Multifunctional nanocarriers for lung drug delivery

Nanocarriers have been increasingly proposed for lung drug delivery applications. The strategy of combining the intrinsic and more general advantages of the nanostructures with specificities that improve the therapeutic outcomes of particular clinical situations is frequent. These include the surface engineering of the carriers by means of altering the material structure (i.e., chemical modifications), the addition of specific ligands so that predefined targets are reached, or even the tuning of the carrier properties to respond to specific stimuli. The devised strategies are mainly directed at three distinct areas of lung drug delivery, encompassing the delivery of proteins and protein-based materials, either for local or systemic application, the delivery of antibiotics, and the delivery of anticancer drugs-the latter two comprising local delivery approaches. This review addresses the applications of nanocarriers aimed at lung drug delivery of active biological and pharmaceutical ingredients, focusing with particular interest on nanocarriers that exhibit multifunctional properties. A final section addresses the expectations regarding the future use of nanocarriers in the area.UID/Multi/04326/2019; PD/BD/137064/2018info:eu-repo/semantics/publishedVersio

Dual antibiotherapy of tuberculosis mediated by inhalable locust bean gum microparticles

Despite the existence of effective oral therapy, tuberculosis remains a deadly pathology, namely because of bacterial resistance and incompliance with treatments. Establishing alternative therapeutic approaches is urgently needed and inhalable therapy has a great potential in this regard. As pathogenic bacteria are hosted by alveolar macrophages, the co-localisation of antitubercular drugs and pathogens is thus potentiated by this strategy. This work proposes inhalable therapy of pulmonary tuberculosis mediated by a single locust bean gum (LBG) formulation of microparticles associating both isoniazid and rifabutin, complying with requisites of the World Health Organisation of combined therapy. Microparticles were produced by spray-drying, at LBG/INH/RFB mass ratio of 10/1/0.5. The aerodynamic characterisation of microparticles revealed emitted doses of more than 90% and fine particle fraction of 38%, thus indicating the adequacy of the system to reach the respiratory lung area, thus partially the alveolar region. Cytotoxicity results indicate moderate toxicity (cell viability around 60%), with a concentration-dependent effect. Additionally, rat alveolar macrophages evidenced preferential capture of LBG microparticles, possibly due to chemical composition comprising mannose and galactose units that are specifically recognised by macrophage surface receptors. (C) 2017 Elsevier B.V. All rights reserved.National Portuguese funding through FCT - Fundacao para a Ciencia e a Tecnologia [PTDC/DTP-FTO/0094/2012, UID/BIM/04773/2013, UID/Multi/04326/2013, UID/QUI/00100/2013, PEst-OE/QUI/UI4023/2011

Nanoparticles in the treatment of chronic lung diseases

Nanoparticles, although considered a topic of modern medicine, actually have an interesting history. Currently, advances in nanomedicine hold great promise as drug carrier systems for sustained release and targeted delivery of diverse therapeutic agents. Nanoparticles can be defined as complex drug carrier systems which incorporate and protect a certain drug or particle. Nanoparticles can be administered via different routes, such as intravenous injection, oral administration, or pulmonary inhalation. Even though the use of nano-carriers via pulmonary inhalation is heavily debated, this system represents an attractive alternative to the intravenous or oral routes, due to the unique anatomical and physiological features of the lungs and the minimal interactions between the targeted site and other organs. Some of the widely used nano-carriers for the treatment of chronic pulmonary diseases, via pulmonary route, are as follows: polymeric nanoparticles, liposomal nano-carriers, solid lipid nanoparticles, and submicron emulsions. Nano-carrier systems provide the advantage of sustained-drug release in the lung tissue resulting in reduced dosing frequency and improved patient compliance. Further studies focusing on understanding the mechanisms of action of nanoparticles and improving their chemical structure are required in order to better understand the potential long-term risk of excipient toxicity and nanoscale carriers

Solidification of nanosuspensions for the production of solid oral dosage forms and inhalable dry powders

INTRODUCTION: Nanosuspensions combine the advantages of nanotherapeutics (e.g. increased dissolution rate and saturation solubility) with ease of commercialisation. Transformation of nanosuspensions to solid oral and inhalable dosage forms minimises the physical instability associated with their liquid state, enhances patient compliance and enables targeted oral and pulmonary drug delivery. AREAS COVERED: This review outlines solidification methods for nanosuspensions. It includes spray and freeze drying as the most widely used techniques. Fluidised-bed coating, granulation and pelletisation are also discussed as they yield nanocrystalline formulations with more straightforward downstream processing to tablets or capsules. Spray-freeze drying, aerosol flow reactor and printing of nanosuspensions are also presented as promising alternative solidification techniques. Results regarding the solid state, in vitro dissolution and/or aerosolisation efficiency of the nanocrystalline formulations are given and combined with available in vivo data. Focus is placed on the redispersibility of the solid nanocrystalline formulations, which is a prerequisite for their clinical application. EXPERT OPINION: A few solidified nanocrystalline products are already on the market and many more are in development. Oral and inhalable nanoparticle formulations are expected to have great potential especially in the areas of personalised medicine and delivery of high drug doses (e.g. antibiotics) to the lungs, respectively

INHALABLE NANOCOMPOSITES AND ANTICANCER AGENTS FOR CANCER THERAPY

Cancer is designated as the leading cause of mortality worldwide and lung cancer is responsible for nearly 30% of all cancer related deaths. Over the last few decades mortality rates have only marginally increased and rates of recurrence remain high. These factors, among others, suggest the need for more innovative treatment modalities in lung cancer therapy. Targeted pulmonary delivery is well established for treating pulmonary diseases such as asthma and provides a promising platform for lung cancer therapy. Increasing local deposition of anticancer agents (ACAs) and reducing systemic exposure of these toxic moieties could lead to better therapeutic outcomes and higher quality of life for lung cancer patients receiving such harsh chemotherapy regimens. In this work, a novel lung cancer treatment modality is presented wherein ACAs are incorporated into inhalable dry powder composites for targeted delivery to the pulmonary tract. Additionally, nanoparticles were added to inhalable composites to increase the therapeutic potential of these unique materials. A variety of dry powder composites were formulated via spray drying and the physicochemical properties of the resulting systems were characterized. Additionally, the performance of the cargo incorporated into these composites was evaluated in order to insure the activity of the components after release from the inhalable dry powders. The aerodynamic performance of the dry powder systems was evaluated with the Next Generation Impactor® to determine if these materials were suitable for inhalation purposes. Iron oxide (Fe3O4) magnetic nanoparticles were synthesized and incorporated into dry powders to examine the feasibility of administering these materials to the lungs for remotely actuated hyperthermia. Remote heating studies were performed on the nanoparticles released from these composites using a custom Taylor Winfield® alternating magnetic field source, and in vitro hyperthermia studies were performed using advanced multicellular spheroid cell culture models. These studies elicited the effectiveness of these systems on physiologically relevant models. In addition to the iron oxide composites, dry powders were formulated with two common ACAs, cisplatin and erlotinib, for inhalable chemotherapy. The activity of the drugs released from these composites was evaluated on the human pulmonary lung cancer cell lines A549 and H358 and compared with the free form of the drugs in order to evaluate the effectiveness of these therapies. Finally, responsive hydrogel nanoparticles (HNPs) that contain the ability to respond to environmental changes in pH were synthesized and evaluated as responsive drug carriers. The response of these particles to pH was evaluated and their stability was examined before and after inclusion into dry powder composites. Overall, inhalable dry powder nanocomposites are promising materials for innovative lung cancer treatment modalities and have the potential to provide a safer and more effective option for addressing this devastating disease

Inhalable fucoidan microparticles combining two antitubercular drugs with potential application in pulmonary tuberculosis therapy

The pulmonary delivery of antitubercular drugs is a promising approach to treat lung tuberculosis. This strategy not only allows targeting the infected organ instantly, it can also reduce the systemic adverse effects of the antibiotics. In light of that, this work aimed at producing fucoidan-based inhalable microparticles that are able to associate a combination of two first-line antitubercular drugs in a single formulation. Fucoidan is a polysaccharide composed of chemical units that have been reported to be specifically recognised by alveolar macrophages (the hosts of Mycobacterium). Inhalable fucoidan microparticles were successfully produced, effectively associating isoniazid (97%) and rifabutin (95%) simultaneously. Furthermore, the produced microparticles presented adequate aerodynamic properties for pulmonary delivery with potential to reach the respiratory zone, with a mass median aerodynamic diameter (MMAD) between 3.6-3.9 mu m. The formulation evidenced no cytotoxic effects on lung epithelial cells (A549), although mild toxicity was observed on macrophage-differentiated THP-1 cells at the highest tested concentration (1 mg/mL). Fucoidan microparticles also exhibited a propensity to be captured by macrophages in a dose-dependent manner, as well as an ability to activate the target cells. Furthermore, drug-loaded microparticles effectively inhibited mycobacterial growth in vitro. Thus, the produced fucoidan microparticles are considered to hold potential as pulmonary delivery systems for the treatment of tuberculosis.Portuguese Foundation for Science and Technology [PTDC/DTP-FTO/0094/2012, UID/Multi/04326/2013, UID/BIM/04773/2013]; CAPES-Brazil [BEX 1168/13-4

Preparation of novel multifunctional formulations intended for pulmonary delivery

The eradication of pathogenic bacteria in cystic fibrosis (CF) lungs is often unsuccessful because of the poor permeability of the drug through the thick respiratory mucus barrier and biofilm. Nanoparticles are promising carriers due to their ability to cross these barriers and to deliver the loaded drug into the site of action. Nanoparticles exhibit a poor lung deposition; therefore, they need to be transformed into microparticles, which are suitable for dry powder inhalers and thus can be applied pulmonary. In this work, PLGA NPs loaded with Curcumin were produced using microfluidic technology. While using different factors during the manufacturing, their effect on the size and the encapsulation efficiency of the drug was evaluated. Also, the particles showed a fast permeability through the mucus barrier. Furthermore, a novel microparticulate matrix (composed of an antibiotic and N-acetylcysteine) was developed using a spray-drying technique in order to embed the NPs within it and to add even more functionality to the formulation. The aerodynamic properties of microparticles were tested using NGI. Then, their impact on the viscosity of mucus was tested. Additionally, a solid-state characterization and investigations regarding the physical stability of the obtained DPI formulations were performed. Finally, their effect against biofilm formation and inflammation was tested. Summarizing, the formulations represent a promising approach for the future treatment of pulmonary infections in CF.Oft misslingt die Eradikation pathogener Bakterien in Atemwegen von Mukoviszidose Patienten. Grund ist die schlechte Permeabilität des Arzneistoffes durch den pulmonalen Mukus und den Biofilm. Nanopartikel sind hierfür vielversprechende Trägersysteme, da sie diese Barrieren durchdringen und den geladenen Arzneistoff an den Wirkort bringen können. Aufgrund der geringen Deposition von Nanopartikeln in der Lunge ist die Umformulierung der Mikropartikel nötig, damit sie pulmonal appliziert werden können. In dieser Arbeit wurden durch Verwendung von Mikrofluidik Kurkumin beladene PLGA Nanopartikel hergestellt. Der Einfluss verschiedener Herstellungsfaktoren auf Partikelgröße und Verkapselungseffizienz wurde bewertet. Die Partikel zeigten eine rasche Permeation in den Mukus. Mittels Sprühtrocknung wurde eine neuartige Matrix (aus Antibiotikum und N-Acetylcystein) entwickelt, die die Einbettung der Nanopartikel erlaubt und die Funktionalität der Formulierung weiter steigert. Die aerodynamischen Eigenschaften der Mikropartikel wurden mittels NGI untersucht und die Verflüssigung des Mukus wurde nach Anwendung gezeigt. Die Formulierungen für den Pulverinhalator wurden im festen Aggregatzustand charakterisiert und ihre physikalische Stabilität getestet. Schließlich wurde ihre biologische Wirkung (gegen Biofilme und Entzündungsreaktionen) untersucht. Die Formulierungen stellen einen vielversprechenden Ansatz für die künftige Behandlung von pulmonalen Infektionen bei Mukoviszidose dar

DRUG-RESISTANT TUBERCULOSIS: RECENT APPROACH IN POLYMER BASED NANOMEDICINE

Tuberculosis (TB) had been a leading chronic bacterial infection since decades. Current therapeutic management of Mycobacterium tuberculosis (MTB) is inadequate due to the lengthy course of treatment, drug-related side effects and ill-planned therapy, and these factors can lead to therapeutic failure and the emergence of drug-resistant TB. The Multi-drug-resistant (MDR) TB needs a lengthy course of treatment with second-line antitubercular drugs (ATDs) having higher side effects and cost. The misuse of second-line ATDs may result in extremely drug-resistant (XDR) strain which is very difficult to treat and require high doses of drugs resulting in more toxicity and side effects. This review highlights the need for novel drug delivery for the treatment of drug-susceptible and resistant TB. The characteristics of the nanoparticulate system in ATDs delivery and its approach in the MDR and XDR TB are discussed. The lung is the site of infection in pulmonary TB and the targeted drug delivery to the site of infection helps in achieving increased efficacy with less dose further reducing the side effects and toxicity. The symbiotic association of nanotechnology and pulmonary drug delivery give rise to an efficient inhalable polymer based nanoparticulate system containing ATDs for the better management of drug-susceptible and resistant TB. Various ATDs loaded polymer based nanocarrier systems like Alginate, PLGA, Chitosan and Gelatin nanocarriers are discussed in detail. Thus, this review highlights the current research in pulmonary drug delivery of polymer based ATDs nanomedicine and their importance in control of drug-resistant TB

Unlocking the potential of RNA interference as a therapeutic tool

The existence of an intrinsic biochemical pathway enabling specified regulation of gene expression was unheard of until the final years of the last decade. The identification of ribonucleic acid interference (RNAi) in mammalian cells has nowadays become of extreme importance in the field of functional genomics and translational medicine. The advent of RNAi technology has brought to the scientific research and pharmaceutical communities the ability to regulate expression of any desired gene in a reproducible manner. Consequently, such technology may be utilised in the design of novel therapeutics for clinical conditions having dys-regulated gene expression. Since most RNAi-based therapies in the drug development pipeline of pharmaceutical companies utilise short interfering RNA (siRNA), this review will focus on the role of siRNA in drug development.peer-reviewe

Toxicity Evaluation of Magnetic Hyperthermia Induced by Remote Actuation of Magnetic Nanoparticles in 3D Micrometastasic Tumor Tissue Analogs for Triple Negative Breast Cancer

Magnetic hyperthermia as a treatment modality is acquiring increased recognition for loco-regional therapy of primary and metastatic lung malignancies by pulmonary delivery of magnetic nanoparticles (MNP). The unique characteristic of magnetic nanoparticles to induce localized hyperthermia in the presence of an alternating magnetic field (AMF) allows for preferential killing of cells at the tumor site. In this study we demonstrate the effect of hyperthermia induced by low and high dose of MNP under the influence of an AMF using 3D tumor tissue analogs (TTA) representing the micrometastatic, perfusion independent stage of triple negative breast cancer (TNBC) that infiltrates the lungs. While application of inhalable magnetic nanocomposite microparticles (MnMs) to the micrometastatic TNBC model comprised of TTA generated from cancer and stromal cells, showed no measureable adverse effects in the absence of AMF-exposure, magnetic hyperthermia generated under the influence of an AMF in TTA incubated in a high concentration of MNP (1 mg/ mL) caused significant increase in cellular death/ damage with mechanical disintegration and release of cell debris indicating the potential of these inhalable composites as a promising approach for thermal treatment of diseased lungs. The novelty and significance of this study lies in the development of methods to evaluate in vitro the application of inhalable composites containing MNPs in thermal therapy using a physiologically relevant metastatic TNBC model representative of the microenvironmental characteristics in secondary lung malignancies