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- Sulfated seaweed polysaccharides as multifunctional materials in drug delivery applicationsPublication . Cunha, Ludmylla; Grenha, AnaIn the last decades, the discovery of metabolites from marine resources showing biological activity has increased significantly. Among marine resources, seaweed is a valuable source of structurally diverse bioactive compounds. The cell walls of marine algae are rich in sulfated polysaccharides, including carrageenan in red algae, ulvan in green algae and fucoidan in brown algae. Sulfated polysaccharides have been increasingly studied over the years in the pharmaceutical field, given their potential usefulness in applications such as the design of drug delivery systems. The purpose of this review is to discuss potential applications of these polymers in drug delivery systems, with a focus on carrageenan, ulvan and fucoidan. General information regarding structure, extraction process and physicochemical properties is presented, along with a brief reference to reported biological activities. For each material, specific applications under the scope of drug delivery are described, addressing in privileged manner particulate carriers, as well as hydrogels and beads. A final section approaches the application of sulfated polysaccharides in targeted drug delivery, focusing with particular interest the capacity for macrophage targeting.
- Sulfated seaweed polysaccharides as multifunctional materials in drug delivery applicationsPublication . Cunha, Ludmylla; Grenha, AnaIn the last decades, the discovery of metabolites from marine resources showing biological activity has increased significantly. Among marine resources, seaweed is a valuable source of structurally diverse bioactive compounds. The cell walls of marine algae are rich in sulfated polysaccharides, including carrageenan in red algae, ulvan in green algae and fucoidan in brown algae. Sulfated polysaccharides have been increasingly studied over the years in the pharmaceutical field, given their potential usefulness in applications such as the design of drug delivery systems. The purpose of this review is to discuss potential applications of these polymers in drug delivery systems, with a focus on carrageenan, ulvan and fucoidan. General information regarding structure, extraction process and physicochemical properties is presented, along with a brief reference to reported biological activities. For each material, specific applications under the scope of drug delivery are described, addressing in privileged manner particulate carriers, as well as hydrogels and beads. A final section approaches the application of sulfated polysaccharides in targeted drug delivery, focusing with particular interest the capacity for macrophage targeting.
- Inhalable fucoidan microparticles combining two antitubercular drugs with potential application in pulmonary tuberculosis therapyPublication . Cunha, Ludmylla Costa; Rodrigues, Susana; Rosa Da Costa, Ana; Faleiro, Maria Leonor; Buttini, Francesca; Grenha, AnaThe 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.
- Spray-dried fucoidan microparticles for pulmonary delivery of antitubercular drugsPublication . Cunha, Ludmylla; Rosa Da Costa, Ana; Lourenço, João P.; Buttini, Francesca; Grenha, AnaPulmonary tuberculosis accounts for 80% of cases and the delivery of antitubercular drugs into the lungs allows targeting the infected organ and, possibly, reducing systemic drug toxicity. This work aimed at using fucoidan as matrix of inhalable microparticles that associate two first-line antitubercular drugs, for an application in pulmonary tuberculosis therapy. Fucoidan is composed of fucose and sulphated sugar residues, moieties described as being recognised by surface receptors of alveolar macrophages, which host mycobacteria. Inhalable fucoidan microparticles loaded with antitubercular drugs were successfully produced with high association efficiencies of either isoniazid (95%) or rifabutin (81%). The microparticles evidenced no cytotoxicity on lung epithelial cells (A549). However, rifabutin-loaded microparticles showed a certain degree of toxicity on macrophage-like cells (THP-1) at the highest tested concentration (1 mg/mL). Furthermore, microparticles showed favourable aerodynamic properties for deep lung delivery (MMAD 2.0-3.8 µm) and, thus, show potential for an application as inhalable tuberculosis therapy.
- Inhalable chitosan microparticles for simultaneous delivery of isoniazid and rifabutin in lung tuberculosis treatmentPublication . Cunha, Ludmylla; Rodrigues, Susana; Rosa Da Costa, Ana; Faleiro, Maria Leonor; Buttini, Francesca; Grenha, AnaThe direct delivery of antibiotics to the lung has been considered an effective approach to treat pulmonary tuberculosis, which represents approximately 80% of total cases. In this sense, this work aimed at producing inhalable chitosan microparticles simultaneously associating isoniazid and rifabutin, for an application in pulmonary tuberculosis therapy. Spray-dried chitosan microparticles were obtained with adequate flow properties for deep lung delivery (aerodynamic diameter of 4 µm) and high drug association efficiencies (93% for isoniazid and 99% for rifabutin). The highest concentration of microparticles that was tested (1 mg/mL) decreased the viability of macrophage-differentiated THP-1 cells to around 60% after 24 h exposure, although no deleterious effect was observed in human alveolar epithelial (A549) cells. The release of LDH was, however, increased in both cells. Chitosan microparticles further evidenced capacity to activate macrophage-like cells, inducing cytokine secretion well above basal levels. Moreover, the propensity of macrophages to internalize microparticles was demonstrated, with uptake levels over 90%. Chitosan microparticles also inhibited bacterial growth by 96%, demonstrating that the microencapsulation preserved drug antibacterial activity in vitro. Overall, the obtained data suggest the potential of chitosan microparticles for inhalable lung tuberculosis therapy.
- Nano and microparticles as carriers for alveolar macrophage targeting in pulmonary tuberculosis therapyPublication . Cunha, Ludmylla Costa; Grenha, AnaTuberculosis (TB) is a leading infectious cause of death worldwide, even though a vaccine and several effective antibiotics are available for its prevention and treatment. Global TB control is very difficult due to various factors, including late diagnosis and patient non-compliance to long-term treatments, which leads to a high incidence of extensive resistance to effective anti-TB drugs. Overall, there are significant challenges associated with conventional TB therapy, including (i) drug resistance and toxicity; (ii) patient non-compliance, given the long-term therapy and severe side effects; (iii) and drug-drug interactions, particularly with antiretroviral drugs in patients co-infected with TB and HIV. Thus, the situation has come to a point where the development of novel intervention strategies is urgently needed. In this context, the pulmonary delivery of anti-TB drugs is a promising approach to treat lung TB. The disease represents approximately 80% of total cases, and thus the lung has been explored as an effective route for the delivery of drugs. This strategy not only allows targeting the infected organ instantly, but it can also reduce the systemic adverse effects of the antibiotics, which are main reasons for patient non-compliance. However, pulmonary drug delivery faces some limitations related with the proper airway structure, local degradation of drugs, and mucociliary clearance. In order to overcome some of these limitations of lung delivery, drug microencapsulation appears as a potential approach. In this sense, this work aimed at producing inhalable microparticles that efficiently associate two anti-TB drugs, isoniazid (INH) and/or rifabutin (RFB), for an application in pulmonary TB therapy. Fucoidan (FUC) and chitosan (CS) were the biomaterials selected to compose the matrix of the carriers. FUC is a polysaccharide composed of fucose units that has been reported to be specifically recognised by surface receptors of alveolar macrophages (the host cells of Mycobacterium tuberculosis). Likewise, CS is a polysaccharide composed of N-acetylglucosamine and D-glucosamine residues, the former being also specifically recognised by macrophages, according to the literature. This recognition by macrophages is believed to potentiate phagocytosis. The first approach involved the production of nanoparticles and it was considered that subsequent microencapsulation of the nanocarriers would be necessary to overcome aerodynamic limitations of nanosized carriers and their ability to reach the alveolar zone. Nanoparticles were spontaneously obtained by complexing FUC with CS, resulting from several formulations (polymeric mass ratio varying from 4:1 to 1:4). The produced unloaded FUC/CS nanoparticles presented average size range of 159 – 266 nm, PdI ranging between 0.21 and 0.36, and zeta potential varying from -39 mV to +12 mV, following the alteration of the mass ratios. The ability of FUC/CS nanoparticles to associate anti-TB drugs was assessed, and tests initiated with the incorporation of RFB, which was associated to obtain final polymer/drug mass ratio of 10/1 (w/w). Several attempts were made unsuccessfully, and therefore the work continued using another production method. Nanoprecipitation technique was then used, resulting in FUC nanoparticles and CS nanoparticles with mean size of 500 nm and 700 nm, respectively. However, the obtained nanoparticles showed little uniformity in size, indicated by PdI values, varying between 0.55 and 0.83. Moreover, an optimal protocol to obtain FUC- and CS-based nanoparticles that efficiently encapsulate INH and RFB could not be established. Taking into consideration the unsuccessful nanoparticle production and time restraints to accomplish the aims of the PhD plan, it was decided to focus the study on the development of polymeric microparticles. Microparticles were produced by spray-drying, associating the model drugs (INH and RFB), either separately or in combination. FUC microparticles effectively associated INH (95%) and RFB (81%), separately. Likewise, FUC microparticles loaded with the two anti-TB drugs simultaneously were also successfully produced, demonstrating high drug association efficiency (97% for INH and 95% for RFB). All FUC-based microparticles evidenced favourable aerodynamic properties for deep lung delivery upon inhalation. Single drug-loaded FUC microparticles showed aerodynamic diameter (MMAD) in the range of 2.0–3.8 μm. Likewise, the dual drug-loaded dry powder presented aerodynamic diameter of 3.6–3.9 μm. Overall, the formulations evidenced no cytotoxic effects on human alveolar epithelium cells (A549), although mild toxicity was observed on macrophage-differentiated THP-1 cells at the highest tested concentration (1 mg/mL). Nonetheless, this dose is considered overestimated compared to that effectively observed in vivo. The produced FUC microparticles also exhibited a propensity to be captured by macrophages or macrophage-like cells (target cells) in a dose-dependent manner. Particularly, dual drug-loaded microparticles displayed ability to activate the target cells and, moreover, effectively inhibited mycobacterial growth in vitro, preserving the bactericidal activity of the drugs. In vivo lung administration (BALB/c mice) of unloaded FUC microparticles indicated, in a preliminary assay, that the carriers induced no allergic responses. CS microparticles also associated INH (90%) and RFB (97%) efficiently, in separate formulations, whereas dual drug-loaded formulation resulted in 93% association efficiency for INH and 99% for RFB. All formulations presented adequate properties for deep lung delivery, with aerodynamic diameters ranging between 2.5 and 4 μm. Absence of toxicity was observed in human alveolar epithelium (A549 cells) but, as observed for FUC carriers, the highest tested concentration of microparticles (1 mg/mL) decreased the viability of macrophage-differentiated THP-1 cells upon 24 h exposure. This dose is however believed to be overestimated, as aforementioned. CS microparticles further evidenced strong ability to be internalised by macrophage-like cells (percentage of phagocytosis up to 99.9%), regardless of the dose. Yet, dual drug-loaded carriers induced macrophage activation and effectively inhibited the growth of mycobacteria in vitro. Moreover, the biomaterial (CS) was well tolerated by BALB/c mice upon pulmonary administration of unloadead CS microparticles. Overall, the obtained data gave positive indications on the potential of the proposed systems for an application as inhalable tuberculosis therapy.