Pulmonary Delivery Research Articles

Intratracheal Administration of Itraconazole-Loaded Hyaluronated Glycerosomes as a Promising Nanoplatform for the Treatment of Lung Cancer: Formulation, Physiochemical, and In Vivo Distribution

Background: Itraconazole (ITZ) is an antiangiogenic agent recognized as a potent suppressor of endothelial cell growth that suppresses angiogenesis. Nevertheless, its exploitation is significantly restricted by its low bioavailability and systematic side effects. The objective of this study was to utilize glycerosomes (GLY), glycerol-developed vesicles, as innovative nanovesicles for successful ITZ pulmonary drug delivery. Methods: The glycerosomes were functionalized with hyaluronic acid (HA-GLY) to potentiate the anticancer efficacy of ITZ and extend its local bio-fate. ITZ-HA-GLY were fabricated using soybean phosphatidylcholine, tween 80, HA, and sonication time via a thin-film hydration approach according to a 24 full factorial design. The impact of formulation parameters on ITZ-HA-GLY physicochemical properties, as well as the optimal formulation option, was evaluated using Design-Expert®. Sulphorhodamine-B (SRB) colorimetric cytotoxicity assay of the optimized ITZ-HA-GLY versus ITZ suspension was explored in the human A549 cell line. The in vivo pharmacokinetics and bio-distribution examined subsequent to intratracheal administrations of ITZ suspension, and ITZ-HA-GLY were scrutinized in rats. Results: The optimized ITZ-HA-GLY unveiled vesicles of size 210.23 ± 6.43 nm, zeta potential of 41.06 ± 2.62 mV, and entrapment efficiency of 73.65 ± 1.76%. Additionally, ITZ-HA-GLY manifested a far lower IC50 of 13.03 ± 0.2 µg/mL on the A549 cell line than that of ITZ suspension (28.14 ± 1.6 µg/mL). Additionally, the biodistribution analysis revealed a higher concentration of ITZ-HA-GLY within the lung tissues by 3.64-fold as compared to ITZ suspension. Furthermore, the mean resistance time of ITZ-HA-GLY declined more slowly with 14 h as compared to ITZ suspension, confirming the accumulation of ITZ inside the lungs and their promising usage as a target for the treatment of lung disease. Conclusions: These data indicate that the improved ITZ-HA-GLY demonstrates significant promise and represents an exciting prospect in intratracheal delivery systems for lung cancer treatment, meriting further investigation.

Bioorthogonal Chemistry-Guided Inhalable Nanoprodrug to Circumvent Cisplatin Resistance in Orthotopic Nonsmall Cell Lung Cancer.

Pulmonary delivery of anticancer therapeutics has shown encouraging performance in treating nonsmall cell lung cancer (NSCLC), which is characterized by high aggressiveness and poor prognosis. Cisplatin, a key member of the family of DNA alkylating agents, is extensively employed during NSCLC therapy. However, the development of chemoresistance and the occurrence of side effects severely impede the long-term application of cisplatin-based chemotherapies. Herein, we propose a meaningful strategy to precisely treat cisplatin-resistant NSCLC based on the combination of bioorthogonal chemistry with an inhalation approach. Ethacraplatin (EA-Pt), a platinum prodrug (IV), was synthesized and encapsulated in nitric oxide (NO)-containing micelles to overcome cisplatin chemoresistance. By further modifying bioorthogonal molecules in this nanoplatform (EA-Pt@MDBCO), an improved targeting performance toward pulmonary cancerous regions is achieved after prelabeling with azide via inhalation. Upon entering acidic cancer cells, EA-Pt is swiftly released due to the pH sensitivity of bioorthogonal micelles, which enables its bifunctions to inhibit glutathione S-transferase activity and deplete intracellular glutathione, eventually reversing cisplatin resistance. Moreover, the released NO also improves the overall therapeutic outcome against NSCLC. Consequently, inhalable EA-Pt@MDBCO prelabeled by azide effectively inhibits the progression of cisplatin-resistant orthotopic NSCLC, offering a feasible nanostrategy to expand the treatment options for NSCLC.

Design and Evaluation of Dry Powder Inhalation Formulation for Pulmonary Delivery of Docetaxel: A Novel Approach in Non-Small Cell Lung Cancer

Design and Evaluation of Dry Powder Inhalation Formulation for Pulmonary Delivery of Docetaxel: A Novel Approach in Non-Small Cell Lung Cancer

Pulmonary-delivered Anticalin Jagged-1 antagonists reduce experimental airway mucus hyperproduction and obstruction.

Mucus hypersecretion and mucus obstruction are pathogenic features in many chronic lung diseases directly linked to disease severity, exacerbation, progression, and mortality. The Jagged-1/Notch pathway is a promising therapeutic target that regulates secretory and ciliated cell trans-differentiation in the lung. However, the Notch pathway is also required in various other organs. Hence, pulmonary delivery of therapeutic agents is a promising approach to target this pathway while minimizing systemic exposure. Using Anticalin® technology, Jagged-1 Anticalin binding proteins were generated and engineered to potent and selective inhalable Jagged-1 antagonists. Their therapeutic potential to reduce airway mucus hyperproduction and obstruction was investigated ex vivo and in vivo. In primary airway cell cultures grown at air-liquid interface and stimulated with inflammatory cytokines, Jagged-1 Anticalin binding proteins reduced both mucin gene expression and mucous cell metaplasia. In vivo, prophylactic and therapeutic treatment with a pulmonary-delivered Jagged-1 Anticalin binding protein reduced mucous cell metaplasia, epithelial thickening and airway mucus hyperproduction in IL-13 and house dust mite allergen-challenged mice, respectively. Further, in a transgenic mouse model with pathophysiologic features of cystic fibrosis and COPD, pulmonary-delivered Jagged-1 Anticalin binding protein reduced hallmarks of airway mucus obstruction. In all in vivo models a reduction of mucous cells with a concomitant increase of ciliated cells was observed. Collectively, these findings support Jagged-1 antagonists' therapeutic potential for patients with muco-obstructive lung diseases, and the feasibility of targeting the Jagged-1/Notch pathway by inhalation.

Advances in Aerogels Formulations for Pulmonary Targeted Delivery of Therapeutic Agents: Safety, Efficacy and Regulatory Aspects.

Aerogels are the 3D network of organic, inorganic, composite, layered, or hybrid-type materials that are used to increase the solubility of Class 1 (low solubility and high permeability) and Class 4 (poor solubility and low permeability) molecules. This approach improves systemic drug absorption due to the alveoli's broad surface area, thin epithelial layer, and high vascularization. Local therapies are more effective and have fewer side effects than systemic distribution because inhalation treatment targets the specific location and raises drug concentration in the lungs. The present manuscript aims to explore various aspects of aerogel formulations for pulmonary targeted delivery of active pharmaceutical agents. The manuscript also discusses the safety, efficacy, and regulatory aspects of aerogel formulations. According to projections, the global respiratory drug market is growing 4-6% annually, with short-term development potential. The proliferation of literature on pulmonary medicine delivery, especially in recent years, shows increased interest. Aerogels come in various technologies and compositions, but any aerogel used in a biological system must be constructed of a material that is biocompatible and, ideally, biodegradable. Aerogels are made via "supercritical processing". After many liquid phase iterations using organic solvents, supercritical extraction, and drying are performed. Moreover, the sol-gel polymerization process makes inorganic aerogels from TMOS or TEOS, the less hazardous silane. The resulting aerogels were shown to be mostly loaded with pharmaceutically active chemicals, such as furosemide-sodium, penbutolol-hemisulfate, and methylprednisolone. For biotechnology, pharmaceutical sciences, biosensors, and diagnostics, these aerogels have mostly been researched. Although aerogels are made of many different materials and methods, any aerogel utilized in a biological system needs to be made of a substance that is both biocompatible and, preferably, biodegradable. In conclusion, aerogel-based pulmonary drug delivery systems can be used in biomedicine and non-biomedicine applications for improved sustainability, mechanical properties, biodegradability, and biocompatibility. This covers scaffolds, aerogels, and nanoparticles. Furthermore, biopolymers have been described, including cellulose nanocrystals (CNC) and MXenes. A safety regulatory database is necessary to offer direction on the commercialization potential of aerogelbased formulations. After that, enormous efforts are discovered to be performed to synthesize an effective aerogel, particularly to shorten the drying period, which ultimately modifies the efficacy. As a result, there is an urgent need to enhance the performance going forward.

Pulmonary Delivery of Dual-Targeted Nanoparticles Improves Tumor Accumulation and Cancer Cell Targeting by Restricting Macrophage Interception in Orthotopic Lung Tumors

Despite the recognized potential of inhaled nanomedicines to enhance and sustain local drug concentrations for lung cancer treatment, the influence of macrophage uptake on targeted nanoparticle delivery to and within tumors remains unclear. Here, we developed three ligand-coated nanoparticles for pulmonary delivery in lung cancer therapy: phenylboronic acid-modified nanoparticles (PBA-NPs), PBA combined with folic acid (FA-PBA-NPs), and PBA with mannose (MAN-PBA-NPs). In vitro, MAN-PBA-NPs were preferentially internalized by macrophages, whereas FA-PBA-NPs exhibited superior uptake by cancer cells compared to macrophages. Following intratracheal instillation into mice with orthotopic Lewis lung carcinoma tumors, all three nanoparticles showed similar lung retention. However, MAN-PBA-NPs were more prone to interception by lung macrophages, which limited their accumulation in tumor tissues. In contrast, both PBA-NPs and FA-PBA-NPs achieved comparable high tumor accumulation (∼11.3% of the dose). Furthermore, FA-PBA-NPs were internalized by ∼30% of cancer cells, significantly more than the 10-18% seen with PBA-NPs or MAN-PBA-NPs. Additionally, FA-PBA-NPs loaded with icaritin effectively inhibited the Wnt/β-catenin pathway, resulting in superior anti-tumor efficacy through targeted cancer cell delivery. Overall, FA-PBA-NPs demonstrated advantageous competitive uptake kinetics by cancer cells compared to macrophages, enhancing tumor targeting and therapeutic outcomes.

Comparison of clinically meaningful improvements following center-based and home-based tele rehabilitation in people with COPD.

Response to pulmonary rehabilitation is not equal for all participants, and may vary across health outcomes for any one individual. Alternative modes of pulmonary rehabilitation delivery, e.g. telerehabilitation, may improve program access but could also affect response to rehabilitation. What is the rate of clinical response to home-based telerehabilitation compared to center-based pulmonary rehabilitation? And, are there participant baseline characteristics associated with pulmonary rehabilitation response relative to model of delivery? Secondary analysis of two randomized controlled trials. Participants were categorized as 'responders' or 'non-responders' according to achievement of the minimal important difference (MID) for each outcome of interest at end rehabilitation and after 12-month follow-up (change from baseline). Outcomes of interest were: functional exercise capacity (six-minute walk distance [6MWD], MID 30m); health-related quality of life (chronic respiratory questionnaire [CRQ], MID 2.5, 2, 3.5 and 2 points for the dyspnea, fatigue, emotion and mastery domains, respectively; CRQ total score MID 10 points); and symptoms (modified Medical Research Council [mMRC], MID -1 point). 266 individuals with COPD were included in the analysis. The proportion of responders was not different between center-based pulmonary rehabilitation and home-based telerehabilitation at either end rehabilitation or 12-month follow-up for any outcome (range 39% to 62%). In a binary logistic regression analysis, baseline outcome values, but not participant demographic characteristics, were most commonly associated with responder status. The relative risk of program non-completion in the center-based group was nearly four times greater than for telerehabilitation (PR completion: center-based PR n=79 (58%) versus home-based telerehabilitation n=116 (90%); RR 3.89, 95%CI 2.28 to 6.63). Responder status to pulmonary rehabilitation was not different between center-based and home-based telerehabilitation. The ability to identify patient characteristics that confer greater potential for rehabilitation response, or better suitability for a particular model of rehabilitation, remains a challenge. Take home points: STUDY QUESTION: What is the rate of clinical response to home-based telerehabilitation compared to center-based pulmonary rehabilitation? And, are participant baseline characteristics, program completion or program location associated with rehabilitation response? The proportion of responders to rehabilitation is not different between center-based and home-based telerehabilitation programs; however the risk of program non-completion is 4 times higher for center-based rehabilitation. Responder status to pulmonary rehabilitation was not different between center-based and home-based telerehabilitation, although rehabilitation completion was higher for home-based telerehabilitation. Identifying participant features that confer greater potential for rehabilitation response, or better suitability for a particular model of rehabilitation, remains a challenge.

Fast onset of thrombolytic effect of efficiently inhalable spray-dried rivaroxaban powder formulations

Pulmonary embolism is a critical medical condition and can lead to cardiovascular arrest or death if left untreated. Pulmonary delivery of an anti-coagulant therapeutic could provide a locally limited and efficient therapy, moreover combined with a potentially fast onset of the therapeutic effect that is demanded in emergency situations. Rivaroxaban (riva) was formulated as an inhalable dry powder that can be administered directly to the lungs in order to reach high local drug doses. Particles obtained spray drying dichloromethane-methanol mixtures yielded an aerodynamic diameter of about or smaller than 5 µm and were found to reach an emitted fine particle fraction (FPFEF) of at least 60 %. Pulmonary administration to rats using a dry powder insufflator revealed a nearly immediate therapeutic onset confirmed by the anticoagulant effects after 5 min in the plasma followed by a plateau over the next 4 h. Such rivaroxaban particles were further formulated in binary blends using different lactose carriers (Inhalac® 70/251/400). These interactive blends resulted in high emitted fractions of at least 87 %, and furthermore, the highest fine particle fraction − total dose (FPFTD) (60 %) of all tested formulations was achieved by using Inhalac® 400 as a carrier. The data strongly suggest a significant therapeutic potential of a rivaroxaban dry powder formulation, combining fast onset and a plateau of plasma concentrations turning it into a potential first aid therapeutic.

Impact of protein aggregation on the immunogenicity of a human monoclonal antibody following pulmonary administration in mice

Spray drying is a widely employed method for generating dry powder formulations for inhalation. Yet, it presents substantial challenges when applied to therapeutic proteins due to stability issues. The formation of protein aggregates during the atomization and the heating steps can diminish protein activity and raise immunogenicity concerns. Here, we assessed the impact of varying levels of protein aggregates generated during spray-drying on the fate and the immunogenicity of the human monoclonal antibody NIP228 following intratracheal administration in mice. Aggregate-free rhodamine labelled NIP228 was spray-dried with or without 1% polysorbate 80 surfactant, resulting in the generation of powder formulations with associated low and high protein aggregate levels, respectively. Confocal imaging highlighted the presence of aggregates in the lungs for both powders but not for the solution, while flow cytometry analysis designated alveolar macrophages as the main immune cells taking up rhod-NIP228 in the lungs with very little involvement of dendritic cells and interstitial macrophages following a single dose administration. Notably, repeated intratracheal administration of the three formulations in mice did not impact the magnitude of the anti-drug antibody response in sera or broncho-alveolar lavages. The pulmonary route appeared to evoke a more robust immune response when compared to subcutaneous administration. Overall, the level of NIP228 aggregation in this study did not appear to be the primary driver of NIP228 immunogenicity following delivery to the lungs in mice, shedding new light on the interplay between protein aggregation and immunogenicity in the context of the pulmonary delivery of therapeutic proteins.

Rifampicin‐Loaded Nano‐in‐Microparticles (Trojan Particles) as a Pulmonary Delivery System for Tuberculosis Treatment

AbstractThe oral rifampicin (RIF) dosage forms possess various side effects and limited efficacy for tuberculosis treatment. Thus, this work developed the nano‐in‐microparticles containing RIF (trojan nRIF) as a novel pulmonary delivery system. The RIF‐loaded nanoparticles (nRIF) were prepared by self‐assembly polyelectrolyte complexation between lecithin and chitosan, whereas the trojan nRIF were formulated by spray‐drying method of nRIF and mannitol/maltodextrin. The nRIF had a spherical shape with sizes of 86–126 nm, zeta potentials of 24–39 mV, entrapment efficiencies of 44–80 %, and drug loading capacities of 13–42 %. The RIF release from nRIF occurred in two stages, the initially rapid release stage and the controlled release stage upto 96 h, followed the Higuchi model. The trojan nRIF possessed the mass median aerodynamic diameter of 3.7–4.6 μm, fine particle fraction of 34–40 %, and alveolar fraction of 17–21 %. Compared to mannitol, maltodextrin was a superior carrier for nRIF, which yielded better aerodynamic properties and RIF was mainly stayed in the amorphous form. Moreover, using the scanning electron microscopy, the nano‐in‐microparticles were clearly observed with hollow structure. Finally, the trojan nRIF could preserve the physical properties of the encapsulated nRIF. In summary, the trojan nRIF could become a potential inhalation anti‐tuberculosis product.

Inhalable cyclodextrin metal-organic framework dry powder enhanced direct pulmonary delivery of paclitaxel for the treatment of lung cancer

Inhalation dry powders are in great demand for the treatment of lung diseases due to their unique advantages such as excellent direct delivery, rapid onset of action, and reduced systemic side effects. Herein, this work highlights the successful development of an inhalable paclitaxel dry powder, which is facilely constructed through the optimization of the formulation between chemotherapy components (paclitaxel) and a metal-organic framework (MOF) carrier (γ-cyclodextrin and KOH). Moderate pore and particle size distribution, as well as low hygroscopicity endow the dry powder with excellent loading efficiency and resistance to degradation. All ingredients and their interactions confer favorable emptying rates, flowability, and pulmonary deposition, as well as direct lung drug delivery and release. These attractive characteristics enable the dry powder to effectively enhance cytotoxicity, improve pharmacokinetics, promote lung accumulation, and reduce the side effects of paclitaxel. Thus, this paclitaxel dry powder may open a new avenue for the inhalation treatment of diseases, greatly advancing its clinical application.

Comparative Preclinical Pharmacokinetics and Disposition of Favipiravir Following Pulmonary and Oral Administration as Potential Adjunct Therapy Against Airborne RNA Viruses.

Favipiravir is administered orally, even against airborne RNA viruses, in a loading-dose/maintenance dose regimen. We investigated whether-(a) pulmonary delivery of favipiravir would generate high concentrations in the luminal side of the respiratory tract; and (b) avoiding first-pass metabolism by the liver by inhaled drug would generate comparable pharmacokinetics (PK) with doses significantly smaller than the oral maintenance dose. A dry powder inhalation (DPI) of favipiravir formulated by mixing with Inhalac 400® was prepared and characterized. Inhalations of ~ 120µg dose strength, with or without a prior oral loading dose were administered to mice. Comparator mice received human-equivalent oral doses (3mg). Three mice per sampling time point were sacrificed and favipiravir concentrations in the blood plasma, bronchio-alveolar lavage fluid (BALF) and lung tissue homogenate determined by HPLC. One-compartment PK modeling of concentration-time data indicated that the area under the curve (AUC0-24h) generated in the BALF recovered from mice receiving inhalations of ~ 1/25th of the oral dose subsequent to an oral loading dose was 86.72 ± 4.48µg⋅mL-1⋅h. This was consistently higher than the AUC observed in the BALF of orally-dosed mice (56.71 ± 53.89µgmL-1⋅h). In blood serum, the respective values of AUC were 321.55 ± 124.91 and 354.71 ± 99.60µg⋅mL-1⋅h. Pulmonary delivery of significantly smaller doses of favipiravir generates meaningful drug disposition and pharmacokinetics at the site of respiratory viral infections. We provide the rationale for designing a self-administered, non-invasive, low-cost, targeted drug delivery system against airborne RNA virus infection.

Advanced Spray-Dried Inhalable Microparticles/Nanoparticles of an Innovative Mitophagy Activator for Targeted Lung Delivery: Design, Comprehensive Characterization, Human Lung Cell Culture, and In Vitro Aerosol Dispersion Performance.

Urolithin A (UA) has demonstrated the ability to stimulate mitophagy and enhance mitochondrial and cellular health in skeletal muscles in humans after oral administration. It is hypothesized that targeted delivery of UA as inhaled dry powders to the lungs will enhance mitochondrial health through mitochondrial biogenesis. This study aimed to engineer inhalable excipient-free powders of UA as dry powder inhalers (DPIs) for targeted pulmonary delivery. The particles were designed by particle engineering from dilute organic solutions of UA using the state-of-the-art spray drying technology in a closed mode. Comprehensive physicochemical characterization and advanced microscopy techniques were conducted to examine phase behavior, molecular properties, and particle properties, which are necessary for the rational design of advanced pulmonary inhalation aerosols. Molecular fingerprinting was conducted by using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and Raman spectroscopy. Chemical imaging and mapping were conducted using confocal Raman microscopy (CRM) and IR microscopy. The advanced spray-dried (SD) excipient-free powders were successfully produced at different spraying pump feed rates and exhibited favorable molecular and particle properties. The excipient-free SD powders exhibited outstanding in vitro aerosol dispersion performance with an FDI-approved human DPI device (Neohaler) and correlated with the spray drying pump rate. In vitro, cell viability of various human pulmonary cells from different lung regions demonstrated biocompatibility and safety at different doses of UA. The transepithelial electrical resistance (TEER) assay shows that UA maintains cell membrane integrity and barrier tightness, indicating its potential for safe and effective localized drug delivery without long-term adverse effects. These results demonstrated that UA has favorable physicochemical and in vitro properties for inhalation and can be successfully engineered into excipient-free inhalable microparticles/nanoparticles as DPIs.

Development of a dry powder formulation for pulmonary delivery of azithromycin-loaded nanoparticles.

The COVID-19 pandemic has raised concern regarding respiratory system diseases and oral inhalation stands out as an attractive non-invasive route of administration for pulmonary diseases such as chronic bronchitis, cystic fibrosis, COVID-19 and community-acquired pneumonia. In this context, we encapsulated azithromycin in polycaprolactone nanoparticles functionalized with phospholipids rich in dipalmitoylphosphatidylcholine and further produced a fine powder formulation by spray drying with monohydrated lactose. Nanoparticles obtained by the emulsion/solvent diffusion-evaporation technique exhibited a mean hydrodynamic diameter around 195-228nm with a narrow monomodal size distribution (PdI < 0.2). Nanoparticle dispersions were spray-dried at different inlet temperatures, atomizing air-flow, aspirator air flow, and feed rate, using lactose as a drying aid, resulting in a maximal process yield of 63% and an encapsulation efficiency of 83%. Excipients and the dry powder formulations were characterized in terms of morphology, chemical structure, thermal analyses and particle size by SEM, FTIR, DSC/TGA and laser light diffraction. The results indicated spherical particles with 90% at 4.06µm or below, an adequate size for pulmonary delivery. Aerosolization performance in a NGI confirmed good aerodynamic properties. Microbiological assays showed that the formulation preserves AZM antimicrobial effect against Staphylococcus aureus and Streptococcus pneumoniae strains, with halos above 18mm. In addition, no formulation-related cytotoxicity was observed against the human cell lines BEAS-2B (lung epithelial), HUVEC (endothelial) and HFF1 (fibroblasts). Overall, the approach described here allows the production of AZM-PCL nanoparticles incorporated into inhalable microparticles, enabling more efficient pulmonary therapy of lung infections.

In vitro Characterization and Drug Release Studies of Ethambutol-Loaded Nanoparticles for Pulmonary Delivery

Background: The development of more effective drug delivery techniques is necessary to increase treatment efficacy and patient compliance since tuberculosis (TB) is still a serious worldwide health concern. Ethambutol is a vital aspect of TB treatment, and using nanoparticles to carry it to the lungs may provide targeted delivery and prolonged release, which might enhance the effectiveness of the treatment. Objective: This work aimed to optimize the formulation for prolonged drug release by synthesizing and assessing ethambutol-loaded nanoparticles using the desolation technique with albumin as the polymer. Additionally, the effects of different drug-polymer ratios and stirring rates were investigated. Methods: Nine formulations of ethambutol-loaded nanoparticles were prepared by varying the drug-polymer ratios (1:1 to 1:2) and stirring speeds (500 to 1500 rpm). Key parameters, such as particle size, drug entrapment efficiency, and zeta potential, were measured. The optimized formulation was selected based on the smallest particle size and highest drug entrapment efficiency. Scanning electron microscopy was used to analyze the surface morphology of the nanoparticles. The in vitro drug release profile of the optimized formulation was studied over 24 hours. Results: Increasing the drug-polymer ratio from 1:1 to 1:2 increased nanoparticle size from 192.1 nm to 605.06 nm and decreased drug entrapment efficiency from 75.7%±0.08 to 34%±0.06. Higher stirring speeds (500 to 1500 rpm) also led to larger particle sizes and reduced drug entrapment due to polymer self-aggregation. Zeta potential values ranged from -5.56 to -25.6 mV. Scanning electron microscopy confirmed smooth, spherical nanoparticles. The optimized formulation, EN-5, exhibited the smallest particle size and highest drug entrapment efficiency. In vitro drug release studies showed a sustained ethambutol release, with 42.66±1.53% released in 12 hours and 79.082±2.98% in 24 hours. Conclusion: Ethambutol-loaded nanoparticles having the ability to transport drugs to the lungs over an extended period of time were developed and optimized in the study. With improved drug delivery systems, the optimized formulation showed notable drug entrapment efficiency and controlled release, suggesting its potential to improve tuberculosis therapy.

Pulmonary delivery of forsythin-phospholipid complexes improves the lung anti-inflammatory efficacy in mice by enhancing dissolution and lung tissue affinity

Forsythin, currently in phase II clinical trials in China for the treatment of the common cold and influenza, faces challenges in achieving adequate lung drug exposure due to its limited dissolution and permeability, thereby restricting its therapeutic efficacy. The objective of this work was to formulate a forsythin-phospholipid complex (FPC) to enhance its dissolution properties and lung affinity with a particular view to improving pulmonary drug exposure and anti-inflammatory response. The results revealed that forsythin reacted with dipalmitoyl-phosphatidylcholine to form a stable, nanosized FPC suspension. This formulation significantly improved the in vitro drug's dissolution, cellular uptake, and lung affinity compared to its uncomplexed form. Intratracheal administration of FPC in a mouse model of acute lung injury induced by lipopolysaccharide (LPS) resulted in a substantial increase in drug exposure to lung tissues (39.6-fold) and immune cells in the epithelial lining fluid (198-fold) compared to intraperitoneal injection. In addition, FPC instillation exhibited superior local anti-inflammatory effects, leading to improved survival rates among mice with LPS-induced acute respiratory distress syndrome, outperforming both instilled forsythin and injected FPC. Overall, this work demonstrated the potential of phospholipid complexes as a viable option for developing inhalation products for drugs with limited solubility and permeability properties.

Inhalable Advanced Co-Spray Dried Microparticles/Nanoparticles of a Novel RhoA/Rho Kinase Inhibitor with Lung Surfactant Biomimetic Phospholipids for Targeted Lung Delivery.

Co-spray dried inhalable powder formulations of fasudil monohydrochloride salt (FMCS) and inhalable lung surfactant-based nanocarriers composed of synthetic phospholipids, zwitterionic DPPC (1,2-palmitoyl-sn-glycero-3-phosphocholine) and anionic DPPG (1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]) sodium salt, were designed and optimized using organic solution advanced spray drying. FMCS can potentially be used for the treatment of various complex pulmonary diseases with this current work focusing on pulmonary arterial hypertension. Comprehensive physicochemical characterization, electron and optical microscopy imaging, thermal analysis, molecular fingerprinting spectroscopy, in vitro aerosol dispersion performance with human dry powder inhaler (DPI) devices, in vitro membrane permeation and drug release, and in vitro human cellular studies were conducted. Well-defined, small, and smooth nanoparticles/microparticles in the solid state were engineered at different molar ratios of FMCS/DPPC/DPPG (25:75, 50:50, and 75:25) and successfully produced as inhalable powders having the properties necessary for targeted pulmonary delivery as dry powder inhalers. In vitro aerosol performance demonstrated excellent aerosol dispersion with different DPI devices. The phospholipid bilayer biophysical properties were confirmed and retained following cospray drying. Sustained release of fasudil drug and in vitro biocompatibility were demonstrated on human lung cells from different airway regions.

Inhalable Dry Powders for Lung mRNA Delivery.

Despite great promise, application of mRNA therapeutics in the lung has proven challenging. Many groups have reported success instilling liquid mRNA formulations in animal models, but direct intratracheal administration of large liquid quantities to the human lung presents significant safety and distribution concerns. To accomplish safe and effective mRNA delivery to the lung, formulations must be prepared for dosing via inhalation. An inhaled mRNA delivery system for the lung must be both robust enough to survive inhalation conditions and potent enough to deliver mRNA upon reaching the lung. In this work dry powder lipid nanoparticle formulations are developed, using spray-freeze-drying, to produce stable, biologically active, inhalable dry powders for mRNA delivery. The final powders have suitable aerosolization properties, with mean mass aerodynamic diameter (MMAD) of 3-4 microns, and fine particle fraction (FPF) ≈40%, allowing for efficient mRNA delivery to the deep lung following inhalation. Importantly, the formulations developed here are suitable for use with different ionizable lipids. Four different ionizable lipid-based formulations are evaluated as powders, and all exhibit in vivo pulmonary mRNA delivery equal to that of instilled liquid formulations. These results lay promising groundwork for the eventual development of an inhalable mRNA dry powder therapeutic.

Therapeutic Efficacy of Nanocarrier‐Mediated Inhalable Gene Transfection for Lung Cancer

AbstractLung cancer is now the leading cause of cancer‐related mortality, eclipsing all other cancer forms, and of all lung malignancies, non‐small cell lung cancer (NSCLC) makes up around 85%. Recently, the use of vectors in gene therapy besides chemotherapy to treat malignancies brought on by gene mutations has gained prominence. Therapeutic molecule inhalation is a direct approach to lung‐targeted medication delivery with low nonspecific toxicity and limited drug exposure. Treatment for lung cancer with chemotherapy and immunotherapy can be aided by inhalable nanomedicine through advanced mechanisms. Viral and nonviral vectors, such as lipid‐based nanoparticles, polymeric nanoparticles, and inorganic nanoparticles, have all drawn a lot of interest for their ability to increase effects and decrease side effects. Nanocarriers have a significant impact on targeted gene delivery, bioavailability, stability, and residence in target areas. The inhaled pulmonary gene delivery approach, when combined with nanomedicine, will offer a noninvasive and successful way to treat lung cancer by taking use of the physiological properties of the lung. The authors have majorly used data from PubMed and Google Scholar to obtain the relevant information required for the article. In general, this review concentrates on the usage of various inhalable nanocarriers, which might serve as an inspiration for the creation and deployment of more potent genetic therapy for the treatment of lung cancer.

Design and development of DSPE-PEG2000/DPPC disk-like micelles for targeted delivery of icariin phytochemical in pulmonary fibrosis

Icariin (ICA)-loaded DSPE-PEG2000/DPPC disk-like micelles were synthesized utilizing the thin film hydration method to enhance the solubility and delivery of ICA to the lungs. The micellar formulation significantly improved the water solubility of ICA. This was attributed to the high encapsulation efficiency (95 %) and drug loading capacity (12 %) of the DSPE-PEG2000/DPPC micelles. Comprehensive characterization using Fourier-transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). Particle size analysis through dynamic light scattering (DLS) and transmission electron microscopy (TEM) demonstrated the formation of stable micelles with an average particle size around 10 nm.In vitro aerosolization studies using the next-generation impactor (NGI) revealed that the fine particle fraction was 63.5 ± 4 %, which means that over 60 % of the aerosolized ICA/DSPE-PEG2000/DPPC micelles were capable of reaching and targeting the deep lung alveoli, indicating their potential efficacy for pulmonary delivery. Cytotoxicity assessments via the MTT assay showed IC50 values of ICA-loaded DSPE-PEG2000/DPPC micelles were 117 ± 8 μg/mL, 29 ± 3 μg/mL, and 21 ± 1 μg/mL at 24, 48, and 72 h, respectively, highlighting the time-dependent cytotoxic effects of the ICA-loaded micelles on A549 cells. However, the IC50 values of free ICA were > 500 μg/mL, 252 ± 3 μg/mL, and 109 ± 2 μg/mL, respectively at three different time points. That indicated that ICA-loaded nano micelles enhanced the cytotoxicity of ICA. Furthermore, the cellular uptake of the nano micelles by A549 cells was visualized and confirmed using EVOS fluorescence imaging and flow cytometry techniques. In addition, RAW 264.7 M2 polarization studies indicated ICA loaded DSPE-PEG2000/DPPC micelles have potential for treating pulmonary fibrosis.These findings suggest that DSPE-PEG2000/DPPC micelles significantly enhance the solubility and delivery of ICA, presenting a promising nanocarrier system for targeted pulmonary fibrosis therapy.