Inhaled Drug Delivery Research Articles

Inhalation of sustained release microparticles for the targeted treatment of respiratory diseases.

Delivering drugs through inhalation for systemic and local applications has been in practice since several decades to treat various diseases. In recent times, inhalation drug delivery is becoming one of the highly focused areas of research in the pharmaceutical industry. It is being considered as one of the major portals for delivering drugs because of its wide range of advantages like requirement of low concentrations of drug to reach therapeutic efficacy, surpassing first pass metabolism and a very low incidence of side effects as compared to conventional delivery of drugs. Owing to these favorable characteristics of pulmonary drug delivery, diverse pharmaceutical formulations like liposomes, nanoparticles, and microparticles are developed through consistent efforts for delivery drugs to lungs in suitable form. However, drug-loaded microparticles have displayed various advantages over the other pharmaceutical dosage forms which give a cutting edge over other inhalational drug delivery systems. Assuring results with respect to sustained release through inhalational delivery of drug-loaded microparticles from pre-clinical studies are anticipative of similar benefits in the clinical settings. This review centralizes partly on the advantages of inhalational microparticles over other inhalational dosage forms and largely on the therapeutic applications and future perspectives of inhalable microparticle drug delivery systems.

Development of new in vitro models of lung protease activity for investigating stability of inhaled biological therapies and drug delivery systems

Proteases play a vital role in lung health and are critically important to the metabolic clearance of inhaled protein-based therapeutics after inhalation. Surprisingly little is known about lung fluid protease composition and there is a consequent lack of biorelevant experimental models, which limits research and development in the burgeoning field of inhaled biologics. The aim of this study was to quantify proteases in human lung fluid and to use this data to design novel in vitro experimental models of lung lining fluid possessing biorelevant lung protease activity for use in biopharmaceutical stability studies. As a proof of concept, these novel models were used to investigate the effect of proteolytic activity on the stability of albumin nanoparticles, a biologic nanoparticle formulation widely investigated as a pulmonary drug delivery system. Bronchoalveolar lavage fluid was collected from healthy human volunteers and proteomic analysis was used to quantify the predominant proteases. Based on these data, four new lung protease models were constructed based on: (i) trypsin as a sole protease, (ii) dipeptidyl peptidase IV, cathepsin D, cathepsin H, and angiotensin converting enzyme in ratio and concentration to mimic the protease concentration in healthy lungs. Neutrophil elastase was used to model protease activity in inflammation. Albumin nanoparticles of 100 nm diameter remained intact over 48 h in phosphate buffered saline, but were degraded more rapidly in trypsin (50% reduction in 10 min) compared to the healthy lung protease model (50% reduction in 150 min). The addition of neutrophil elastase to the healthy lung protease model resulted in a similar, but more variable degradation profile. Nanoparticle degradation was associated with concomitant appearance of small fragments and aggregates. In conclusion, we have characterised the protease concentration in the lungs of healthy humans, designed models of lung protease activity and demonstrated their utility in studying albumin nanoparticle degradation. These methods and models have wide application to study the influence of proteases in lung disease, expression of proteases in respiratory cell culture models, stability of peptide and protein-based drugs and inhaled drug delivery systems.

Inhalation therapy in children: new opportunities

Inhalation therapy is widely used for treatment of acute respiratory infections and asthma in children, and provides more rapid drug delivery in the airways. Treatment success in children with respiratory diseases is defined not only by an adequate choice of the drug and the dosage regimen, but also by inhalation drug delivery system. The choice of drug delivery device in children depends on the child's age and ability to carry out instructions related to the inhalation technique. Incorrect inhalation technique is associated with inappropriate distribution of the drug in the respiratory tract and an unreasonable increase in the volume of therapy, risk of adverse effects, and the total cost of the treatment. Currently, a great number of various drug delivery systems are commercially available, such as a pressurised metered dose inhaler (MDI), a MDI with spacer and facemask, a dry powder inhaler, and a nebulizer. The most optimal inhalation drug delivery device for children is a nebulizer. In this article, the authors discussed benefits and limitations of various drug delivery systems and modern nebulizers used for treatment of the upper and the lower airways including DuoBaby nebulizer 2-in-1 with a nasal aspirator.

Clinical, instrumental and pharmacological comparisons of patients with chronic obstructive pulmonary disease (COPD) and asthma in real clinical practice

The objective of this study was to compare demographic, clinical, functional, laboratory data, and therapy in patients with chronic obstructive pulmonary disease (COPD) and asthma who seek for medical aid at medical institutions of Kazan’. Methods. The study involved 153 patients with COPD aged 33 to 89 years and 229 patients with asthma aged 18 to 87 years. Clinical status, rate of exacerbations, spirometric data, treatment and compliance during the previous year were analyzed. Statistical analysis was performed using the SPSS-18 software. Results. COPD patients were older (64.1 ± 0,7 vs 55.4 ± 0,9 years in asthma patients; p < 0,01), more often were males (98.7% vs 1.3%, p < 0.001) and smokers. Coronary heart disease (39.0% vs 25.3%; p < 0.010) and chronic heart failure (35.7% vs 17.5%; p < 0.001) were more common in patients with COPD, while rhinitis (42.4 % vs 3.9%; p < 0.001) and chronic kidney disease (13.1% vs 4.5%; p < 0.001) were more common in asthma patients. Allergic disease was 5-fold more often in asthma patients. Morning symptoms affected daily activity in 77.3% of COPD patients compared to 66.8% of asthma patients (p < 0.05). Generally, daytime activity was impaired in 55.2% of patients with COPD and in 12.7% of patients with asthma (p < 0.05). Excessive use of short-acting bronchodilators was noted at nighttime in 89.6% with COPD and 70.7% with asthma (p < 0.001). Other treatment was in line with guidelines for each the disease. The most convenient inhalational drug delivery device for COPD patients was a metered dosed inhaler, while patients with asthma preferred dry powder inhalers. Compliance of asthma patients was significantly higher than that of COPD patients (57.2% vs 27.8%; p < 0.001). The level of compliance did not change while fixed and free combinations of ICS and LABA or different inhalational devices were used in patients with COPD or asthma. Conclusion. There is a number of clinical signs to distinguish COPD and asthma quite easily in primary care facilities. Excessive use of short-acting bronchodilators and a low compliance of patients are issues requiring to be improved.

Inhalable nanotherapeutics to improve treatment efficacy for common lung diseases.

Respiratory illnesses are prevalent around the world, and inhalation-based therapies provide an attractive, noninvasive means of directly delivering therapeutic agents to their site of action to improve treatment efficacy and limit adverse systemic side effects. Recent trends in medicine and nanoscience have prompted the development of inhalable nanomedicines to further enhance effectiveness, patient compliance, and quality of life for people suffering from lung cancer, chronic pulmonary diseases, and tuberculosis. Herein, we discuss recent advancements in the development of inhalable nanomaterial-based drug delivery systems and analyze several representative systems to illustrate their key design principles that can translate to improved therapeutic efficacy for prevalent respiratory diseases. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease.

Age-Dependent Translocation of Gold Nanoparticles across the Air-Blood Barrier.

Do immature lungs have air-blood barriers that are more permeable to inhaled nanoparticles than those of fully developed mature lungs? Data supporting this notion and explaining the underlying mechanisms do not exist as far as we know. Using a rat model of postnatal lung development, here the data exactly supporting this notion, that is, significantly more gold nanoparticles (NPs) cross from the air space of the lungs to the rest of the body in neonates than in adults, are presented. Moreover, in neonates the translocation of gold NPs is not size dependent, whereas in adult animals smaller NPs cross the air-blood lung barrier much more efficiently than larger NPs. This difference in air-blood permeability in neonate versus adult animals suggests that NP translocation in the immature lungs may follow different rules than in mature lungs. Supporting this notion, we propose that the paracellular transport route may play a more significant role in NP translocation in immature animals, as suggested by protein expression studies. Findings from this study are critical to design optimal ways of inhalation drug delivery using NP nanocarriers for this age group, as well as for better understanding of the potential adverse health effects of nanoparticle exposures in infants and young children.

Pulmonary and Regional Deposition of Nebulized and Dry Powder Aerosols in Ferrets.

The utilization of ferrets as a non-clinical model for disease is rapidly increasing within drug development. Many of these models include respiratory diseases that involve targeted drug delivery via nose-only inhalation. While the deposition patterns within other non-clinical models (mice, rats, canines, and non-human primates) have been well studied, the local and regional deposition of aerosols in ferrets has not been well characterized. Therefore, inhalation aerosols were developed, radiolabeled and the radiolabeling methods validated to support SPECT-CT imaging and quantification of regional deposition within ferrets. The studies were conducted with one liquid formulation and one dry powder formulation (two concentrations of dry powder). Additionally, both aerosols were polydisperse and therefore reflect the majority of pharmaceutical aerosols. Overall, the studies showed lung deposition fractions between 5 and 10% with median aerodynamic particle sizes of 2.5 and 2.8μm. The lung deposition fraction of the liquid aerosol was ~ 9%, nearly double observed in rats with a similarly sized aerosol. Analysis of respiratory tract (oropharynx, laryngopharynx, trachea, bifurcation area, and lung) deposition indicates increased deposition of the liquid aerosol compared to the dry powder aerosol, however, when this analysis was refined to the pulmonary region (trachea, bifurcation, and lung) the deposition was similar between formulations. These data provide the first description of the regional deposition of inhalation aerosols in ferrets with standard nose-only inhalation procedures. These data can be used for calculations of both total and regional doses within ferret inhalation drug delivery.

Decision Science for Generic Drug Development and Review.

Decision Science for Generic Drug Development and Review.

Inhaled Biologicals for the Treatment of Cystic Fibrosis.

Background: Cystic Fibrosis (CF), one of the most frequent genetic diseases, is characterized by the production of viscous mucus in several organs. In the lungs, mucus clogs the airways and traps bacteria, leading to recurrent/resistant infections and lung damage. For cystic fibrosis patients, respiratory failure is still lethal in early adulthood since available treatments display incomplete efficacy.Objective: The objective of this review is to extend the current knowledge in the field of available treat-ments for cystic fibrosis. A special focus has been given to inhaled peptide-based drugs.Methods: The current review is based on recent and/or relevant literature and patents already available in various scientific databases, which include PubMed, PubMed Central, Patentscope and Science Direct. The information obtained through these diverse databases is compiled, critically interpreted and presented in the current study. An in-depth but not systematic approach to the specific research question has been adopted.Results: Recently, peptides have been proposed as possible pharmacologic agents for the treatment of respiratory diseases. Of note, peptides are suitable to be administered by inhalation to maximize efficacy and reduce systemic side effects. Moreover, innovative delivery carriers have been developed for drug administration through inhalation, allowing not only protection against proteolysis, but also a prolonged and controlled release.Conclusion: Here, we summarize newly patented peptides that have been developed in the last few years and advanced technologies for inhaled drug delivery to treat cystic fibrosis.

INSPIRE: A Phase 3 Open-Label, Multicenter Study to Evaluate the Safety and Tolerability of LIQ861 in Pulmonary Arterial Hypertension (PAH) (Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil NCT03399604)

Summary of Objectives Inhalational drug delivery to treat PAH is attractive due to enhanced pulmonary specificity and reduced systemic adverse effects. LIQ861 is a dry powder formulation of Treprostinil (TRE) designed to enhance deep-lung delivery and achieve higher tolerated dose levels than current inhaled therapies. LIQ861’s uniform (1µm) particle size with a trefoil, pollen-like shape, enables QID delivery of TRE doses in a convenient, palm-sized, disposable dry powder inhaler (DPI). The primary objective of the INSPIRE study is the safety and tolerability of LIQ861 in subjects transitioning from stable doses of Tyvaso® or as combination therapy with ≤2 approved non-prostacyclin (PGI) oral PAH drugs. The secondary objective is to evaluate the comparative bioavailability (BA) of TRE between LIQ861 and Tyvaso®. Methods Target enrollment is 100 Functional Class (FC) II/III subjects with 18 subjects on Tyvaso® included in a BA sub-study comparing TRE exposure in a one-directional crossover. PGI-naive subjects stable on ≤2 approved, non-PGI oral PAH therapies received LIQ861 at an initial dose of 25mcg QID, increasing in 25mcg increments weekly to tolerance and symptom relief. Subjects transitioning from Tyvaso® received LIQ861 at an initial dose comparable to their Tyvaso® dose, with titration in 25mcg QID increments to tolerance and symptom relief. Endpoints The primary endpoint is the incidence of treatment-emergent Adverse Events and Serious Adverse Events. Safety endpoints: • Changes from Baseline to Month 2 or Early Termination in clinical laboratory, physical exam findings, and vital signs. • Proportion of patients maintaining a stable clinical status from transition through Month 2. Stable clinical status defined as: 1) LIQ861 treatment through at least 2 months beyond transition from Tyvaso® and six-minute walk distance (6MWD) decrease no more than 10%, 2) no interruptions to treatment totaling more than 7 days prior to the end of Month 2, and 3) no treatment with any other PGI analogs or P`GI receptor agonists. Secondary endpoints: NYHA FC, N-terminal B-type natriuretic peptide and Quality of Life will be reported when available. Analysis for the Primary Endpoint and BA sub-study is expected to be completed in 2019.

A Design of Experiment (DoE) approach to optimise spray drying process conditions for the production of trehalose/leucine formulations with application in pulmonary delivery

The present study evaluates the effect of L-leucine concentration and operating parameters of a laboratory spray dryer on characteristics of trehalose dry powders, with the goal of optimizing production of these powders for inhaled drug delivery. Trehalose/L-leucine mixtures were spray dried from aqueous solution using a laboratory spray dryer. A factorial design of experiment (DoE) was undertaken and process parameters adjusted were: inlet temperature, gas flow rate, feed solution flow rate (pump setting), aspiration setting and L-leucine concentration. Resulting powders were characterised in terms of particle size, yield, residual moisture content, and glass transition temperature. Particle size was mainly influenced by gas flow rate, whereas product yield and residual moisture content were found to be primarily affected by inlet temperature and spray solution feed rate respectively. Interactions between a number of different process parameters were elucidated, as were relationships between different responses. The leucine mass ratio influenced the physical stability of powders against environmental humidity, and a high leucine concentration (30% w/w) protected amorphous trehalose from moisture induced crystallization. High weight ratio of leucine in the formulation, however, negatively impacted the aerosol performance. Thus, in terms of L-leucine inclusion in a formulation designed for pulmonary delivery, a balance needs to be found between physical stability and deposition characteristics.

Nanoengineering of Crystal and Amorphous Surfaces of Pharmaceutical Particles for Biomedical Applications.

The morphology, size, and surface properties of pharmaceutical particles form an essential role in the therapeutic performance of active pharmaceutical ingredients (APIs) and excipients as constituents in various drug delivery systems and clinical applications. Recent advances in methods for surface modification, however, rely heavily on liquid-phase-based modification processes and afford limited control over the thickness and conformality of the coating. Atomic layer deposition (ALD), on the other hand, enables the formation of conformal nanoscale films on complex structures with thickness control on the molecular level, while maintaining the substrate particle size and morphology. Moreover, this enables nanoengineering of surfaces of pharmaceutical particles also in the dry state. Successful nanoengineeering of crystal and amorphous surfaces of pharmaceutical particles is demonstrated in this study whereby functional properties, such as dissolution and dispersibility, were tailored for drug delivery applications. This expands on our initial work on ALD of alumina on pharmaceutical particles within the lower micro- to higher nanosize ranges to here probe both crystalline and amorphous lactose substrate surfaces (d50 = 3.5 and 21 μm). In addition, both water and ozone coreactants were evaluated, the latter having not been evaluated previously for pharmaceutical particles. The deposition process is carried out at ambient conditions in a fluidized bed reactor for a low number of cycles (i.e., from 4 to 14). Improved dissolution and extended release were achieved by the ALD nanoengineering of both crystalline and amorphous surfaces. This novel concept opens up exciting opportunities to produce more complex materials and structures using temperature- and moisture-sensitive drugs, e.g., targeting and drug delivery opportunities, as well as delivering new functionalities for novel applications in the pharmaceutical, medical, biological, and advanced materials fields. The prospects for advancing inhaled drug delivery are exemplified by the ALD surface nanoengineering concept.

Inhaled Micro/Nanoparticulate Anticancer Drug Formulations: An Emerging Targeted Drug Delivery Strategy for Lung Cancers.

Local delivery of drug to the target organ via inhalation offers enormous benefits in the management of many diseases. Lung cancer is the most common of all cancers and it is the leading cause of death worldwide. Currently available treatment systems (intravenous or oral drug delivery) are not efficient in accumulating the delivered drug into the target tumor cells and are usually associated with various systemic and dose-related adverse effects. The pulmonary drug delivery technology would enable preferential accumulation of drug within the cancer cell and thus be superior to intravenous and oral delivery in reducing cancer cell proliferation and minimising the systemic adverse effects. Site-specific drug delivery via inhalation for the treatment of lung cancer is both feasible and efficient. The inhaled drug delivery system is non-invasive, produces high bioavailability at a low dose and avoids first pass metabolism of the delivered drug. Various anticancer drugs including chemotherapeutics, proteins and genes have been investigated for inhalation in lung cancers with significant outcomes. Pulmonary delivery of drugs from dry powder inhaler (DPI) formulation is stable and has high patient compliance. Herein, we report the potential of pulmonary drug delivery from dry powder inhaler (DPI) formulations inhibiting lung cancer cell proliferation at very low dose with reduced unwanted adverse effects.

Inhalational Drug Delivery in Pulmonary Aspergillosis.

Pulmonary infections have long represented one of the major threats to humans. These vary from acute to chronic conditions, depending upon the underlying disease of the airways. Pulmonary aspergillosis (PMAP) has raised vital concerns in the immunocompromised patients. The fungal infection is difficult to diagnose in the early stages, often making the disease more complicated. Currently, three classes of antifungal agents are available on the market for the treatment of pulmonary infections. These agents are available in oral and intravenous forms only, which limits the availability of therapeutic concentrations of drug in the lungs for longer durations. Consequently, this leads to therapeutic failure and/or resistance of the organism(s) towards the antifungal agents because the optimum amount of drug does not reach the infection site. To combat the issues associated with the conventional regimens, inhalation of antifungal agents is gaining importance because administration to the lungs offers huge advantages of localized and targeted delivery. A wide range of inhalational devices such as nebulizers, dry powder inhalers, and metered dose inhalers are available on the market to deliver drug molecules to the lungs effectively. However, their clinical utility is limited to conditions such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis only. For a few decades, inhalation therapy has also been gaining importance to treat infectious diseases such as tuberculosis and aspergillosis, though more research efforts are required to make the transition from bench to bedside. The current review provides an explicit account of the potential role of inhalation drug delivery in PMAP.

Numerical Studies of Nanoparticle Transport and Deposition in Terminal Alveolar Models with Varying Complexities

Background: The integration of inhalation drug delivery and nanotechnology offers exciting potentials to enhance the targeting, release, diagnostic, and therapeutic outcomes of drugs. Human lungs provide many advantages over other routers such as noninvasive delivery, a large surface area for absorption, avoiding the first-pass metabolism, and quick therapeutic onset. It is crucial to understand nanoparticle dosimetry in the acinar region to reliably evaluate the therapeutic outcomes of nanomedicines. However, an acinus unit comprises up to 10,000 alveoli and to model a complete acinus is still a prohibitive task. Besides, the presence of inter-alveolar septa creates a labyrinth pathway for inhaled airflow and particles. Methods: The objective of this study is to numerically investigate nanoparticle deposition in three alveolar models with varying physical complexities, which retain 1, 4, and 45 alveoli, respectively. A discrete-phase Lagrangian model was implemented to track nanoparticle trajectories under the influence of rhythmic wall expansion and contraction. Both temporal and spatial dosimetry in the alveoli were computed. Results: Strikingly different behaviors were observed in the dynamic alveolar model between micron particles and nanoparticles. Minimal deposition rates were predicted for 500–600 nm particles for all the three models considered. Consistently lower deposition rates were found in the 45-alveoli model than the other two simplified models for all particles ranging from 1 nm to 1000 nm. Considering the gravitational orientation effect, nanoparticles smaller than 200 nm appears insensitive to the alveolar orientation and only becomes perceivable around 500 nm. For nanoparticles larger than 500 nm, lower doses were predicted in the horizontal alveoli than in the vertical alveoli, regardless of the model complexity. Conclusions: The magnitude of the airflow velocity (depending on ventilated volume) is an essential factor in determining the deposition of inhaled nanoparticles. Future correlation development for acinar deposition should consider the velocity distribution in different regions of the acinus.

Evaluation of Appropriateness of Inhaled Drug Delivery Systems in COPD Patients

Evaluation of Appropriateness of Inhaled Drug Delivery Systems in COPD Patients

Crystal Engineering: Upcoming Paradigm for Efficacious Pulmonary Drug Delivery.

Pulmonary drug delivery has transformed over a past few decades from being a platform for local pulmonary disease treatment to systemic drug delivery opportunities. In case of pulmonary delivery systems, particle properties are critical as they affect inhalation efficacy, pulmonary deposition, drug delivery and overall performance. With this in view, particle engineering has emerged as an advanced science that helps in designing of efficacious pulmonary delivery systems. Among various particle engineering branches, crystal engineering is being extensively explored as it provides an opportunity to optimize particles at morphological, physicochemical and molecular levels which are essential to understand the role of crystal engineering in pulmonary drug delivery. A thorough literature survey in the field of crystal engineering approaches explored for pulmonary drug delivery was conducted and the collected data was meticulously studied and summarized. In the review, pulmonary system is discussed with respect to various sites for drug deposition in respiratory tract, mechanism of drug deposition and clearance. Further, critical crystal parameters are discussed in-depth and various crystal engineering methods are summarized with emphasis on their impact on pulmonary delivery. Also, inhalation devices are overviewed to understand their performance in relation to crystal based pulmonary formulations. The review enabled a detailed insight on crystal engineering approaches for design of pulmonary delivery systems.

Quantitative Gd-DOTA-based aerosol deposition mapping in the lungs of asthmatic rats using 3D UTE-MRI.

Asthma is a chronic respiratory disease, commonly treated with inhaled therapy. Better understanding of the mechanisms of aerosol deposition is required to improve inhaled drug delivery. Three-dimensional ultrashort echo time (UTE) MRI acquisitions at 1.5T were combined with spontaneous nose-only inhalation of aerosolized gadolinium (Gd) to map the aerosol deposition and to characterize signal enhancement in asthmatic rat lungs. The rats were sensitized to ovalbumin (OVA) to develop asthmatic models and challenged before imaging by nebulization of OVA to trigger asthmatic symptoms. The negative controls were not sensitized or challenged by nebulization of saline. The animal lungs were imaged before and after administration of Gd-based aerosol in freely breathing rats, by using a T1 -weighted 3D UTE sequence. A contrast-enhanced quantitative analysis was performed to assess regional concentration. OVA-sensitized rats had lower signal enhancement and lower deposited aerosol concentration. Their enhancement dynamics showed large inter-subject variability. The signal intensity was homogeneously enhanced for controls while OVA-sensitized rats showed heterogeneous enhancement. Contrast-enhanced 3D UTE was applied with aerosolized Gd to efficiently measure spatially resolved deposition in asthmatic lungs. The small administered dose (around 1μmol/kg body weight) and the use of standard clinical MRI suggest a potential application for the exploration of asthma.

Matrix metalloproteinase 2/9-triggered-release micelles for inhaled drug delivery to treat lung cancer: preparation and in vitro/in vivo studies.

BackgroundImprovement in drug accumulation in the lungs through inhalation administration and high expression of MMP2 and MMP9 in lung tumors have both been widely reported.MethodsMMP2/9-triggered-release micelles were constructed and in vitro and in vivo studies of inhalation administration against lung tumor carried out. Pluronic P123 (P123) was modified with GPLGIAGQ-NH2 (GQ8) peptide to obtain P123-GQ8 (PG). MMP2/9-triggered-release micelles were constructed using PG and succinylated gelatin (SG) and loading paclitaxel (Ptx). To study biodistribution of micelles, DiR encapsulated in micelles was dosed to rats via intravenous injection or inhalation before ex vivo imaging for detecting DiR quantity in lungs. And B16F10 lung cancer-bearing nude mice were chosen as animal models to evaluate in vivo efficacy of MMP2/9-triggered-release micelles.ResultsPtx-release efficiency from PG-SG-Ptx micelles was MMP2/9-concentration-dependent. For A549 cells, PG-SG-Ptx cytotoxicity was significantly greater (P<0.001) compared to P123-Ptx. Aerosol inhalation was chosen as the method of administration. In biodistribution experiment, DiR quantity in lungs was 5.8%±0.4% of that in major organs, while the ratio was 38.8%±0.5% for inhalation. For B16F10 lung cancer-bearing nude mice, the efficacy of inhalation of PG-SG-Ptx was significantly higher (P<0.001) than Taxol inhalation and injected PG-SG-Ptx. Inhaled PG-SG-Ptx also significantly inhibited the expression of Pgp in lung cancer.ConclusionInhalation of MMP2/9-triggered-release micelles increased tumor sensitivity to chemotherapeutics and reduced the toxicity of chemotherapy to healthy lung cells, which has great potential in lung cancer therapy.

Doxorubicin Conjugation and Drug Linker Chemistry Alter the Intravenous and Pulmonary Pharmacokinetics of a PEGylated Generation 4 Polylysine Dendrimer in Rats

PEGylated polylysine dendrimers have demonstrated potential as inhalable drug delivery systems that can improve the treatment of lung cancers. Their treatment potential may be enhanced by developing constructs that display prolonged lung retention, together with good systemic absorption, the capacity to passively target lung tumors from the blood and highly selective, yet rapid liberation in the tumor microenvironment. This study sought to characterize how the nature of cathepsin B–cleavable peptide linkers, used to conjugate doxorubicin (Dox) to a PEGylated (PEG570) G4 polylysine dendrimer, affects drug liberation kinetics and intravenous and pulmonary pharmacokinetics in rats. The construct bearing a self-emolative diglycolic acid-V-Citrulline linker exhibited faster Dox release kinetics compared to constructs bearing self-emolative diglycolic acid-glycine-leucine-phenylalanine-glycine (GLFG), or non-self-emolative glutaric acid-GLFG linkers. The V-Citrulline construct exhibited slower plasma clearance, but faster absorption from the lungs than a GLFG construct, although mucociliary clearance and urinary elimination were unchanged. Dox-conjugation enhanced localization in the bronchoalveolar lavage fluid compared to lung tissue, suggesting that projection of Dox from the dendrimer surface reduced tissue uptake. These data show that the linker chemistry employed to conjugate drugs to PEGylated carriers can affect drug release profiles and systemic and lung disposition.