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Polymyxins are the last line of defense against multidrug-resistant (MDR) Gram-negative bacterial infections. However, this last resort has been threatened by the emergence of superbugs carrying the mobile colistin resistance gene-1 (mcr-1). Given the high concentration of matrix metalloproteinase 3 (MMP-3) in bacterial pneumonia, limited plasma accumulation of colistin (CST) in the lung, and potential toxicity of ionic silver (Ag+), we designed a feasible clinical transformation platform, an MMP-3 high-performance lung-targeted bio-responsive delivery system, which we named “CST&Ag@CNMS”. This system exhibited excellent lung-targeting ability (>80% in lungs), MMP-3 bio-responsive release property (95% release on demand), and synergistic bactericidal activity in vitro (2–4-fold minimum inhibitory concentration reduction). In the mcr-1+ CST-resistant murine pneumonia model, treatment with CST&Ag@CNMS improved survival rates (70% vs. 20%), reduced bacteria burden (2–3 log colony-forming unit [CFU]/g tissue), and considerably mitigated inflammatory response. In this study, CST&Ag@CNMS performed better than the combination of free CST and AgNO3. We also demonstrated the superior biosafety and biodegradability of CST&Ag@CNMS both in vitro and in vivo. These findings indicate the clinical translational potential of CST&Ag@CNMS for the treatment of lung infections caused by CST-resistant bacteria carrying mcr-1.

Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer, although it is limited by the low tumor delivery efficacy of anticancer drugs. Bacterial therapy is emerging for cancer treatment due to its high immune stimulation effect; however, excessively generated immunogenicity will cause serious inflammatory response syndrome. Here, we prepared cancer cell membrane-coated liposomal paclitaxel-loaded bacterial ghosts (LP@BG@CCM) by layer-by-layer encapsulation for the treatment of metastatic lung cancer. The preparation processes were simple, only involving film formation, electroporation, and pore extrusion. LP@BG@CCM owned much higher 4T1 cancer cell toxicity than LP@BG due to its faster fusion with cancer cells. In the 4T1 breast cancer metastatic lung cancer mouse models, the remarkably higher lung targeting of intravenously injected LP@BG@CCM was observed with the almost normalized lung appearance, the reduced lung weight, the clear lung tissue structure, and the enhanced cancer cell apoptosis compared to its precursors. Moreover, several major immune factors were improved after administration of LP@BG@CCM, including the CD4+/CD8a+ T cells in the spleen and the TNF-α, IFN-γ, and IL-4 in the lung. LP@BG@CCM exhibits the optimal synergistic chemo-immunotherapy, which is a promising medication for the treatment of metastatic lung cancer.

Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer, although it is limited by the low tumor delivery efficacy of anticancer drugs. Bacterial therapy is emerging for cancer treatment due to its high immune stimulation effect; however, excessively generated immunogenicity will cause serious inflammatory response syndrome. Here, we prepared cancer cell membrane-coated liposomal paclitaxel-loaded bacterial ghosts (LP@BG@CCM) by layer-by-layer encapsulation for the treatment of metastatic lung cancer. The preparation processes were simple, only involving film formation, electroporation, and pore extrusion. LP@BG@CCM owned much higher 4T1 cancer cell toxicity than LP@BG due to its faster fusion with cancer cells. In the 4T1 breast cancer metastatic lung cancer mouse models, the remarkably higher lung targeting of intravenously injected LP@BG@CCM was observed with the almost normalized lung appearance, the reduced lung weight, the clear lung tissue structure, and the enhanced cancer cell apoptosis compared to its precursors. Moreover, several major immune factors were improved after administration of LP@BG@CCM, including the CD4+/CD8a+ T cells in the spleen and the TNF- α , IFN- γ , and IL-4 in the lung. LP@BG@CCM exhibits the optimal synergistic chemo-immunotherapy, which is a promising medication for the treatment of metastatic lung cancer. Cancer cell membrane-coated liposomal-paclitaxel-loaded bacterial ghosts (LP@BG@CCM) were prepared for the treatment of metastatic lung cancer by immune stimulation and lung targeting. [Display omitted] [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is a global leading cause of cancer mortality. Herein, remdesivir (RDV) was loaded into biocompatible liposomes (RDV-Lips) composed of 1,2-dipalmitoyl-sn‑glycero-3-phosphocholine (DPPC), cholesterol, and polyethylene glycol hexadecyl ether (Brij-58) to enhance its solubility and anticancer efficiency. The study highlighted the possible RDV-induced underlying events, emphasizing its inhibitory potential of telomerase activity through in-silico docking and in vitro studies. RDV-Lips were developed using thin-film hydration and then subjected to physicochemical characterizations. The selected formulations were evaluated for their stability, in vitro release, and in vitro anticancer activity. The size range of RDV-Lips was 83.8–157.9 nm with a polydispersity index (PDI) lower than 0.23 and entrapment exceeded 93%. The cholesterol content of RDV-Lips offered a control point of RDV release, where high and low concentrations exerted slow and fast release patterns, respectively. RDV-Lips showed enhanced anticancer activity and selectivity. They inhibited colony formation, increased lipid peroxidation, induced apoptosis, and inhibited the telomerase activity in a dose-dependent manner. In conclusion, RDV-Lips overcame RDV solubility problems and enhanced its anticancer efficiency. RDV could be a potential therapy against NSCLC via induction of oxidative stress and inhibition of the telomerase activity, which, in turn, restricts unlimited cellular proliferation and apoptosis induction.

Lung metastatic breast cancer is a leading cause of cancer-related death in women and difficult to treat due to non-specific drug delivery. Herein a sequential targeting dual-responsive magnetic nanoparticle was fabricated, where Fe3O4 nanoparticle was used as magnetic core, then sequentially coated with tetraethyl orthosilicate, bis[3-(triethoxy-silyl)propyl] tetrasulfide, and 3-(trimethoxysilyl) propylmethacrylate to afford -C = C- on the surface for further polymerisation with acrylic acid, acryloyl-6-ethylenediamine-6-deoxy-β-cyclodextrin using N, N-bisacryloylcy- stamine as cross-linker, obtaining pH/redox dual-responsive magnetic nanoparticle (MNPs-CD) to delivery doxorubicin (DOX) for suppressing lung metastatic breast cancer. Our results suggested DOX-loaded nanoparticle could target the lung metastases site by sequential targeting, in which they first be delivered to the lung and even the metastatic nodules through size-driven, electrical interaction, and magnetic field-guided mechanisms, then be effectively internalised into the cancer cells followed by intelligently triggering DOX release. MTT analysis demonstrated DOX-loaded nanoparticle exhibited high anti-tumour activity against 4T1 and A549 cells. 4T1 tumour-bearing mice were employed to confirm the higher specific accumulation in lung and improved anti-metastatic therapy efficiency of DOX by focussing an extracorporeal magnetic field on the biological target. Our findings suggested the as-proposed dual-responsive magnetic nanoparticle offered a prerequisite to inhibit lung metastasis of breast cancer tumours. [ABSTRACT FROM AUTHOR]

[Display omitted] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal lung disease caused by multiple factors. Currently, safe, and effective drugs for the treatment of IPF have been extremely scarce. Baicalin (BA) is used to treat pulmonary fibrosis, IPF, chronic obstructive pulmonary disease, and other lung diseases. Ambroxol hydrochloride (AH), a respiratory tract lubricant and expectorant, is often used to treat chronic respiratory diseases, such as bronchial asthma, emphysema, tuberculosis, and cough. The combination of BA and AH can relieve cough and phlegm, improve lung function, and potentially treat IPF and its symptoms. However, given the extremely low solubility of BA, its bioavailability for oral absorptions is also low. AH, on the other hand, has been associated with certain side effects, such as gastrointestinal tract and acute allergic reactions, which limit its applicability. Therefore, an efficient drug delivery system is urgently needed to address the mentioned problems. This study combined BA and AH as model drugs with L-leucine (L-leu) as the excipient to prepare BA/AH dry powder inhalations (BA/AH DPIs) using the co-spray drying method. We the performed modern pharmaceutical evaluation, which includes particle size, differential scanning calorimetry analysis, X-ray diffraction, scanning electron microscope, hygroscopicity, in vitro aerodynamic analysis, pharmacokinetics, and pharmacodynamics. Notably, BA/AH DPIs were found to be advantageous over BA and AH in treating IPF and had better efficacy in improving lung function than did the positive drug pirfenidone. The BA/AH DPI is a promising preparation for the treatment of IPF given its lung targeting, rapid efficacy, and high lung bioavailability. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Effectively controlling cytokine storm is important to reduce the mortality of severe pneumonia. In this work a bio-functional dead cell was engineered by one-time quick shock of live immune cells in liquid nitrogen, and the obtained immunosuppressive dead cell could server as both lung-targeting vehicle and cytokine absorption material. After loading the anti-inflammatory drugs of dexamethasone (DEX) and baicalin (BAI), the drug-loaded dead cell (DEX&BAI/Dead cell) could first passively target to the lung after intravenous administration and quickly release the drugs under high shearing stress of pulmonary capillaries, realizing drug enrichment in the lung. Then, the immunosuppressive dead cell acted as the camouflage of normal immune cells with various cytokine receptors exposing on their surface, to “capture” the cytokines and further reduce the state of inflammation. With above formulation design, a synergic anti-inflammatory effect between drugs and carrier could be achieved. In a lipopolysaccharide-induced pneumonia mice model, this system could calm down the cytokine storm with high efficacy and elongate the survival of mice.

Aims: The present investigation aimed at the comparative evaluation of the developed nanocarriers, viz. spherulites and cubosomes for lung targeting., Materials and Methods: Both the spherulites and cubosomes were characterized for their entrapment efficiency, drug loading, size and zeta potential, in-vitro drug release profile, surface morphology, hemocompatibility, and in-vivo pharmacokinetic and lung biodistribution., Results and Conclusions: The optimized batches of spherulites and cubosomes possessed high entrapment efficiency and drug loading with size around 200 nm, which is suitable for lung targeting. The zeta potential value for both the nanoformulations was found to be between -20 and -30 mv indicating the physical stability against aggregation. The SEM and TEM analysis revealed the presence of spherical and discrete particles in both the types of nanocarriers. Water channels were observed in case of cubosomes. Spherulites and cubosomes showed pH-dependent drug release with lower release at physiological pH while higher release at the pH of the tumor microenvironment. Both spherulites and cubosomes exhibited highly significant increase in the half-life and mean residence time in the plasma. The prepared nanoformulations were hemocompatible and had higher lung targeting potential compared to the plain drug solution.

Extracellular vehicles (EVs) are naturally occurring nanocarriers that participate in the transportation of biologics between cells. Despite their potential in drug delivery, their optimal use in therapy remains a challenge, which comes from the difficulty in preparation scale-up and cargo loading efficiency. As a membrane-enclosed nanoscale system, EVs are reluctant to be transfected with cargos and purified by conventional methods. In the present study, we proposed an EV-mimetic nanovesicle system to overcome the challenges. Using the easy-culture mammalian cells as raw materials, we isolated the plasma membrane sheets and vesiculated them into membrane-enclosed nanovesicles as an EV mimic by the mechanical extrusion through porous membranes. In order to controllably load the cargos in the lumen of vesicles, the endogenous actin filament was chosen as an anchor to capture the cargos (fused with an anti-actin nanobody) in the inner leaflet of plasma membrane sheets and vesiculated inside after extrusion. By loading the bioluminescent tracer nano-luciferase (Nluc) and tracking biodistribution in mice, we unclosed the lung-tropic nature of these nanovesicles. Furthermore, we demonstrated that nanovesicles can be genetically engineered with chimeric antigen receptors to achieve the active targeting of lung cancer cells. In conclusion, our study indicated that plasma membrane extrusion might be an applicable approach to generate EV mimics for drug delivery, especially to the lung tissue.

Humanity has suffered from the coronavirus disease 2019 (COVID-19) pandemic over the past two years, which has left behind millions of deaths. Azithromycin (AZ), an antibiotic used for the treatment of several bacterial infections, has shown antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as against the dengue, Zika, Ebola, and influenza viruses. Additionally, AZ has shown beneficial effects in non-infective diseases such as cystic fibrosis and bronchiectasis. However, the systemic use of AZ in several diseases showed low efficacy and potential cardiac toxicity. The application of nanotechnology to formulate a lung delivery system of AZ could prove to be one of the solutions to overcome these drawbacks. Therefore, we aimed to evaluate the attenuation of acute lung injury in mice via the local delivery of an AZ nanoformulation. The hot emulsification–ultrasonication method was used to prepare nanostructured lipid carrier of AZ (AZ-NLC) pulmonary delivery systems. The developed formulation was evaluated and characterized in vitro and in vivo. The efficacy of the prepared formulation was tested in the bleomycin (BLM) -mice model for acute lung injury. AZ-NLC was given by the intratracheal (IT) route for 6 days at a dose of about one-eighth oral dose of AZ suspension. Samples of lung tissues were taken at the end of the experiment for immunological and histological assessments. AZ-NLC showed an average particle size of 453 nm, polydispersity index of 0.228 ± 0.07, zeta potential of −30 ± 0.21 mV, and a sustained release pattern after the initial 50% drug release within the first 2 h. BLM successfully induced a marked increase in pro-inflammatory markers and also induced histological changes in pulmonary tissues. All these alterations were significantly reversed by the concomitant administration of AZ-NLC (IT). Pulmonary delivery of AZ-NLC offered delivery of the drug locally to lung tissues. Its attenuation of lung tissue inflammation and histological injury induced by bleomycin was likely through the downregulation of the p53 gene and the modulation of Bcl-2 expression. This novel strategy could eventually improve the effectiveness and diminish the adverse drug reactions of AZ. Lung delivery could be a promising treatment for acute lung injury regardless of its cause. However, further work is needed to explore the stability of the formulation, its pharmacokinetics, and its safety. [ABSTRACT FROM AUTHOR]

Recombinant human endostatin (rhES) is a protein drug with poor stability and short in vivo circulation time. The present study was therefore aimed at developing sustained-release lung targeted microspheres drug delivery system and evaluating its targeting efficiency using in vivo imaging techniques with quantum dots (QDs) as the imaging material. The oil-soluble QDs were coated with amphiphilic polymers to obtain a polymer-quantum dots micelle (QDs-M) with the potential to stably disperse in water. The rhES and QDs-M were combined using covalent bonds. The rhES-QDs-M microspheres (rhES-QDs-M-MS) were prepared using electrostatic spray technology and also evaluated via in vivo imaging techniques. The pharmacodynamics was further studied in mice. The rhES-QDs-M-MS (4–8 μm) were stable in an aqueous medium with good optical properties. The in vitro studies showed that the rhES-QDs-M-MS had sustained release which was maintained for at least 15 days (cumulative release >80%) without any burst release. The rhES-QDs-M-MS had a very high safety profile and also effectively inhibited the in vitro proliferation of human umbilical vein endothelial cells by about 70%. The pharmacokinetic results showed that the rhES could still be detected at 72 h in the experimental group which meant that the rhES-QDs-M-MS had a significant sustained-release effect. The rhES-QDs-M-MS had a better lung targeting effect and higher antitumor activity compared with the rhES. The traceable rhES-QDs-M-MS served as a promising drug delivery system for the poorly stable rhES proteins and significantly increased its lung-targeted effect, sustained-release properties, and antitumor activities. [ABSTRACT FROM AUTHOR]

3DNA holds promise as a carrier for drugs that can be intercalated into its core or linked to surface arms. Coupling 3DNA to an antibody targeting intercellular adhesion molecule 1 (ICAM-1) results in high lung-specific biodistributions in vivo. While the role of individual parameters on ICAM-1 targeting has been studied for other nanocarriers, it has never been examined for 3DNA or in a manner capable of revealing the hierarchic interplay among said parameters. In this study, we used 2-layer vs. 4-layer anti-ICAM 3DNA and radiotracing to examine biodistribution in mice. We found that, below saturating conditions and within the ranges tested, the density of targeting antibodies on 3DNA is the most relevant parameter driving lung targeting over liver clearance, compared to the number of antibodies per carrier, total antibody dose, 3DNA dose, 3DNA size, or the administered concentration, which influenced the dose in organs but not the lung specific-over-liver clearance ratio. Data predicts that lung-specific delivery of intercalating (core loaded) drugs can be tuned using this biodistribution pattern, while that of arm-linked (surface loaded) drugs requires a careful parametric balance because increasing anti-ICAM density reduces the number of 3DNA arms available for drug loading. [ABSTRACT FROM AUTHOR]

Oxidative stress plays a key role in the progress of acute lung injury (ALI), which is an acute, progressive respiratory failure characterized by alveolar capillary injury caused by various external and internal factors other than cardiogenic factors. Pulmonary vascular endothelial cells are the main target cells during ALI, and therefore the mitochondrial targeting antioxidant derivative triphenylphosphine-melatonin (TPP-MLT) was encapsulated in VCAM-1 antibodies-conjugated nanostructured lipid carriers (VCAM@TPP-MLT NLCs) for lung targeting delivery. VCAM@TPP-MLT NLCs could be preferentially internalized by inflammatory endothelial cells in lung tissues, and then the released TPP-MLT from NLCs effectively eliminated the excessive reactive oxide species (ROS) and ameliorated cell apoptosis. Overall, the results suggested that VCAM@TPP-MLT NLCs exhibited remarkable in vitro and in vivo therapeutic effect on ALI, and could be a promising and efficient strategy for the treatment of ALI.

The objective of the current study was to develop poly (lactic-co-glycolic acid) (PLGA) microspheres loaded with the anti-tuberculosis (anti-TB) fluoroquinolone, Levofloxacin (LVX), in the form of dry powder inhalation (DPI). LVX-loaded microspheres were fabricated by solvent evaporation technique. Central Composite Design (CCD) was adopted to optimize the microspheres, with desired particle size, drug loading, and drug entrapment efficiency, for targeting alveolar macrophages via non-invasive pulmonary delivery. Structural characterization studies by differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction analysis revealed the absence of any possible chemical interaction between the drug and the polymer used for the preparation of microspheres. In addition, the optimized drug-loaded microspheres exhibited desired average aerodynamic diameter of 2.13 ± 1.24 μm and fine particle fraction of 75.35 ± 1.42%, indicating good aerosolization properties. In vivo data demonstrated that LVX-loaded microspheres had superior lung accumulation, as evident by a two-fold increase in the area under the curve AUC0–24h, as compared with plain LVX. Furthermore, LVX-loaded microspheres prolonged drug residence time in the lung and maintained a relatively high drug concentration for a longer time, which contributed to a reduced leakage in the systemic circulation. In conclusion, inhalable LVX-loaded microspheres might represent a plausible delivery vehicle for targeting pulmonary tuberculosis via enhancing the therapeutic efficacy of LVX while minimizing its systemic off-target side effects. [ABSTRACT FROM AUTHOR]

This study evaluated the D-mannose modified polyethyleneimine-block-polycaprolactone biomacromolecule copolymer micelles (PCL-PEI-mannose) as a targeted delivery of the glucocorticoid dexamethasone (DXM) to lung inflammation tissues and enhances the vehicle for its anti-inflammatory effects. Dexamethasone was encapsulated in the hydrophobic core of cationic polymer micelles by solvent evaporation. The polymeric micelles exhibited sustained-release within 48 h, good blood compatibility, and colloidal stability in vitro. The cellular uptake of mannose-modified micelles was higher compared with the non-modified micelles. And drug-loaded targeted micelles could inhibit the production of inflammatory factors in activated RAW264.7 cells. The distribution results indicated that drug-loaded targeted micelles highly improved the lung targeting ability, reduced the wet/dry ratio of injured lung tissue, and relieved the lung inflammation, accompanied by the decrease of inflammatory cell infiltration, myeloperoxidase activity, and inflammatory mediator levels in bronchoalveolar lavage fluid. These findings suggested that PCL-PEI-mannose delivery system could facilitate the lung-specific delivery and inhibit the inflammatory response. Collectively, PCL-PEI-mannose polymer micelles could be used as a potential delivery system for the treatment of acute lung injury (ALI). [ABSTRACT FROM AUTHOR]

Several studies have stated that mucus is a critical hurdle for drug delivery to the mucosal tissues. As a result, Polymeric nanoparticles that can overcome mucus barriers are gaining popularity for controlled drug delivery into intra-macrophages to attain high intracellular drug concentration. The present study was aimed to fabricate inhalable N-acetylcysteine (NAC) modified PLGA mucus penetrating particles using the double emulsion method (w/o/w) for target delivery to alveolar macrophages and minimize the dose-related adverse effects, efficiently encapsulate hydrophilic drug, sustain the release profile and prolong the retention time for the management of tuberculosis. Among the numerous formulations, the drug/polymer ratio of 1:10 with 0.50% PVA concentration and sonication time for 2 ​min ​s was chosen for further research. The formulated nanoparticles had a mean particle size of 307.50 ​± ​9.54 ​nm, PDI was 0.136 ​± ​0.02, zeta potential about −11.3 ​± ​0.4 ​mV, decent entrapment efficiency (55.46 ​± ​2.40%), drug loading (9.05 ​± ​0.22%), and excellent flowability. FTIR confirmed that NAC and PLGA were compatible with each other. SEM graphs elucidated that the nanoparticles were spherically shaped with a slightly rough surface whereas TEM analysis ensured the nanometer size nanoparticles and coating of lipid over NPs surface. PXRD spectrum concluded the transformation of the drug from crystalline to amorphous state in the formulation. In vitro release pattern was biphasic started with burst release (64.67 ​± ​1.53% within 12hrs) followed by sustained release over 48hrs thus enabling the prolonged replenishing of NAC. In vitro lung deposition study pronounced that coated NAC-PLGA-MPPs showed favorable results in terms of emitted dose (86.67 ​± ​2.52%), MMAD value (2.57 ​± ​0.12 ​μm), GSD value (1.55 ​± ​0.11 ​μm), and FPF of 62.67 ​± ​2.08% for the deposition and targeting the lungs. Finally, in vitro efficacy studies demonstrated that NAC-PLGA-MPPs presented more prominent antibacterial activity against MTB H37Rv strain as compared to NAC. Hence, PLGA based particles could be a better strategy to deliver the NAC for lung targeting.

The entire world has recently been witnessing an unprecedented upsurge in microbial lung infections. The major challenge encountered in treating the same is to ensure the optimum drug availability at the infected site. Aerosolization of antimicrobials, in this regard, has shown immense potential owing to their localized and targeted effect. Efforts, therefore, have been undertaken to systematically develop lung-phosphatidylcholine-based lipid nanovesicles of voriconazole for potential management of the superinfections like aspergillosis. LNVs, prepared by thin-film hydration method, exhibited a globule size of 145.4 ± 19.5 nm, polydispersity index of 0.154 ± 0.104 and entrapment efficiency of 71.4 ± 2.2% with improved in vitro antifungal activity. Aerodynamic studies revealed a microdroplet size of ≤5 μm, thereby unraveling its promise to target the physical barrier of lungs effectively. The surface-active potential of LNVs, demonstrated through Langmuir-Blodgett troughs, indicated their ability to overcome the biochemical pulmonary surfactant monolayer barrier, while the safety and uptake studies on airway-epithelial cells signified their immense potential to permeate the cellular barrier of lungs. The pharmacokinetic studies showed marked improvement in the retention profile of voriconazole in lungs following LNVs nebulization compared to pristine voriconazole. Overall, LNVs proved to be safe and effective delivery systems, delineating their distinct potential to efficiently target the respiratory fungal infections. [ABSTRACT FROM AUTHOR]

Schematic representation of functional pattern of Magnolol-NLC against Chronic obstructive pulmonary disease. (Created with BioRender, agreement number: AI272U59N1). [Display omitted] Chronic obstructive pulmonary disease (COPD) is a prevalent lung condition characterized by airflow obstruction, disability, and high mortality rates. Magnolol (MA), known for its anti-inflammatory and antioxidant properties, holds the potential for alleviating COPD symptoms. However, MA faces challenges like poor aqueous solubility and low bioavailability. Herein MA-loaded nanostructured lipid carriers (MA-NLC) were prepared using emulsification and solvent evaporation. These carriers exhibited a particle size of (19.67 ± 0.36) nm, a polydispersity index of (0.21 ± 0.01), and a zeta potential of (−5.18 ± 0.69) mV. The fine particle fraction of MA-NLC was (68.90 ± 0.07)%, indicating minimal lung irritation and enhanced safety. Pulmonary delivery of MA-NLC via nebulizer actively targeted the diseased lung tissues, facilitated slow release, and overcame the challenges of low oral absorption and bioavailability associated with MA. This formulation prolonged the residence time of MA and optimized its therapeutic effect in pulmonary tissues. Upon pulmonary administration, MA-NLC effectively regulated inflammatory and oxidative stress markers in COPD models, demonstrating its potential as a promising therapeutic platform for COPD management. [ABSTRACT FROM AUTHOR]

Hongfei Liu,1 Jie Zhu,1 Pengyue Bao,2 Yueping Ding,3 Yan Shen,4 Thomas J Webster,5 Ying Xu11College of Pharmacy, Jiangsu University, Zhenjiang 212013, People’s Republic of China; 2Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing 210023, People’s Republic of China; 3Jiangsu Sihuan Biopharmaceutical Co., Ltd, Wuxi 214000, People’s Republic of China; 4State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People’s Republic of China; 5Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USABackground: Like most protein macromolecular drugs, the half-life of rhIFNɑ-2b is short, with a low drug utilization rate, and the preparation and release conditions significantly affect its stability.Methods: A nanoporous ion-responsive targeted drug delivery system (PIRTDDS) was designed to improve drug availability of rhIFNα-2b and target it to the lung passively with sustained release. Chitosan rhIFNα-2b carboxymethyl nanoporous microspheres (CS-rhIFNα-2b-CCPM) were prepared by the column method. Here, an electrostatic self-assembly technique was undertaken to improve and sustain rhIFNα-2b release rate.Results: The size distribution of the microspheres was 5∼15 μm, and the microspheres contained nanopores 300∼400 nm in diameter. The in vitro release results showed that rhIFNα-2b and CCPM were mainly bound by ionic bonds. After self-assembling, the release mechanism was transformed into being membrane diffusion. The accumulative release amount for 24 hrs was 83.89%. Results from circular dichrogram and SDS-PAGE electrophoresis showed that there was no significant change in the secondary structure and purity of rhIFNα-2b. Results from inhibition rate experiments for A549 cell proliferation showed that the antitumor activity of CS-rhIFNα-2b-CCPM for 24 hrs retained 91.98% of the stock solution, which proved that the drug-loaded nanoporous microspheres maintained good drug activity. In vivo pharmacokinetic experimental results showed that the drugs in CS-rhIFNα-2b-CCPM can still be detected in vivo after 24 hrs, equivalent to the stock solution at 6 hrs, which indicated that CS-rhIFNα-2b-CCPM had a certain sustained-release effect in vivo. The results of in vivo tissue distribution showed that CS-rhIFNα-2b-CCPM was mainly concentrated in the lungs of mice (1.85 times the stock solution). The pharmacodynamics results showed that CS-rhIFNα-2b-CCPM had an obvious antitumor effect, and the tumor inhibition efficiency was 29.2%.Conclusion: The results suggested a novel sustained-release formulation with higher drug availability and better lung targeting from CS-rhIFNα-2b-CCPM compared to the reference (the stock solution of rhIFNα-2b), and, thus, should be further studied.Keywords: nanoporous, ion-responsive, recombinant human interferon α-2b, ion exchange technique, sustained release, lung targeting

Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but has yet to achieve this goal with the vast majority of targets. One rare example of success in this pursuit has been the 25+ years of studies targeting the lung endothelium using nanoparticles conjugated to antibodies against endothelial surface molecules. However, here we show that such "endothelial-targeted" nanocarriers also effectively target the lungs' numerous marginated neutrophils, which reside in the pulmonary capillaries and patrol for pathogens. We show that marginated neutrophils' uptake of many of these "endothelial-targeted" nanocarriers is on par with endothelial uptake. This generalizes across diverse nanomaterials and targeting moieties and was even found with physicochemical lung tropism (i.e., without targeting moieties). Further, we observed this in ex vivo human lungs and in vivo healthy mice, with an increase in marginated neutrophil uptake of nanoparticles caused by local or distant inflammation. These findings have implications for nanomedicine development for lung diseases. These data also suggest that marginated neutrophils, especially in the lungs, should be considered a major part of the reticuloendothelial system (RES), with a special role in clearing nanoparticles that adhere to the lumenal surfaces of blood vessels.

Among various mRNA carrier systems, lipid nanoparticles (LNPs) stand out as the most clinically advanced. While current clinical trials of mRNA/LNP therapeutics mainly address liver diseases, the potential of mRNA therapy extends far beyond─yet to be unraveled. To fully unlock the promises of mRNA therapy, there is an urgent need to develop safe and effective LNP systems that can target extrahepatic organs. Here, we report on the development of sulfonium lipid nanoparticles (sLNPs) for systemic mRNA delivery to the lungs. sLNP effectively and specifically delivered mRNA to the lungs following intravenous administration in mice. No evidence of lung and systemic inflammation or toxicity in major organs was induced by sLNP. Our findings demonstrated that the newly developed lung-specific sLNP platform is both safe and efficacious. It holds great promise for advancing the development of new mRNA-based therapies for the treatment of lung-associated diseases and conditions.

Fetal treatment of congenital lung disease, such as cystic fibrosis, surfactant protein syndromes, and congenital diaphragmatic hernia, has been made possible by improvements in prenatal diagnostic and interventional technology. Delivery of therapeutic agents to fetal lungs in nanoparticles improves cellular uptake. The efficacy and safety of nanoparticle-based fetal lung therapy depends on targeting of necessary cell populations. This study aimed to determine the relative distribution of nanoparticles of a variety of compositions and sizes in the lungs of fetal mice delivered through intravenous and intra-amniotic routes. Intravenous delivery of particles was more effective than intra-amniotic delivery for epithelial, endothelial and hematopoietic cells in the fetal lung. The most effective targeting of lung tissue was with 250nm Poly-Amine-co-Ester (PACE) particles accumulating in 50% and 44% of epithelial and endothelial cells. This study demonstrated that route of delivery and particle composition impacts relative cellular uptake in fetal lung, which will inform future studies in particle-based fetal therapy. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Leveraging the extensive surface area of the lungs for gene therapy, the inhalation route offers distinct advantages for delivery. Clinical nebulizers that employ vibrating mesh technology are the standard choice for converting liquid medicines into aerosols. However, they have limitations when it comes to delivering mRNA through inhalation, including severe damage to nanoparticles due to shearing forces. Here, we introduce a microfluidic aerosolization platform (MAP) that preserves the structural and physicochemical integrity of lipid nanoparticles, enabling safe and efficient delivery of mRNA to the respiratory system. Our results demonstrated the superiority of the MAP over the conventional vibrating mesh nebulizer, as it avoided problems such as particle aggregation, loss of mRNA encapsulation, and deformation of the nanoparticle morphology. Notably, aerosolized nanoparticles generated by the microfluidic device led to enhanced transfection efficiency across various cell lines. In vivo experiments with mice that inhaled these aerosolized nanoparticles revealed successful lung-specific mRNA transfection without observable signs of toxicity. This MAP may represent an advancement for the pulmonary gene therapy, enabling precise and effective delivery of aerosolized nanoparticles.

Two camps have emerged for targeting nanoparticles to specific organs and cell types: affinity moiety targeting and physicochemical tropism. Here we directly compare and combine both using intravenous (IV) lipid nanoparticles (LNPs) designed to target the lungs. We utilized PECAM antibodies as affinity moieties and cationic lipids for physicochemical tropism. These methods yield nearly identical lung uptake, but aPECAM LNPs show higher endothelial specificity. LNPs combining these targeting methods had >2-fold higher lung uptake than either method alone and markedly enhanced epithelial uptake. To determine if lung uptake is because the lungs are the first organ downstream of IV injection, we compared IV vs intra-arterial (IA) injection into the carotid artery, finding that IA combined-targeting LNPs achieve 35% of the injected dose per gram (%ID/g) in the first-pass organ, the brain, among the highest reported. Thus, combining the affinity moiety and physicochemical strategies provides benefits that neither targeting method achieves alone.

Acute respiratory distress syndrome (ARDS), a catastrophic illness of multifactorial etiology, involves a rapid upsurge in inflammatory cytokines that leads to hypoxemic respiratory failure. Dexamethasone, a synthetic corticosteroid, mitigates the glucocorticoid-receptor-mediated inflammation and accelerates tissue homeostasis towards disease resolution. To minimize non-target organ side effects arising from frequent and chronic use of dexamethasone, we designed biodegradable, lung-targeted microspheres with sustained release profiles. Dexamethasone-loaded lipopolymeric microspheres of PLGA (Poly Lactic-co-Glycolic Acid) and DPPC (Dipalmitoylphosphatidylcholine) stabilized with vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate) were prepared by a single emulsion technique that had a mean diameter of 8.83 ± 0.32 μm and were spherical in shape as revealed from electron microscopy imaging. Pharmacokinetic and biodistribution patterns studied in the lungs, liver, and spleen of Wistar rats showed high selectivity and targeting efficiency for the lung tissue (re 13.98). As a proof-of-concept, in vivo efficacy of the microspheres was tested in the lipopolysaccharide-induced ARDS model in rats. Inflammation markers such as IL-1β, IL-6, and TNF-α, quantified in the bronchoalveolar lavage fluid indicated major improvement in rats treated with dexamethasone microspheres by intravenous route. Additionally, the microspheres substantially inhibited the protein infiltration, neutrophil accumulation and lipid peroxidation in the lungs of ARDS bearing rats, suggesting a reduction in oxidative stress. Histopathology showed decreased damage to the pulmonary tissue upon treatment with the dexamethasone-loaded microspheres. The multipronged formulation technology approach can thus serve as a potential treatment modality for reducing lung inflammation in ARDS. An improved therapeutic profile would help to reduce the dose, dosing frequency and, eventually, the toxicity.

In this work, montelukast (MTK) was incorporated in inhalable soft agglomerates (SA) exhibiting inherent characteristics for deep lung deposition while expressing good flowability and enhanced shelf-life stability. Mannitol and ovalbumin were used as particle shapers and lecithin as binder during microparticles (MPs) preparation by spray drying. The spontaneously agglomerated MPs with an adhesive surface were designed to deagglomerate under the effect of aerosolization with selected dry powder inhaler device, achieving satisfactory lung deposition. A pharmacodynamic study was also undertaken to evaluate MTK-SA effectiveness in asthmatic rats. Optimized SA showed agglomerated small MPs capable of dispersing into individual particles under pressures exceeding 1Bar. They exhibited high respirable fraction of >54% and were able to release MTK in <15 min. MTK-SA, delivered by pulmonary insufflation, was able to equally reduce the inflammatory response in asthmatic rats at a ten fold lower dose compared to oral tablet. Unlabelled Image • Inhalable soft agglomerates (SA) were developed using spray drying technology. • Mannitol/albumin acted as particle shaper improving spray dried powder attributes. • Lecithin, leucine & a particle shaper, produced SA with high respirable fraction. • Montelukast lung targeted SA exhibited enhanced pharmacodynamics activity. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a critical illness without effective therapeutic modalities currently. Recent studies indicated potential efficacy of statins for ALI, while high-dose statins was suggested to be significant for attenuating inflammation in vivo. Therefore, a lung-targeted drug delivery system (DDS) delivering simvastatin (SV) for ALI therapy was developed, attempting to improve the disease with a decreased dose and minimize potential adverse effects. SV-loaded nanostructured lipid carriers (SV/NLCs) with different size were prepared primarily. With particle size increasing from 143.7 nm to 337.8 nm, SV/NLCs showed increasing drug-encapsulated efficiency from 66.70% to 91.04%. Although larger SV/NLCs exhibited slower in vitro cellular uptake by human vascular endothelial cell line EAhy926 at initial stage, while in vivo distribution demonstrated higher pulmonary accumulation of the larger ones. Thus, the largest size SV/NLCs (337.8 nm) were conjugated with intercellular adhesion molecule 1 (ICAM-1) antibody (anti-ICAM/SV/NLCs) for lung-targeted study. The anti-ICAM/SV/NLCs exhibited ideal lung-targeted characteristic in lipopolysaccharide-induced ALI mice. In vivo i.v. administration of anti-ICAM/SV/NLCs attenuated TNF-α, IL-6 and inflammatory cells infiltration more effectively than free SV or non-targeted SV/NLCs after 48-h administration. Significant histological improvements by anti-ICAM/SV/NLCs were further revealed by H&E stain. Therefore, ICAM-1 antibody-conjugated NLCs may represent a potential lung-targeted DDS contributing to ALI therapy by statins.

Yumeng Wei,1 Jing Liang,1 Xiaoli Zheng,2 Chao Pi,1 Hao Liu,1 Hongru Yang,3 Yonggen Zou,4 Yun Ye,1,5 Ling Zhao1 1Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, 2Department of Biochemistry, The Institute of Basic Medical Sciences, Southwest Medical University, Jiangyang District, 3Department of Oncology, The Affiliated Hospital of Southwest Medical University, 4Department of Orthopedics, The Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University, Longma Tan District, 5Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, People’s Republic of China Abstract: The present study aims to develop a kind of novel nanoliposomes for the lung-targeting delivery system of baicalin as a Chinese medicine monomer. Baicalin-loaded nanoliposomes were prepared by the effervescent dispersion and lyophilized techniques. Baicalin-loaded nanoliposomes had an average particle size of 131.7±11.7 nm with 0.19±0.02 polydispersity index, 82.8%±1.24% entrapment efficiency and 90.47%±0.93% of yield and sustaining drug release effect over 24 h and were stable for 12 months at least. In vitro no hemolytic activity was observed for the experimental drug concentration. After intravenous administration of baicalin-loaded nanoliposomes to rabbits, drug concentration in the lungs was the highest among the tested organs at all time points and was significantly higher than that of its solution. For the targeting parameters, the relative intake rate and the ratio of peak concentration of lung were 4.837 and 2.789, respectively. Compared with plasma, liver, spleen, and kidney, the ratios of targeting efficacy (Te)liposomes to (Te)injection of lung were increased by a factor of 14.131, 1.893, 3.357, and 3.470, respectively. Furthermore, the results showed that the baicalin-loaded nanoliposomes did not induce lung injury. Importantly, baicalin-loaded nanoliposomes showed better antitumor therapeutic efficacy in the nude mice bearing orthotopic human lung cancer with the median survival time of blank liposomes (11.40±0.16 days), baicalin solution (17.30±0.47 days), and baicalin-loaded nanoliposomes (25.90±0.53 days). Therefore, the liposome is a promising drug carrier with an excellent lung-targeting property and therapeutic effect for the treatment of lung disease, such as lung cancer. Keywords: liposomes, biodistribution, lung-targeting drug delivery, cancer therapy, baicalin

Therapeutic antibodies that block vascular endothelial growth factor (VEGF) show clinical benefits in treating nonsmall cell lung cancers (NSCLCs) by inhibiting tumor angiogenesis. Nonetheless, the therapeutic effects of systemically administered anti-VEGF antibodies are often hindered in NSCLCs because of their limited distribution in the lungs and their adverse effects on normal tissues. These challenges can be overcome by delivering therapeutic antibodies in their mRNA form to lung endothelial cells, a primary target of VEGF-mediated pulmonary angiogenesis, to suppress the NSCLCs. In this study, we synthesized derivatives of poly(β-amino esters) (PBAEs) and prepared nanoparticles to encapsulate the synthetic mRNA encoding bevacizumab, an anti-VEGF antibody used in the clinic. Optimization of nanoparticle formulations resulted in a selective lung transfection after intravenous administration. Notably, the optimized PBAE nanoparticles were distributed in lung endothelial cells, resulting in the secretion of bevacizumab. We analyzed the protein corona on the lung- and spleen-targeting nanoparticles using proteomics and found distinctive features potentially contributing to their organ-selectivity. Lastly, bevacizumab mRNA delivered by the lung-targeting PBAE nanoparticles more significantly inhibited tumor proliferation and angiogenesis than recombinant bevacizumab protein in orthotopic NSCLC mouse models, supporting the therapeutic potential of bevacizumab mRNA therapy and its selective delivery through lung-targeting nanoparticles. Our proof-of-principle results highlight the clinical benefits of nanoparticle-mediated mRNA therapy in anticancer antibody treatment in preclinical models.

Background: As the overwhelming majority of advanced mRNA delivery systems are preferentially accumulated in the liver, there is an accelerating growth in the demand for the development of non-liver mRNA delivery platforms. Methods: In this study, we prepared cationic lipid-like nanoassemblies through a N-quaternizing strategy. Their physicochemical properties, in vitro mRNA delivery efficiency, and organ tropism in mice were investigated. Results: Introduction of quaternary ammonium groups onto lipid-like nanoassemblies not only enhances their mRNA delivery performance in vitro, but also completely alters their tropism from the spleen to the lung after intravenous administration in mice. Quaternized lipid-like nanoassemblies exhibit ultra-high specificity to the lung and are predominantly taken up by pulmonary immune cells, leading to over 95% of exogenous mRNA translation in the lungs. Such mRNA delivery carriers are stable even after more than one-year storage at ambient temperature. Conclusions: Quaternization provides an alternative method for design of new lung-targeted mRNA delivery systems without incorporation of targeting ligands, which should extend the therapeutic applicability of mRNA to lung diseases., Competing Interests: Competing Interests: The authors declare the following financial interest which may be considered as potential competing interests: Y. Huang, J. Wu, S. Li, and B. Li are listed as inventors on an issued patent related to this work., (© The author(s).)

Abstract Effective treatment for acute lung injury (ALI) is in high demand. Lung-targeted ternary nanoparticles containing anti-intercellular adhesion molecule-1 (ICAM-1) antibody-conjugated simvastatin-loaded nanostructured lipid carrier (ICAM/NLC), protamine (Pro), and angiopoietin-1 (Ang-1) gene (ICAM-NLC/Pro/Ang) were developed for ALI therapy. The ternary nanoparticles with different weight ratios of ICAM-NLC to Ang-1 gene were prepared via charge interaction. The anti-ICAM-1 antibody-conjugated ternary nanoparticles exhibited higher cellular uptake and transfection efficiency (from 26.7% to 30.9%) in human vascular endothelial cell line EAhy926 than the non-targeted control. The largest size of ICAM-NLC/Pro/Ang (357.1 nm) was employed for further study, which significantly up-regulated in vitro and in vivo Ang-1 protein expression. In vivo i.v. administration of ICAM-NLC/Pro/Ang (357.1 nm) significantly attenuated pulmonary TNF-α and IL-6 levels, inflammatory cell infiltration, and led to positive histological improvements in lipopolysaccharide-induced ALI mice. Collectively, the ICAM-NLC/Pro/Ang that co-delivered simvastatin and Ang-1 gene may represent a potential treatment modality for ALI. Graphical Abstract The ternary ICAM-NLC/Pro/Ang nanoparticles containing angiopoietin-1 gene, protamine and ICAM-NLC were prepared via charge interaction firstly. The ICAM-NLC/Pro/Ang exhibited ideal lung-targeted ability in lipopolysaccharide-induced ALI mice after i.v. administration, as well as the significant up-regulation of Ang-1 protein in lung tissue. The ICAM-NLC/Pro/Ang realized an effective attenuation of pulmonary inflammation via co-delivery of Ang-1 gene and simvastatin to the injured lung. Collectively, the ICAM-NLC/Pro/Ang may represent a promising candidate favoring the clinical ALI therapy. Unlabelled Image [ABSTRACT FROM AUTHOR]

First, the SA-TDZA-Lips were prepared by reverse-phase evaporation method. Then, the drug release behaviour was evaluated by dynamic membrane dialysis in vitro and the preliminary safety was evaluated by haemolysis method. Finally, with tedizolid phosphate injection (TDZA-Inj) and tedizolid phosphate loaded liposomes (TDZA-Lips) as the control groups, the pharmacokinetic characteristic and tissues distribution of SA-TDZA-Lips were evaluated after intravenous injection. As a result, the stearylamine modified tedizolid phosphate liposomal delivery system was constructed successfully and the particle size was 194.9 ± 2.93 nm. The encapsulation efficiency (EE) was 53.52 ± 2.18%. The in vitro release of SA-TDZA-Lips was in accordance with Weibull equation. And there was no haemolysis happened, which indicated good preliminary safety for injection. The results of pharmacokinetics showed that the t1/2β increased by 0.74 times and 0.51 times higher than that of TDZA-Inj group and TDZA-Lips group, respectively. The MRT of SA-TDZA-Lips was 1.30 and 1.09 times higher than that of TDZA-Inj group and TDZA-Lips group, respectively. The AUC was 2.40 times and 0.23 times higher than that of TDZA-Inj group and TDZA-Lips group, respectively. The tissue distribution results showed that the relative uptake rate (Re) of TDZA in the lung was 1.527, which indicated the targeting. In conclusion, the SA-TDZA-Lips prepared in this study had several advantages like positive charge, strong cell affinity, prolonged circulation time in vivo, sustained release effect, and increased drug concentration in lungs. All advantages above provided significant clinical value of application for the treatment of bacterial pneumonia with tedizolid phosphate. [ABSTRACT FROM AUTHOR]

Vinorelbine Tartrate (VLB) is the first line chemotherapeutic agent for treatment of Non-Small Cell Lung Cancer, whose non-specific distribution causes unwanted side effects. The aim of the present investigation was to formulate VLB loaded spherulites intended for targeting the lung. Spherulites were composed of Soyabean Phosphatidylcholine (SPC), Cholesterol (Chol), Potassium oleate and Mannitol. Lipid film prepared using SPC, Chol and Potassium oleate, was dispersed in aqueous phase comprising Mannitol and VLB, followed by controlled shearing and extrusion. PEGylated Spherulites were prepared by incorporating 1,2-distearoyl-sn-glycero-3 phosphatidylethanolamine-N-[methoxy poly (ethylene glycol)] (DSPE-PEG 2000) in the lipid phase. Vesicles were characterized for size, entrapment efficiency and drug release. In vitro cell cytotoxicity and apoptosis study were performed on A549 cell line. Radiolabeling of VLB was performed by direct labeling with reduced technetium-99m. Binding affinity of 99m Tc- labelled complexes was assessed by diethylenetriaminepenta acetic acid (DTPA) challenge test. Biodistribution study was done in Sprague Dawley rats. Dynamic light scattering and Transmission electron micrographs confirmed that PEGylated and non-PEGylated Spherulites were discrete, spherical and exhibited the size range of 120–130 nm. Non-PEGylated and PEGylated Spherulites had an entrapment efficiency of 95.65% and 94.2% respectively. In vitro drug release study indicated VLB plain drug solution diffused completely within 24 h, however, Non-PEGylated and PEGylated Spherulites showed similar release pattern till 48 h. Results of cell line study showed that cells treated with VLB loaded Spherulites showed more cytotoxicity and underwent high degree of apoptosis at lower concentration compared to the VLB solution. Radiolabeled complex was stable in saline and serum, further, DTPA challenge study ensured the high binding strength. Gamma Scintigraphy displayed that PEGylated Spherulites were localized within lungs at higher concentration than non-PEGylated followed by plain drug. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop PEGylated phosphatidylcholine (PC)-rich nanovesicles (phosphatiosomes) carrying ciprofloxacin (CIPX) for lung targeting to eradicate extracellular and intracellular methicillin-resistant Staphylococcus aureus (MRSA). Soyaethyl morphonium ethosulfate (SME) was intercalated in the nanovesicle surface with the dual goals of achieving strengthened bactericidal activity of CIPX-loaded phosphatiosomes and delivery to the lungs. The isothermal titration calorimetry (ITC) results proved the strong association of SME phosphatiosomes with pulmonary surfactant. We demonstrated a superior anti-MRSA activity of SME phosphatiosomes compared to plain phosphatiosomes and to free CIPX. A synergistic effect of CIPX and SME nanocarriers was found in the biofilm eradication. SME phosphatiosomes were readily engulfed by the macrophages, restricting the intracellular MRSA count by 1-2 log units. SME phosphatiosomes efficiently accumulated in the lungs after intravenous injection. In a rat model of lung infection, the MRSA burden in the lungs could be decreased by 8-fold after SME nanosystem application. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a critical illness without effective therapeutic modalities currently. Recent studies indicated potential efficacy of statins for ALI, while high-dose statins was suggested to be significant for attenuating inflammationin vivo. Therefore, a lung-targeted drug delivery system (DDS) delivering simvastatin (SV) for ALI therapy was developed, attempting to improve the disease with a decreased dose and minimize potential adverse effects. SV-loaded nanostructured lipid carriers (SV/NLCs) with different size were prepared primarily. With particle size increasing from 143.7 nm to 337.8 nm, SV/NLCs showed increasing drug-encapsulated efficiency from 66.70% to 91.04%. Although larger SV/NLCs exhibited slowerin vitrocellular uptake by human vascular endothelial cell line EAhy926 at initial stage, whilein vivodistribution demonstrated higher pulmonary accumulation of the larger ones. Thus, the largest size SV/NLCs (337.8 nm) were conjugated with intercellular adhesion molecule 1 (ICAM-1) antibody (anti-ICAM/SV/NLCs) for lung-targeted study. The anti-ICAM/SV/NLCs exhibited ideal lung-targeted characteristic in lipopolysaccharide-induced ALI mice.In vivoi.v. administration of anti-ICAM/SV/NLCs attenuated TNF-α, IL-6 and inflammatory cells infiltration more effectively than free SV or non-targeted SV/NLCs after 48-h administration. Significant histological improvements by anti-ICAM/SV/NLCs were further revealed by H&E stain. Therefore, ICAM-1 antibody-conjugated NLCs may represent a potential lung-targeted DDS contributing to ALI therapy by statins. [ABSTRACT FROM AUTHOR]

Purpose: High dosage and repeated ingestion of antibiotics in the treatment of pneumonia lead to inappropriate disposition of the drug and thus increase undesirable effects. Hence, this study was intended to achieve high levofloxacin concentration in lungs by targeted levofloxacin gelatin microspheres (LGMs). Methods: The optimized LGM prepared by emulsion method was characterized for particle size, drug encapsulation efficiency, in vitro study, X-ray diffraction (XRD), and stability studies. The in vivo lung targeting efficiency parameters such as intake rate ( r ), targeting efficacy ( t ), overall drug targeting efficacy ( T ), percentage of drug distributed to lungs ( j), and ratio of peak concentration ( C ) were investigated. Results: The mean particle size ranged from 6.28 to 19.72 μm, which can get deposited in lungs by mechanical entrapment. The curve fitting analysis showed significance for Koresmeyer-Peppas model ( R-square = 0.9959). The levofloxacin area under the curve (AUC; 899.62 μg h mL) and r (5.74) for lung were higher and statistically significant in LGM group. Compared with spleen and liver, the t in mice lung increased by a factor of 33.45 and ∼12.74, respectively. The targeting ratio of LGM increased by a factor of 26.22 (compared to spleen) and ∼10.58 (compared to liver). Subsequently by a factor of 4.63, C in lung was higher in LGM-treated mice. An overall 87.14 % of the drug was distributed to lungs when administrated as LGM formulation. The histopathology confirmed tissue tolerability. Conclusions: The gelatin microsphere allows for surface modification, and mechanically entrapped in endothelial capillary of the lung further increases affinity leading to higher levofloxacin concentration in lungs, which helps in optimizing the therapeutic efficacy in the treatment of pneumonia. [ABSTRACT FROM AUTHOR]

Lung-targeting sophoridine-loaded poly(lactide-co-glycolide) (PLGA) microspheres were constructed by a simple oil-in-oil emulsion-solvent evaporation method. The obtained microspheres were systematically studied on their morphology, size distribution, drug loading, encapsulation efficiency,in vitrorelease profile, and biodistribution in rats. The drug-loaded microparticles showed as tiny spheres under SEM and had an average size of 17 μm with 90% of the microspheres ranging from 12 to 24 μm. The drug loading and encapsulation efficiency were 65% and 6.5%, respectively. Thein vitrodrug release behavior of microspheres exhibited an initial burst of 16.6% at 4 h and a sustained-release period of 14 days. Drug concentration in lung tissue of rats was 220.10 μg/g for microspheres and 6.77 μg/g for solution after intraveneous injection for 30 min, respectively. And the microsphere formulation showed a significantly higher drug level in lung tissue than in other major organs and blood samples for 12 days. These results demonstrated that the obtained PLGA microspheres could potentially improve the treatment efficacy of sophoridine against lung cancer. [ABSTRACT FROM AUTHOR]

Chitosan (CS)-modified poly( d , l -lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) were prepared and their lung targetability after intravenous administration was elucidated. PLGA NPs (mean diameter: 225 nm; polydispersity index: 0.11; zeta potential: −15 mV), 0.2% (w/v) CS-coated PLGA NPs (CS02-PLGA NPs, mean diameter: 264 nm; polydispersity index: 0.17; zeta potential: −7 mV), and 0.5% (w/v) CS-coated PLGA NPs (CS05-PLGA NPs, mean diameter: 338 nm; polydispersity index: 0.23; zeta potential: 12 mV) were fabricated by a modified solvent evaporation method. PLGA NPs maintained their initial particle size in different media, such as human serum albumin (HSA) solution, rat plasma, and distilled water (DW), while CS05-PLGA NPs exhibited the formation of aggregates in early incubation time and disassembly of those into the NPs in late incubation time (at 24 h). According to the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis, the binding affinity of CS05-PLGA NPs with HSA and rat plasma was higher than that of PLGA NPs. By a near-infrared fluorescence (NIRF) imaging test in the mouse, the selective accumulation of CS05-PLGA NPs, rather than PLGA NPs, in lung tissue was demonstrated. These findings suggest that CS05-PLGA NPs can form transient aggregates in the blood stream after intravenous administration and markedly improve lung targeting efficiency, compared with PLGA NPs. [ABSTRACT FROM AUTHOR]

Background: Following administration, the antibiotic travels freely through the body and also accumulates in other parts apart from the infection site. High dosage and repeated ingestion of antibiotics in the treatment of pneumonia leads to undesirable effects and inappropriate disposition of the drug. By way of targeted lung delivery, this study was intended to eliminate inappropriate azithromycin disposition and to achieve higher azithromycin concentration to treat deeper airway infections. Methods: The Azithromycin Albumin Microspheres (AAM) was prepared by emulsion polymerization technique. The optimized AAM was subjected to in vitro release study, release kinetics, XRD and stability studies. Further, in vivo pharmacokinetics and tissue distribution of azithromycin released from AAM and azithromycin solution in albino mice was investigated to prove suitability of moving forward the next steps in the clinic. Results: The mean particle size of the optimized AAM was 10.02 µm, an optimal size to get deposited in the lungs by mechanical entrapment. The maximum encapsulation efficiency of 82.3% was observed in this study. The release kinetic was significant and best fitted for Korsmeyer-Peppas model (R² = 0.9962, n = 0.41). The XRD and stability study showed favorable results. Azithromycin concentration in mice lungs (40.62 µg g-1, 30 min) of AAM was appreciably higher than other tissues and plasma. In comparison with control, azithromycin concentration in lungs was 30.15 µg g-1 after 30 min. The azithromycin AUC (929.94 µg h mL-1) and intake rate (re) (8.88) for lung were higher and statistically significant in AAM group. Compared with spleen and liver, the targeting efficacy (te) in mice lung increased by a factor of 40.15 and ~14.10 respectively. Subsequently by a factor of 8.94, the ratio of peak concentration (Ce) in lung was higher in AAM treated mice. The AAM lung tissue histopathology did not show any degenerative changes. Conclusions: High azithromycin concentration in albino mice lung was adequately achieved by targeted drug delivery. [ABSTRACT FROM AUTHOR]

Objectives In this review paper, we explore the interaction between the functioning mechanism of different nebulizers and the physicochemical properties of the formulations for several types of devices, namely jet, ultrasonic and vibrating-mesh nebulizers; colliding and extruded jets; electrohydrodynamic mechanism; surface acoustic wave microfluidic atomization; and capillary aerosol generation. Key findings Nebulization is the transformation of bulk liquids into droplets. For inhalation therapy, nebulizers are widely used to aerosolize aqueous systems, such as solutions and suspensions. The interaction between the functioning mechanism of different nebulizers and the physicochemical properties of the formulations plays a significant role in the performance of aerosol generation appropriate for pulmonary delivery. Certain types of nebulizers have consistently presented temperature increase during the nebulization event. Therefore, careful consideration should be given when evaluating thermo-labile drugs, such as protein therapeutics. We also present the general approaches for characterization of nebulizer formulations. Summary In conclusion, the interplay between the dosage form (i.e. aqueous systems) and the specific type of device for aerosol generation determines the effectiveness of drug delivery in nebulization therapies, thus requiring extensive understanding and characterization. [ABSTRACT FROM AUTHOR]

A simple and sensitive LC-UV method to investigate the pharmacokinetics and biodistribution pattern of baicalin in rabbits was established and validated. Baicalin and the internal standard, rutin, were extracted from biosamples using acetonitrile as protein precipitation after pretreated with ammonium acetate buffer (pH 3.5; 1 M) to obtain a pure chromatographic peak and high extraction recovery. Chromatographic separation was achieved on a reverse-phase C18 column with a gradient elution at flow rate of 1.0 mL/min. UV absorption was set at 278 nm. Chromatographic response was linear over the ranges of 0.05–10.00 μg/mL in plasma and 0.05–300.00 μg/g in tissues with the limits of quantification of 50.0 ng/mL in plasma and tissues, and the limit of detection of baicalin in bio-samples of 15 ng/mL. The RSD of intra-and inter-day for the biosamples were from 4.19% to 10.84% and from 4.37% to 10.93%, respectively. The accuracy of plasma and tissue samples ranged from 81.6% to 95.2% and 80.8% to 98.4%, respectively. The extraction recoveries ranged from 81.5% to 88.3% for plasma, from 73.1% to 93.2% for tissues, respectively. Baicalin was stable in rabbit biosamples. The validated method was successfully applied to the study of the pharmacokinetics and tissue distribution of baicalin after intravenous administration of liposomal and injectable formulations to rabbits. Compared to baicalin injection, the pharmacokinetics and biodistribution behavior of baicalin was altered significantly in rabbits treated with its liposomes and drug concentration in the lungs was greatly increased. [ABSTRACT FROM AUTHOR]

Background: Reliable, reproducible deposition to the lung is a major prerequisite for the clinical use of inhaled drugs. Ciprofloxacin dry powder for inhalation (ciprofloxacin DPI; Bayer HealthCare AG, Leverkusen, Germany) is an antibacterial therapy in development using Novartis' PulmoSphere™ technology (Novartis Pharma AG, Basel, Switzerland) for the targeted delivery of ciprofloxacin to the lung via a T-326 inhaler. Methods: This randomized, single-blind, placebo-controlled, dose-escalation study investigated the safety, tolerability, and pharmacokinetics of single-dose ciprofloxacin DPI (32.5 mg [ n=6] or 65 mg [ n=6]) and matching placebo ( n=4) in adult patients with cystic fibrosis and stable pulmonary status (forced expiratory volume in 1 sec ≥30%) who were colonized with Pseudomonas aeruginosa. Results: Peak sputum concentrations of 34.9 mg/L (range 2.03-229) and 376 mg/L (8.95-1283) for ciprofloxacin 32.5 mg and 65 mg, respectively, indicated targeting of ciprofloxacin DPI to the lung. This contrasted with low systemic exposure (peak plasma concentrations: 0.0790 mg/L [32.5 mg] and 0.182 mg/L [65 mg]). Single-dose ciprofloxacin DPI 32.5 mg or 65 mg was well tolerated with similar incidences of adverse events across all groups. No deaths, discontinuations, treatment-related serious adverse events, or clinically relevant changes in laboratory parameters, vital signs, or lung function tests were reported. Conclusions: Lung targeting with high pulmonary concentrations of ciprofloxacin combined with low systemic exposure was confirmed. These results support further study of ciprofloxacin DPI as a potentially more convenient alternative to nebulized antibiotic solutions for managing chronic lung infections. [ABSTRACT FROM AUTHOR]

Carbopol microspheres of methotrexate (MxtCM), a drug used in the treatment of lung cancer, were prepared using a Buchi B-90 nano spray dryer. The surface morphology was found to be shriveled to nearly spherical, with an average size of 6.8 µm. The drug loading and percentage yield were found to be 77% ± 0.3% and 89% ± 0.4%, respectively. The in-vitro release was suggestive of the Baker and Lonsdale model, as the release pattern involved swelling and diffusion; the total methotrexate release after 12 h was 98.2% from MxtCM while, for the pure drug, it was 94.2% at 0.5 h. Liquification was witnessed during the stability studies at 37°C and at a relative humidity of 75%. This study concludes that the microsphere could be one of the most appropriate drug delivery methods for the successful delivery of methotrexate to the lungs. The pharmacokinetic (drug concentration) results following intravenous administration were 1,021 µg/g after 15 min; in comparison, in the spleen and liver, the concentration of the conventional dosage of Mxt was <401 µg/g after 10 min. We concluded that the methotrexate concentration was increased in the lungs when compared to the blood, spleen, and liver. The ingredients used in the formulation were confirmed harmless from histopathological studies. Thus, microspheres can be adopted in formulating and targeting methotrexate to the lungs. [ABSTRACT FROM AUTHOR]

In order to develop a novel lung targeting drug delivery system (LTDDS) with large-sized liposomes containing paclitaxel (PTX), the liposomes composed of PTX, phosopholipon 90H and tween-80 were prepared by the effervescent dispersion technique with optimal formulation composition. The liposomes were found to be relatively uniform in particle size (8.166 ± 0.459 μm) with a negative zeta-potential (−12.45 ± 1.34 mv), and high entrapment efficiency (92.20 ± 2.56 %). They kept stable for at least 3 months and exhibited a slow release behavior without any hemolysis reaction. Via intravenous administration in rabbits, the PTX liposomes presented a longer mean residence time and elimination half-life, and a much larger area under the plasma drug concentration-time curve compared with its injection; meanwhile, the liposomes altered its biodistribution and exhibited a significant lung targeting characteristic. For example, the relative intake rate (Re) and the ratio of peak concentration (Ce) of lung were 14.87 and 26.44, respectively. Compared with heart, liver, spleen and kidney, the ratios of targeting efficacy (Te) to (Te) of lung were increased by a factor of 20.08, 11.10, 6.97 and 14.41, respectively. To sum up, the liposome could be a promising drug carrier for PTX as LTDDS for lung cancer treatment. [ABSTRACT FROM AUTHOR]