients with mild to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I~IV) and 12 control participants with normal lung functions (forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) > 0.7) were evaluated. The final model was trained with stratified cross-validation on randomly selected 75% of the dataset (n = 76) and tested on the remaining dataset (n = 23). The dispersed cases of LAV% inconsistent with their lung function outcome were evaluated, and the correlation study suggests that comparing to LAV of larger bullae, the widely spread smaller bullae with equivalent LAV has a larger impact on lung function. The testing dataset has the correlation of r = −0.76 (p < 0.01) between the whole lung LAV% and FEV1/FVC, whereas using two ED % of scales and location-dependent variables to predict the emphysema-associated FEV1/FVC, the results shows their correlation of 0.82 (p < 0.001) with clinical FEV1/FVC.

Novel Lung Biopsy Surgical Technique for Definitive Diagnosis of Pulmonary Capillary Hemangiomatosis

The 2015 European Society of Cardiology/European Respiratory Society Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension state that lung biopsy is still the gold standard for confirming pulmonary capillary hemangiomatosis; however, the surgical lung biopsy is no longer recommended in most cases for its inherent risks. Nonintubated and uniportal video-assisted thoracoscopic surgery are the new developments in video-assisted thoracoscopic surgery technology. We combined these 2 technologies to create a novel approach for pulmonary capillary hemangiomatosis lung biopsy. A incision is made in chest wall. Sponge forceps are used to pull the lung out of the pleural space, and to resect target lung tissue. The incised margin is sutured with 3-0 Prolene (Ethicon, Somerville, NJ), and a negative pressure suction tube is used to fully expand the lung. Three patients were definitively diagnosed with pulmonary capillary hemangiomatosis by this technology. One patient developed a postoperative fever, with no other complications. The tubeless and uniportal video-assisted thoracoscopic surgery lung biopsy is a safe, effective, and feasible technology for definitively diagnosing patients with pulmonary capillary hemangiomatosis.

A Smart Metal–Organic Framework Nanomaterial for Lung Targeting

AbstractDespite high morbidity and mortality associated with lung diseases, addressing drugs towards lung tissue remains a pending task. Particle lung filtration has been proposed for passive lung targeting and drug delivery. However, toxicity issues derived from the long‐term presence of the particles must be overcome. By exploiting some of the ignored properties of nanosized metal–organic frameworks it is possible to achieve impressive antitumoral effects on experimental lung tumors, even without the need to engineer the surface of the material. In fact, it was discovered that, based on unique pH‐responsiveness and reversible aggregation behaviors, nanoMOF was capable of targeting lung tissue. At the neutral pH of the blood, the nanoMOFs form aggregates with the adequate size to be retained in lung capillaries. Within 24 h they then disaggregate and release their drug payload. This phenomenon was compatible with lung tissue physiology.

A Smart Metal-Organic Framework Nanomaterial for Lung Targeting.

Despite high morbidity and mortality associated with lung diseases, addressing drugs towards lung tissue remains a pending task. Particle lung filtration has been proposed for passive lung targeting and drug delivery. However, toxicity issues derived from the long-term presence of the particles must be overcome. By exploiting some of the ignored properties of nanosized metal-organic frameworks it is possible to achieve impressive antitumoral effects on experimental lung tumors, even without the need to engineer the surface of the material. In fact, it was discovered that, based on unique pH-responsiveness and reversible aggregation behaviors, nanoMOF was capable of targeting lung tissue. At the neutral pH of the blood, the nanoMOFs form aggregates with the adequate size to be retained in lung capillaries. Within 24 h they then disaggregate and release their drug payload. This phenomenon was compatible with lung tissue physiology.

Pharma embraces imaging mass spec

Genentech was testing a drug candidate targeting lung tissue, and the data didn’t add up. Data from cell-based assays suggested that the drug was potent, and analyses of ground-up tissue suggested that plenty of drug was reaching the lung. But the agent wasn’t consistently producing the expected effect in animals. So the project team asked Sheerin K. Shahidi-Latham, head of imaging mass spectrometry at Genentech, for help. Her team used matrix-assisted laser desorption ionization (MALDI) MS to acquire images of the compound’s distribution in lung tissue and find out where the drug was going. They took images at different time points with different drug formulations and different routes of administration. They even tried different drugs to make sure the problem wasn’t compound-specific. “We found that the route of administration and the formulation influenced the distribution of the drug in the lung and whether it reached the target tissue,” Shahidi-Latham says.

Dihydromethysticin (DHM) Blocks Tobacco Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-Induced O6-Methylguanine in a Manner Independent of the Aryl Hydrocarbon Receptor (AhR) Pathway in C57BL/6 Female Mice.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a key carcinogen responsible for tobacco smoke-induced lung carcinogenesis. Among the types of DNA damage caused by NNK and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), O6-methylguanine (O6-mG) is likely the most carcinogen in A/J mice. Results of our previous studies showed that levels of O6-mG and other types of NNAL-derived DNA damage were preferentially reduced in the lung of female A/J mice upon dietary treatment with dihydromethysticin (DHM), a promising lung cancer chemopreventive agent from kava. Such a differential blockage may be mediated via an increased level of NNAL glucuronidation, thereby leading to its detoxification. The potential of the aryl hydrocarbon receptor (AhR) as an upstream target of DHM mediating these events was evaluated herein using Ahr+/- and Ahr-/- C57BL/6 female mice because DHM was reported as an AhR agonist. DHM (0.05, 0.2, and 1.0 mg/g of diet) and dihydrokavain (DHK, an inactive analogue, 1.0 mg/g of diet) were given to mice for 7 days, followed by a single intraperitoneal dose of NNK at 100 mg/kg of body weight. The effects of DHM on the amount of O6-mG in the lung, on the urinary ratio of glucuronidated NNAL (NNAL-Gluc) and free NNAL, and on CYP1A1/2 activity in the liver microsomes were analyzed. As observed in A/J mice, DHM treatment significantly and dose-dependently reduced the level of O6-mG in the target lung tissue, but there were no significant differences in O6-mG reduction between mice from Ahr+/- and Ahr-/- backgrounds. Similarly, in both strains, DHM at 1 mg/g of diet significantly increased the urinary ratio of NNAL-Gluc to free NNAL and CYP1A1/2 enzymatic activity in liver with no changes detected at lower DHM dosages. Because none of these effects of DHM were dependent on Ahr status, AhR clearly is not the upstream target for DHM.

A novel tetrandrine-loaded chitosan microsphere: characterization and in vivo evaluation.

In this study, novel tetrandrine-loaded chitosan microspheres were prepared by the emulsion cross-linking method. The systems were then characterized for physicochemical properties and in vitro drug release. In addition, the pharmacokinetics and tissue distribution of microspheres were further verified in animal models. Particle-size distribution indicated that the size of microspheres was within the range of 7–15 μm, with a median diameter of 12.4 μm. The drug loading and entrapment efficiency of the formulation were 34.6%±12.5% and 87.3%±9.7% (mean ± SD), respectively. In vitro release showed a typical sustained and long-term drug release behavior. The Higuchi equation was the model that fit best with release data. Maintaining a relatively constant plasma concentration in the long-term drug treatment is an outstanding pharmacokinetic advantage of tetrandrine microspheres in vivo. Moreover, compared with tetrandrine solution, tetrandrine microspheres produced a lower drug concentration in the heart, liver, and kidneys. This indicated that the microspheres used in this study were preferable for targeting lung tissue versus other tissues. No damage to the tissues of the lung was found in histopathological examination.

A combinatorial microRNA therapeutics approach to suppressing non-small cell lung cancer

Targeted cancer therapies, while often effective, have limited utility due to preexisting primary or acquired secondary resistance. Consequently, agents are sometimes used in combination to simultaneously affect multiple targets. MicroRNA mimics are excellent therapeutic candidates because of their ability to repress multiple oncogenic pathways at once. Here we treated the aggressive Kras;p53 non-small cell lung cancer mouse model and demonstrated efficacy with a combination of two tumor-suppressive microRNAs. Systemic nano-delivery of miR-34 and let-7 suppressed tumor growth leading to a survival advantage. This combinatorial microRNA therapeutic approach engages numerous components of tumor-cell addictive pathways and highlights the ability to deliver multiple microRNAs in a safe and effective manner to target lung tissue.

Pulmonary delivery and tissue distribution of aerosolized antisense 2′-O-Methyl RNA containing nanoplexes in the isolated perfused and ventilated rat lung

Pulmonary delivery of drugs, particularly in the treatment of lung cancer, is an attractive strategy for future targeted therapy. In this context, inhalation of nanoplexes might offer a new mode for drug delivery in gene therapy. However, limited data are currently available demonstrating pulmonary delivery, cellular uptake as well as local tolerability in lung tissue.The aim of this study was to elucidate the pulmonary delivery, tissue distribution and local tolerability of aerosolized chitosan-coated poly(lactide-co-glycolide) based nanoplexes containing antisense 2′-O-Methyl RNA (OMR). Therefore, an aerosol of OMR-nanoplexes or OMR alone was administered intra-tracheally using the model of the isolated perfused and ventilated rat lung. Localization of OMR in rat lung tissue was examined by immunohistochemistry. Administration of the OMR-nanoplex formulation resulted in significantly higher cellular OMR uptake of the respiratory epithelium in contrast to the administration of OMR alone, indicating that drug administration via aerosolized nanoplexes is able to target lung tissue. No prominent changes in lung physiology parameters were observed following inhalation, suggesting good local tolerability of OMR-nanoplex formulation.