Review of inhalable nanoparticles for the pulmonary delivery of anti-tuberculosis drugs.

Tuberculosis is an airborne disease caused by the pathogen, Mycobacterium tuberculosis, which predominantly affects the lungs. World Health Organization (WHO) has reported that about 85% of TB patients are cured with the existing 6-month antibiotic regimen. However, the lengthy oral administration of high-dose anti-TB drugs is associated with significant side effects and leads to drug resistance cases. Alternatively, reformulating existing anti-tubercular drugs into inhalable nanoparticulate systems is a promising strategy to overcome the challenges associated with oral treatment as they could enhance drug retention in the pulmonary region to achieve an optimal drug concentration in the infected lungs. Hence, this review provides an overview of the literature on inhalable nano-formulations for the delivery of anti-TB drugs, including their formulation techniques and preclinical evaluations between the years 2000 and 2020, gathered from electronic journals via online search engines such as Google Scholar and PubMed. Previous in vitro and in vivo studies highlighted that the nano-size, low toxicity, and high efficacy were among the factors influencing the fate of nanoparticulate system upon deposition in the lungs. Although many preclinical studies have shown that inhalable nanoparticles increased therapeutic efficacy and minimised adverse drug reactions when delivered through the pulmonary route, none of them has progressed into clinical trials to date. This could be attributed to the high cost of inhaled regimes due to the expensive production and characterisation of the nanoparticles as well as the need for an inhalation device as compared to the oral treatment. Another barrier could be the lack of medical acceptance due to insufficient number of trained staff to educate the patients on the correct usage of the inhalation device. Hence, these barriers should be addressed satisfactorily to make the inhaled nanoparticles regimen a reality for the treatment of TB.

Bioactive Metabolites of Lactiplantibacillus plantarum K014 Against Methicillin-Resistant Staphylococcus aureus ATCC43300 and In Vitro Evaluation of Its Antibacterial, Antioxidant and Anti-inflammatory Activities.

This study aims to evaluate the effects of bioactive metabolites produced by lactic acid bacteria against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. A total of six lactic acid bacteria (LAB) were selected to evaluate the antimicrobial activity against MRSA ATCC 43300, a skin pathogen that is highly resistant to most antibiotics. The K014 isolate from a fermented vegetable recorded the highest inhibition against MRSA ATCC 43300 at 91.93 ± 0.36%. 16S rRNA sequencing revealed the K014 isolate is closely related to L. plantarum and the sequence was subsequently deposited in the GenBank database with an accession number of MW180960, named as Lactiplantibacillus plantarum K014. The cell-free supernatant (CFS) of L. plantarum K014 had tolerance to high temperature as well as acidic pH. The bioactive metabolites, such as hydrogen peroxide, lactic acid and hyaluronic acid, were produced by L. plantarum K014. Result from ABTS assay showed higher antioxidant activity (46.28%) as compared to that obtained by DPPH assay (2.97%). The CFS had showed anti-inflammatory activity for lipoxygenase (LOX) assay at 43.66%. The bioactive metabolites of L. plantarum K014 showed very promising potential to be used topical skin pathogens.

Andrographis paniculata Dosage Forms and Advances in Nanoparticulate Delivery Systems: An Overview.

Andrographis paniculata is a well-known Asian medicinal plant with a major phytoconstituent of diterpene lactones, such as andrographolide, 14-deoxyandrographolide, and neoandrographolide. A World Health Organization (WHO) monograph on selected medicinal plants showed that A. paniculata extracts and its major diterpene lactones have promising anti-inflammatory, antidiabetic, antimalarial, anticancer, antifungal, antibacterial, antioxidant, and hypoglycemic activities. However, these active phytochemicals have poor water solubility and bioavailability when delivered in a conventional dosage form. These biological barriers can be mitigated if the extract or isolated compound are delivered as nanoparticles. This review discusses existing studies and marketed products of A. paniculata in solid, liquid, semi-solid, and gaseous dosage forms, either as an extract or isolated pure compounds, as well as their deficits in reaching maximum bioavailability. The pharmaceutics and pharmacological activity of A. paniculata as a nano-delivery system are also discussed.

Synthesis, Characterization and Biological Evaluation of New 3,5-Disubstituted-Pyrazoline Derivatives as Potential Anti-Mycobacterium tuberculosis H37Ra Compounds.

A total of fourteen pyrazoline derivatives were synthesized through cyclo-condensation reactions by chalcone derivatives with different types of semicarbazide. These compounds were characterized by IR, 1D-NMR (1H, 13C and Distortionless Enhancement by Polarization Transfer - DEPT-135) and 2D-NMR (COSY, HSQC and HMBC) as well as mass spectroscopy analysis (HRMS). The synthesized compounds were tested for their antituberculosis activity against Mycobacterium tuberculosis H37Ra in vitro. Based on this activity, compound 4a showed the most potent inhibitory activity, with a minimum inhibitory concentration (MIC) value of 17 µM. In addition, six other synthesized compounds, 5a and 5c-5g, exhibited moderate activity, with MIC ranges between 60 µM to 140 µM. Compound 4a showed good bactericidal activity with a minimum bactericidal concentration (MBC) value of 34 µM against Mycobacterium tuberculosis H37Ra. Molecular docking studies for compound 4a on alpha-sterol demethylase was done to understand and explore ligand-receptor interactions, and to hypothesize potential refinements for the compound.

Antituberculosis activity, phytochemical identification of Costus speciosus (J. Koenig) Sm., Cymbopogon citratus (DC. Ex Nees) Stapf., and Tabernaemontana coronaria (L.) Willd. and their effects on the growth kinetics and cellular integrity of Mycobacterium tuberculosis H37Rv.

BACKGROUND: Costus speciosus, Cymbopogon citratus, and Tabernaemontana coronaria are herbal plants traditionally used as remedies for symptoms of tuberculosis (TB) including cough. The aims of the present study were to evaluate the in vitro anti-TB activity of different solvent partitions of these plants, to identify the phytochemical compounds, and to assess the effects of the most active partitions on the growth kinetics and cellular integrity of the tubercle organism. METHODS: The in vitro anti-TB activity of different solvent partitions of the plant materials was determined against M. tuberculosis H37Rv using a tetrazolium colorimetric microdilution assay. The phytochemical compounds in the most active partition of each plant were identified using gas chromatography-mass spectrometry (GC-MS) analysis. The effects of these partitions on the growth kinetics of the mycobacteria were evaluated over 7-day treatment period in a batch culture system. Their effects on the mycobacterial cellular integrity were observed under a scanning electron microscope (SEM). RESULTS: The respective n-hexane partition of C. speciosus, C. citratus, and T. coronaria exhibited the highest anti-TB activity with minimum inhibitory concentrations (MICs) of 100-200 µg/mL and minimum bactericidal concentration (MBC) of 200 µg/mL. GC-MS phytochemical analysis of these active partitions revealed that majority of the identified compounds belonged to lipophilic fatty acid groups. The active partitions of C. speciosus and T. coronaria exhibited high cidal activity in relation to time, killing more than 99% of the cell population. SEM observations showed that these active plant partitions caused multiple structural changes indicating massive cellular damages. CONCLUSIONS: The n-hexane partition of the plant materials exhibited promising in vitro anti-TB activity against M. tuberculosis H37Rv. Their anti-TB activity was supported by their destructive effects on the integrity of the mycobacterial cellular structure.

Inhalation of Respirable Crystalline Rifapentine Particles Induces Pulmonary Inflammation.

Rifapentine is an anti-tuberculosis (anti-TB) drug with a prolonged half-life, but oral delivery results in low concentrations in the lungs because of its high binding (98%) to plasma proteins. We have shown that inhalation of crystalline rifapentine overcomes the limitations of oral delivery by significantly enhancing and prolonging the drug concentration in the lungs. The delivery of crystalline particles to the lungs may promote inflammation. This in vivo study characterizes the inflammatory response caused by pulmonary deposition of the rifapentine particles. The rifapentine powder was delivered to BALB/c mice by intratracheal insufflation at a dose of 20 mg/kg. The inflammatory response in the lungs and bronchoalveolar lavage (BAL) was examined at 12 h, 24 h, and 7 days post-treatment by flow cytometry and histopathology. At 12 and 24 h post-treatment, there was a significant influx of neutrophils into the lungs, and this returned to normal by day 7. A significant recruitment of macrophages occurred in the BAL at 24 h. Consistent with these findings, histopathological analysis demonstrated pulmonary vascular congestion and significant macrophage recruitment at 12 and 24 h post-treatment. In conclusion, the pulmonary delivery of crystalline rifapentine caused a transient neutrophil-associated inflammatory response in the lungs that resolved over 7 days. This observation may limit pulmonary delivery of rifapentine to once a week at a dose of 20 mg/kg or less. The effectiveness of weekly dosing with inhalable rifapentine will be assessed in murine Mycobacterium tuberculosis infection.

Production of Inhalation Phage Powders Using Spray Freeze Drying and Spray Drying Techniques for Treatment of Respiratory Infections.

PURPOSE: The potential of aerosol phage therapy for treating lung infections has been demonstrated in animal models and clinical studies. This work compared the performance of two dry powder formation techniques, spray freeze drying (SFD) and spray drying (SD), in producing inhalable phage powders. METHOD: A Pseudomonas podoviridae phage, PEV2, was incorporated into multi-component formulation systems consisting of trehalose, mannitol and L-leucine (F1 = 60:20:20 and F2 = 40:40:20). The phage titer loss after the SFD and SD processes and in vitro aerosol performance of the produced powders were assessed. RESULTS: A significant titer loss (~2 log) was noted for droplet generation using an ultrasonic nozzle employed in the SFD method, but the conventional two-fluid nozzle used in the SD method was less destructive for the phage (~0.75 log loss). The phage were more vulnerable during the evaporative drying process (~0.75 log further loss) compared with the freeze drying step, which caused negligible phage loss. In vitro aerosol performance showed that the SFD powders (~80% phage recovery) provided better phage protection than the SD powders (~20% phage recovery) during the aerosolization process. Despite this, higher total lung doses were obtained for the SD formulations (SD-F1 = 13.1 ± 1.7 × 10(4) pfu and SD-F2 = 11.0 ± 1.4 × 10(4) pfu) than from their counterpart SFD formulations (SFD-F1 = 8.3 ± 1.8 × 10(4) pfu and SFD-F2 = 2.1 ± 0.3 × 10(4) pfu). CONCLUSION: Overall, the SD method caused less phage reduction during the powder formation process and the resulted powders achieved better aerosol performance for PEV2.

Novel inhaled andrographolide for treatment of lung cancer: In vitro assessment.

Andrographolide is a plant-based compound that showed promising activity against lung cancer. However, the compound's poor water solubility and low bioavailability limit its oral administration. Inhaled drug delivery of andrographolide is highly favourable as it delivers active ingredients directly into the affected lungs. In the current study, we compared in vitro aerosol performance, anti-cancer activity and storages stability of two (2) inhalable andrographolide formulations. Formulation 1 was prepared using precipitation and spray drying techniques, while Formulation 2 was prepared via direct spray drying technique. Drug morphology and physicochemical properties were confirmed using scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis. In vitro aerosol dispersion profile was evaluated using the next-generation impactor (NGI). Formulation 1 consisted of elongated crystals while Formulation 2 was made up of amorphous spherical particles. Both formulations had an inhalable fraction (<5 µm) of more than 40 %, making them suitable for pulmonary drug delivery. The formulations also showed an IC25 of less than 100 µg/mL against the human lung carcinoma cells (A549). Formulation 1 and 2 was stable in a vacuum condition at 30 °C for up to 6 and 3 months, respectively. Novel inhalable andrographolide dry powders were successfully produced with a good aerosol profile, potent anti-cancer activity and adequate storage stability, which deserve further in vivo investigations.

Economic Burden of Alzheimer's Disease: A Systematic Review.

OBJECTIVES: Alzheimer's disease (AD) has become one of the most prevalent neurodegenerative disorders among the elderly. The global cost of dementia is expected to reach US $2 trillion in 2030. In this systematic review, existing evidence on the cost of dementia specific to AD is appraised. METHODS: A comprehensive search was done on 3 databases, namely PubMed, ScienceDirect, and Web of Science, to identify original cost-of-illness studies that only evaluate the economic burden of AD up to August 2022. The risk of bias in the studies was assessed using Consolidated Health Economic Evaluation Reporting Standards 2022 criteria. Cost articles without specifying etiology of AD or those in non-English were excluded. RESULTS: Twelve of 5536 studies met the inclusion criteria. The total annual cost of AD per capita ranged from US $468.28 in mild AD to US $171 283.80 in severe AD. The cost of care raised nonlinearly with disease severity. Indirect caregiving cost represented the main contributor to societal cost in community-dwelling patients. When special caregiving accommodation was opted in daily care, it results in cost shifting from indirect cost to direct nonmedical cost. Formal caregiving accommodation caused increase in direct cost up to 67.3% of overall economic burden of the disease. CONCLUSIONS: AD exerts a huge economic burden on patients and caregivers. Overall rise of each cost component could be anticipated with disease deterioration. Choice of special caregiving accommodation could reduce caregiver's productivity loss but increase the direct nonmedical expenditure of the disease from societal perspective.

Medium-chain dicarboxylic acids: chemistry, pharmacological properties, and applications in modern pharmaceutical and cosmetics industries.

Succinic (SUA), glutaric (GLA), pimelic (PA), suberic (SUBA), adipic (ADA), azelaic (AZA), and sebacic acids (SA) make up the majority of medium-chain dicarboxylic acids (MCDAs) with chain lengths of C4-C10, and are widely utilised in the chemical, food, textile, pesticide, pharmaceutical, and liquid crystal sectors. The MCDAs' two carboxyl groups provide them with an incredibly broad variety of applications. The focus of significant scientific research now is on the increasingly varied pharmacological effects of MCDAs. However, only a few studies have compared the biological characteristics of MCDAs in the contemporary pharmaceutical and cosmetic sectors and thoroughly examined the most recent research and marketing initiatives for MCDAs. This review's objective is to offer a thorough analysis of academic works on MCDAs, to assess the usefulness of these substances' chemical-pharmacological properties for use in the contemporary pharmaceutical and cosmetic industries, and to investigate the direction of their possible applications in these two disciplines. In addition, this review investigates how these compounds are metabolised in the human body.

Eurycoma longifolia: an overview on the pharmacological properties for the treatment of common cancer.

Eurycoma longifolia plant, the so called Tongkat Ali in Malaysia, is a well grown prominent tree in all Southeast Asia. It is well known among traditional medicine practitioners as a curative plant for many diseases and health conditions. The major quassinoid from the plant is eurycomanone, which exhibits many prominent effects on various cancer cell lines. Numerous studies have shown that eurycomanone inhibits cancerous cell growth and encourages cell death both in vitro and in vivo test. Even though analyses of safety and toxicity have been conducted, there is still a substantial knowledge barrier when it comes to providing a scientific foundation for the molecular mechanism as well as intervention strategy in the living people cancer cell. In a way to offer adequate baseline data for future investigations based on molecular mechanism and intervention, the present work seeks to review the researches conducted to date on this herbal plant.

Biomedical Applications of Polyhydroxyalkanoate in Tissue Engineering.

Tissue engineering technology aids in the regeneration of new tissue to replace damaged or wounded tissue. Three-dimensional biodegradable and porous scaffolds are often utilized in this area to mimic the structure and function of the extracellular matrix. Scaffold material and design are significant areas of biomaterial research and the most favorable material for seeding of in vitro and in vivo cells. Polyhydroxyalkanoates (PHAs) are biopolyesters (thermoplastic) that are appropriate for this application due to their biodegradability, thermo-processability, enhanced biocompatibility, mechanical properties, non-toxicity, and environmental origin. Additionally, they offer enormous potential for modification through biological, chemical and physical alteration, including blending with various other materials. PHAs are produced by bacterial fermentation under nutrient-limiting circumstances and have been reported to offer new perspectives for devices in biological applications. The present review discusses PHAs in the applications of conventional medical devices, especially for soft tissue (sutures, wound dressings, cardiac patches and blood vessels) and hard tissue (bone and cartilage scaffolds) regeneration applications. The paper also addresses a recent advance highlighting the usage of PHAs in implantable devices, such as heart valves, stents, nerve guidance conduits and nanoparticles, including drug delivery. This review summarizes the in vivo and in vitro biodegradability of PHAs and conducts an overview of current scientific research and achievements in the development of PHAs in the biomedical sector. In the future, PHAs may replace synthetic plastics as the material of choice for medical researchers and practitioners.

Advances in Polyhydroxyalkanoate Nanocarriers for Effective Drug Delivery: An Overview and Challenges.

Polyhydroxyalkanoates (PHAs) are natural polymers produced under specific conditions by certain organisms, primarily bacteria, as a source of energy. These up-and-coming bioplastics are an undeniable asset in enhancing the effectiveness of drug delivery systems, which demand characteristics like non-immunogenicity, a sustained and controlled drug release, targeted delivery, as well as a high drug loading capacity. Given their biocompatibility, biodegradability, modifiability, and compatibility with hydrophobic drugs, PHAs often provide a superior alternative to free drug therapy or treatments using other polymeric nanocarriers. The many formulation methods of existing PHA nanocarriers, such as emulsion solvent evaporation, nanoprecipitation, dialysis, and in situ polymerization, are explained in this review. Due to their flexibility that allows for a vessel tailormade to its intended application, PHA nanocarriers have found their place in diverse therapy options like anticancer and anti-infective treatments, which are among the applications of PHA nanocarriers discussed in this article. Despite their many positive attributes, the advancement of PHA nanocarriers to clinical trials of drug delivery applications has been stunted due to the polymers' natural hydrophobicity, controversial production materials, and high production costs, among others. These challenges are explored in this review, alongside their existing solutions and alternatives.

Antimicrobial resistance: Prevalence, economic burden, mechanisms of resistance and strategies to overcome.

Antibiotic resistance is a major health concern globally and has been estimated to cause 10 million deaths worldwide by year 2050 if the current trend of inappropriate and excessive use of antibiotics continues. Although, the discovery of antibiotics has saved countless of lives for the past 80 years, increasing levels of bacterial resistance to antibiotics would jeopardize the progress in clinical and agricultural sectors and may cause life-threatening situations even for previously treatable bacterial infections. Antibiotic resistance would increase the levels of poverty of low-middle income countries mostly due to extended hospital stays, higher cost of treatment and untimely deaths that directly affect the total productivity rate. Recent incidences of antibiotic resistance have been gradually increasing globally and this may potentiate horizontal transmission of the resistant gene and have been linked with cross-resistance to other antibiotic families as well. This review summarizes the global burden of antibiotic resistance from the economic viewpoint, highlights the recent incidences of antibiotic resistance mainly related to Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Salmonella spp. and Staphylococcus aureus, describes the common mechanistic actions of antibiotic resistance and potential strategies to overcome antibiotic resistance.

Advances in Nanocarriers for Effective Delivery of Docetaxel in the Treatment of Lung Cancer: An Overview.

Docetaxel (DCX) is a highly effective chemotherapeutic drug used in the treatment of different types of cancer, including non-small cell lung cancer (NSCLC). The drug is known to have low oral bioavailability due to its low aqueous solubility, poor membrane permeability and susceptibility to hepatic first-pass metabolism. To mitigate these problems, DCX is administered via the intravenous route. Currently, DCX is commercially available as a single vial that contains polysorbate 80 and ethanol to solubilize the poorly soluble drug. However, this formulation causes short- and long-term side effects, including hypersensitivity, febrile neutropenia, fatigue, fluid retention, and peripheral neuropathy. DCX is also a substrate to the drug efflux pump P-glycoprotein (P-gp) that would reduce its concentration within the vicinity of the cells and lead to the development of drug resistance. Hence, the incorporation of DCX into various nanocarrier systems has garnered a significant amount of attention in recent years to overcome these drawbacks. The surfaces of these drug-delivery systems indeed can be functionalized by modification with different ligands for smart targeting towards cancerous cells. This article provides an overview of the latest nanotechnological approaches and the delivery systems that were developed for passive and active delivery of DCX via different routes of administration for the treatment of lung cancer.

Pulmonary Delivery of Anticancer Drugs via Lipid-Based Nanocarriers for the Treatment of Lung Cancer: An Update.

Lung cancer (LC) is the leading cause of cancer-related deaths, responsible for approximately 18.4% of all cancer mortalities in both sexes combined. The use of systemic therapeutics remains one of the primary treatments for LC. However, the therapeutic efficacy of these agents is limited due to their associated severe adverse effects, systemic toxicity and poor selectivity. In contrast, pulmonary delivery of anticancer drugs can provide many advantages over conventional routes. The inhalation route allows the direct delivery of chemotherapeutic agents to the target LC cells with high local concertation that may enhance the antitumor activity and lead to lower dosing and fewer systemic toxicities. Nevertheless, this route faces by many physiological barriers and technological challenges that may significantly affect the lung deposition, retention, and efficacy of anticancer drugs. The use of lipid-based nanocarriers could potentially overcome these problems owing to their unique characteristics, such as the ability to entrap drugs with various physicochemical properties, and their enhanced permeability and retention (EPR) effect for passive targeting. Besides, they can be functionalized with different targeting moieties for active targeting. This article highlights the physiological, physicochemical, and technological considerations for efficient inhalable anticancer delivery using lipid-based nanocarriers and their cutting-edge role in LC treatment.

Antibacterial potential of Malaysian ethnomedicinal plants against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA).

This study aimed to evaluate the antibacterial activities of 61 plant extracts from 49 Malaysian ethnomedicinal plants and to investigate the interaction of the active plant extracts in combination with synthetic antibiotics against the MSSA and MRSA strains. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the plant extracts were determined using a microdilution method against MSSA and MRSA strains. The interaction between active plant extracts and the antibiotics was assessed using the checkerboard method. The total fractional inhibitory concentration (∑FIC) indices from the combination were calculated to determine the nature of the interaction. Out of the 61 plant extracts tested against the MSSA strain, 7 plant extracts (~ 11%) showed MIC values of less than 200 µg/mL, 17 extracts (~ 28%) showed MIC between 200 and 800 µg/mL and seed extracts of Areca catechu showed MBC values of 400 µg/mL. The seed extract of A. catechu showed MIC and MBC of 400 µg/mL against the MRSA strains while leaf extract of Cocos nucifera showed MIC of 400 µg/mL against MRSA NCTC 12493. When the active plant extracts (MIC ≤ 200 µg/mL for MSSA, and ≤ 400 µg/mL for MRSA) were tested in combination with vancomycin and ciprofloxacin, they showed no interaction against both MSSA and MRSA with ∑FIC between 1.06 and 2.03. These findings provide a preliminary overview of the anti-MSSA and anti-MRSA properties of Malaysian ethnobotanical plants to combat Staphylococcal infections. Further research is needed to establish an antibacterial profile of the tested plant extracts.

Advanced Nanoparticle-Based Drug Delivery Systems and Their Cellular Evaluation for Non-Small Cell Lung Cancer Treatment.

Lung cancers, the number one cancer killer, can be broadly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC being the most commonly diagnosed type. Anticancer agents for NSCLC suffer from various limitations that can be partly overcome by the application of nanomedicines. Nanoparticles is a branch within nanomedicine that can improve the delivery of anticancer drugs, whilst ensuring the stability and sufficient bioavailability following administration. There are many publications available in the literature exploring different types of nanoparticles from different materials. The effectiveness of a treatment option needs to be validated in suitable in vitro and/or in vivo models. This includes the developed nanoparticles, to prove their safety and efficacy. Many researchers have turned towards in vitro models that use normal cells or specific cells from diseased tissues. However, in cellular works, the physiological dynamics that is available in the body could not be mimicked entirely, and hence, there is still possible development of false positive or false negative results from the in vitro models. This article provides an overview of NSCLC, the different nanoparticles available to date, and in vitro evaluation of the nanoparticles. Different types of cells suitable for in vitro study and the important precautions to limit the development of false results are also extensively discussed.

PLGA particulate subunit tuberculosis vaccines promote humoral and Th17 responses but do not enhance control of Mycobacterium tuberculosis infection.

Tuberculosis places a staggering burden on human health globally. The new World Health Organisation End-TB Strategy has highlighted the urgent need for more effective TB vaccines to improve control of the disease. Protein-based subunit vaccines offer potential as safe and effective generators of protective immunity, and the use of particulate vaccine formulation and delivery by the pulmonary route may enhance local immunogenicity. In this study, novel particulate subunit vaccines were developed utilising biodegradable poly(lactic-co-glycolic acid) (PLGA) slow-release particles as carriers for the Mycobacterium tuberculosis lipoprotein MPT83, together with the adjuvants trehalose-dibehenate (TDB) or Monophosphoryl lipid A (MPL). Following delivery by the pulmonary or subcutaneous routes, the immunogenicity and protective efficacy of these vaccines were assessed in a murine model of M. tuberculosis infection. When delivered peripherally, these vaccines induced modest, antigen-specific Th1 and Th17 responses, but strong anti-MPT83 antibody responses. Mucosal delivery of the PLGA(MPT83) vaccine, with or without TDB, increased antigen-specific Th17 responses in the lungs, however, PLGA-encapsulated vaccines did not provide protection against M. tuberculosis challenge. By contrast, peripheral delivery of DDA liposomes containing MPT83 and TDB or MPL, stimulated both Th1 and Th17 responses and generated protection against M. tuberculosis challenge. Therefore, PLGA-formulated vaccines primarily stimulate strong humoral immunity, or Th17 responses if used mucosally, and may be a suitable carrier for vaccines against extracellular pathogens. This study emphasises the critical nature of the vaccine carrier, adjuvant and route of delivery for optimising vaccine efficacy against TB.

Novel combination proliposomes containing tobramycin and clarithromycin effective against Pseudomonas aeruginosa biofilms.

Tobramycin (TOB) and clarithromycin (CLA) can potentially be used synergistically for the treatment of respiratory infections caused by Pseudomonas aeruginosa (P. aeruginosa) in cystic fibrosis (CF) patients. This study aimed to develop a novel combination proliposome formulation (TOB/CLA-CPROLips) containing both hydrophilic TOB and hydrophobic CLA via a core-carrier approach. The combination proliposomes were produced by spray drying a suspension comprising spray-driedmannitol (SD-MAN, 0.45%) and spray-dried tobramycin (SD-TOB, 0.05%) particles suspended in an ethanolic lipid solution of CLA (0.05%). The lipid layer coated on the surface of the dry proliposome particles conferred moisture protection and sustained drug release properties in comparison to the pure drugs. The optimized TOB/CLA-CPROLips formulation was stable after 3 months of storage at 60% relative humidity (RH) and 25 °C. The combination drug proliposomes showed a synergistic antimicrobial activity against planktonic cells and biofilm cultures of P. aeruginosa. In conclusion, the core-carrier method coupled with spray-drying provided a novel approach for the preparation of combination antibiotics proliposomes.