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

Chitosan nanoparticles: a survey of preparation methods

The application of macromolecules in therapy is frequently hindered by stability and/or permeation issues. These limitations have been addressed by the pharmaceutical industry through the development of suitable non-injectable drug carriers. In this context, nanoparticles have emerged as one of the most exciting tools, due to the increased surface-to-volume ratio, which provides an intimate interaction with epithelial surfaces. Nanoparticles further enable the encapsulated molecules to retain their biological activity, from the production steps to the final release. Chitosan has reached a prominent position as carrier-forming material, as diverse methods can be applied to produce nanoparticles using that excipient. These involve either hydrophilic or lipophilic environments that generally result in mild conditions or aggressive and time-consuming processes, respectively. In this review, a detailed description of methods employed to produce chitosan nanocarriers is provided, accompanied by illustrative schemes of the procedures. The emphasis is on the variables reported to affect the final properties of the vehicles

Microencapsulación de nanopartículas de quitosano para la administración pulmonar de macromoléculas terapéuticas

[ES] El objetivo de esta tesis doctoral ha sido el diseño de sistemas microparticulares capaces de actuar como vehículos de nanopartículas de quitosano, obtenidas por gelificación iónica, y de complejos de lípidos y nanopartículas de quitosano hacía el pulmón, con el fin de conseguir una absorción pulmonar de la macromolécula terapéutica asociada a las nanopartículas. Para ello, se ha seleccionado como excipiente el manitol y como procedimiento de microencapsulación la técnica de atomización, optimizando las condiciones de este proceso para obtener microsferas con propiedades morfológicas y aerodinámicas adecuadas para su administración por vía pulmonar. Para la preparación de los sistemas complejos de lípidos y nanopartículas de quitosano, se han elegido dos lípidos endógenos del pulmón, la dipalmitoilfosfatidilcolina (DPPC) y el dimiristoilfosfatidilglicerol (DMPG), con carga neutra y negativa, respectivamente, y se ha comprobado que el recubrimiento lipídico de las nanopartículas es más eficaz cuando ambos fosfolípidos están presentes en la formulación. El análisis estructural de las microsferas conteniendo nanopartículas, ha demostrado que éstas se distribuyen uniformemente en la matriz de manitol. Utilizando la insulina y la albúmina bovina marcada con isotiocianato de fluoresceína (FITC-BSA) como modelos, se ha evidenciado el potencial de ambos sistemas para asociar péptidos y proteínas. Además, se ha observado que el proceso de atomización no produce ningún efecto negativo sobre las propiedades de los sistemas encapsulados, ni en el perfil de liberación de la insulina a partir de los mismos. Los estudios realizados con las microsferas conteniendo nanopartículas en dos líneas celulares del epitelio respiratorio (Calu-3 y A549), han demostrado la biocompatibilidad del sistema, evidenciando además fenómenos de mucoadhesión. Por otro lado, estudios preliminares in vivo realizados con este mismo sistema, tras la administración intratraqueal a ratas, han demostrado que las microsferas alcanzan el espacio alveolar, siendo más eficaces en la reducción de los niveles de glucosa que la disolución de insulina con una dosis equivalente. En definitiva, el conjunto de los resultados obtenidos en este trabajo experimental pone de manifiesto el interés de estos sistemas como vehículos para la administración pulmonar de péptidos y proteínas terapéuticos.[EN] The goal of this thesis was the design of microparticulate systems which act as vehicles of chitosan nanoparticles and complexes formed between nanoparticles, produced by ionic gelation, and lipids, to the lung, in order to achieve a pulmonary absorption of the therapeutic macromolecule associated to the nanoparticles. To do so, manitol and spray-drying were selected as excipient and microencapsulation technique, respectively, and the process parameters were optimized to obtain microspheres with such morphological and aerodynamic properties, that allowed their lung delivery. To prepare the lipid/nanoparticles complexes, we chose two endogenous lipids of the lung, dipalmitoylphophatidylcholine (DPPC) and dimyristoylphosphatidylglycerol (DMPG), with neutral and negative charge, respectively. It was demonstrated that the lipidic coating of the nanoparticles was more efficient when both phospholipids were present in the formulation. The structural analysis of microspheres containing nanoparticles showed that nanoparticles are homogeneously distributed in the mannitol microspheres. Using insulin and fluorescein isothiocyanate albumin (FITC-BSA) as models, the potential of both drug delivery systems to associate peptides and proteins was elicited. Moreover, it was observed that the spray-drying process does not induce any negative effect neither on the characteristics of the microencapsulated systems, nor on the insulin release profile. Studies performed with microspheres containing nanoparticles, in two respiratory epithelial cell lines (Calu-3 and A549), revealed the system biocompatibility, evidencing also mucoadhesion properties. Furthermore, preliminary in vivo studies performed with this system, upon intratracheal administration to rats, demonstrated that microspheres reach the alveolar region, providing significantly better hypoglycemic effect as compared to a an insulin solution of similar dose. As a whole, results obtained from this experimental work evidenced the interest of these systems as vehicles for the pulmonary administration of therapeutic macromolecules

Locust bean gum: exploring its potential for biopharmaceutical applications

Polysaccharides have been finding, in the last decades, very interesting and useful applications in the biomedical and, specifically, in the biopharmaceutical field. Locust bean gum is a polysaccharide belonging to the group of galactomannans, being extracted from the seeds of the carob tree (Ceratonia siliqua). This polymer displays a number of appealing characteristics for biopharmaceutical applications, among which its high gelling capacity should be highlighted. In this review we describe critical aspects of locust bean gum, contributing for its role in biopharmaceutical applications. Physicochemical properties, as well as strong and affective synergies with other biomaterials are described. The potential for in vivo biodegradation is explored and the specific biopharmaceutical applications are discussed

Chitosan/carrageenan nanoparticles: effect of cross-linking with tripolyphosphate

Chitosan/carrageenan/tripolyphosphate nanoparticles were prepared by polyelectrolyte complexation/ionic gelation, the latter compound acting as cross-linker. The incorporation of the three components in the nanoparticle matrix was assessed by analytical techniques (FTIR, XPS and TOF-SIMS). Using chitosan/carrageenan nanoparticles as control, the effect of the cross-linker in the particles properties was studied. A decrease in size (from 450-500 nm to 150-300 nm) and in zeta potential (from +75 - +85 mV to +50 - +60 mV), and an increase in production yield (from 15-20% to 25-35%), and in stability (from one week to up to 9 months) were observed. Also, a correlation between positive to negative charge ratios in the formulations and the above characteristics was established. The small size and high positive surface charge make the developed chitosan/carrageenan/tripolyphosphate nanoparticles potential tools for an application in mucosal delivery of macromolecules

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

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

Microspheres loaded with polysaccharide nanoparticles for pulmonary delivery: preparation, structure and surface analysis

In this work, we report the preparation of a nanoparticle-based dry powder for pulmonary administration. Hybrid chitosan/hyaluronic acid nanoparticles were produced by ionotropic gelation and characterized for their physicochemical properties, being further studied by solid nuclear magnetic resonance (NMR). Using mannitol as carrier, nanoparticles were microencapsulated by spray drying, resulting in a dry powder with appropriate aerodynamic properties for lung delivery. In order to investigate the nanoparticles distribution within the carrier matrix, several techniques were applied that permitted an in-depth analysis of the system structure and surface, such as confocal laser scanning microscopy (CLSM) and X-ray photoelectron spectroscopy (XPS) in combination with time-of-flight secondary ion mass spectroscopy (TOF-SIMS). Overall, the studies conducted revealed that nanoparticles are homogeneously distributed through mannitol microspheres, suggesting the success of the microencapsulation process. In the light of these findings, it was concluded that the developed delivery system holds great potential for lung delivery of macromolecules

Inhalable spray-dried chondroitin sulphate microparticles: effect of different solvents on particle properties and drug activity

Spray-drying stands as one of the most used techniques to produce inhalable microparticles, but several parameters from both the process and the used materials affect the properties of the resulting microparticles. In this work, we describe the production of drug-loaded chondroitin sulphate microparticles by spray-drying, testing the effect of using different solvents during the process. Full characterisation of the polymer and of the aerodynamic properties of the obtained microparticles are provided envisaging an application in inhalable tuberculosis therapy. The spray-dried microparticles successfully associated two first-line antitubercular drugs (isoniazid and rifabutin) with satisfactory production yield (up to 85%) and drug association efficiency (60%-95%). Ethanol and HCl were tested as co-solvents to aid the solubilisation of rifabutin and microparticles produced with the former generally revealed the best features, presenting a better ability to sustainably release rifabutin. Moreover, these presented aerodynamic properties compatible with deep lung deposition, with an aerodynamic diameter around 4 μm and fine particle fraction of approximately 44%. Finally, it was further demonstrated that the antitubercular activity of the drugs remained unchanged after encapsulation independently of the used solvent.UID/Multi/04326/2019; SFRH/BD/52426/2013; ED481B 2018/071info:eu-repo/semantics/publishedVersio