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- Biocompatibility and stability of polysaccharide polyelectrolyte complexes aimed at respiratory deliveryPublication . Rodrigues, Susana; Cardoso, Lurdes; Costa, Ana M. Rosa da; Grenha, AnaChitosan (CS) and chondroitin sulfate (CHS) are natural polymers with demonstrated applicability in drug delivery, while nanoparticles are one of the most explored carriers for transmucosal delivery of biopharmaceuticals. In this work we have prepared CS/CHS nanoparticles and associated for the first time the therapeutic protein insulin. Fluorescein isothiocyanate bovine serum albumin (FITC-BSA) was also used to enable comparison of behaviors regarding differences in molecular weight (5.7 kDa versus 67 kDa). Nanoparticles of approximately 200 nm and positive zeta potential around +20 mV were obtained. These parameters remained stable for up to 1 month at 4 C. Proteins were associated with efficiencies of more than 50%. The release of FITC-BSA in PBS pH 7.4 was more sustained (50% in 24 h) than that of insulin (85% in 24 h). The biocompatibility of nanoparticles was tested in Calu-3 and A549 cells by means of three different assays. The metabolic assay MTT, the determination of lactate dehydrogenase release, and the quantification of the inflammatory response generated by cell exposure to nanoparticles have indicated an absence of overt toxicity. Overall, the results suggest good indications on the application of CS/CHS nanoparticles in respiratory transmucosal protein delivery, but the set of assays should be widened to clarify obtained results.
- Dual antibiotherapy of tuberculosis mediated by inhalable locust bean gum microparticlesPublication . Rodrigues, Susana; Alves, Ana D.; Cavaco, Joana S.; Pontes, Jorge Filipe; Guerreiro, Filipa; Rosa Da Costa, Ana; Buttini, Francesca; Grenha, AnaDespite 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.
- Pullulan-based nanoparticles: future therapeutic applications in transmucosal protein deliveryPublication . Rodrigues, Susana; Grenha, AnaCurrent advances in the field of drug delivery are aimed at finding adequate strategies for the administration of different drugs. Transmucosal delivery is the first-line option for the systemic delivery of many drugs, including proteins, a group of molecules with recognised therapeutic potential and wide range of applications (drug and genetic therapy, immunisation, among others).
- Guia orientador para a análise das PSF à luz da fonologia não linearPublication . Fernandes, Ana Margarida; Marques, Carolina; Gonçalves, Filipa; Afonso, Maria Alexandra; Baptista, Ana Catarina; Rodrigues, SusanaAs crianças com Perturbações dos Sons da Fala (PSF) constituem um grupo heterogéneo, uma vez que diferem entre si quanto à idade, gravidade, etiologia, tipo de erros de fala, envolvimento de outros aspetos do sistema linguístico, desenvolvimento e resposta ao tratamento, o que acarreta dificuldades na classificação, que são acrescidas pela ausência de guidelines claras de diagnóstico para a identificação de crianças com PSF (Dodd, 2011). Ao longo do tempo, foram surgindo diversas propostas de classificação das PSF. Estas classificações têm em conta diferentes fatores, tais como a etiologia subjacente às alterações evidenciadas – classificação de Shriberg et al. (2017) –, o perfil linguístico apresentado pela criança – classificação de Dodd (2014) –, ou os níveis subjacentes de dificuldade – classificação de Bowen (2011) –, entre outras.
- Evolução das competências do brincar numa criança com necessidades educativas específicas – estudo de casoPublication . Silva, Isabel Freitas; Baptista, Ana Catarina; Rodrigues, SusanaO presente artigo resulta de um trabalho de investigação, uma dissertação, que está a ser desenvolvida, no âmbito do Mestrado em Educação Especial, na Universidade do Algarve, cujo tema intitula-se por “Evolução das competências do brincar numa criança com Necessidades Educativas Específicas: Estudo de Caso”. Esta investigação centra-se na importância do brincar livre no desenvolvimento e aprendizagem de uma criança com necessidades educativas específicas, analisando a evolução das suas competências do brincar, através da sua interação com um ambiente lúdico, com materiais desafiantes e, maioritariamente, ao ar livre. Através do favorecimento do ambiente do brincar, pretende-se contribuir para o desenvolvimento global da criança e para a sua interação em contexto de uma educação inclusiva. Trata-se de um estudo observacional, de natureza longitudinal, que carateriza as competências do brincar da criança em três momentos diferentes, através da Escala Lúdica Pré-Escolar de Knox. Para além desta escala, foram também aplicados questionários aos restantes participantes, dando a conhecer a perspetiva do brincar e as competências e aprendizagens da criança do estudo em relação ao brincar e ao seu desenvolvimento, por parte dos profissionais de educação que o acompanham e do Encarregado de Educação Considera-se que o ambiente e os materiais que foram dispostos à criança, na sua interação, exploração e estruturação contribuem para estimular e promover as competências do brincar da criança e, posteriormente, através da observação e análise dos resultados obtidos, avaliar a evolução dessas mesmas competências e do seu desenvolvimento global. Caraterizar o ambiente lúdico da criança, avaliando o seu efeito em diversas áreas do seu desenvolvimento global, nomeadamente, ao nível da integração sensorial e da interação e comunicação entre os pares são pontos fundamentais da investigação.
- Chitosan/carrageenan nanoparticles: effect of cross-linking with tripolyphosphatePublication . Rodrigues, Susana; Costa, Ana M. Rosa da; Grenha, AnaChitosan/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 spray-dried chondroitin sulphate microparticles: effect of different solvents on particle properties and drug activityPublication . Rodrigues, Susana; da Costa, Ana M Rosa; Flórez Fernández, Noelia; Torres, María Dolores; Faleiro, Maria Leonor; Buttini, Francesca; Grenha, AnaSpray-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.
- Cytocompatibility and cellular interactions of chondroitin sulfate microparticles designed for inhaled tuberculosis treatmentPublication . Rodrigues, Susana; Cunha, Ludmylla Costa; Kollan, Julia; Neumann, Paul Robert; Costa, Ana Rosa da; Dailey, Lea Ann; Grenha, AnaTuberculosis remains a leading cause of death, therapeutic failure being mainly due to non-compliance with prolonged treatments, often associated with severe side-effects. New therapeutic strategies are demanded and, considering that the lung is the primary site of infection, direct lung delivery of antibiotics is possibly an effective approach. Therapeutic success in this context depends on suitable carriers that reach the alveoli where Mycobacterium hosts (macrophages) reside, as well as on their ability to promote macrophage capture and intracellular accumulation of drugs. In this work, we propose inhalable polymeric microparticles produced from chondroitin sulfate, a polymer composed by moieties recognized by macrophage receptors. Spray-drying of chondroitin sulfate in combination with two first-line antitubercular drugs (isoniazid and rifabutin) yielded respirable microparticles that evidenced no cytotoxic effects on lung epithelial cells (A549) and macrophages (dTHP1 and J744A.1). The microparticles exhibited tendency for macrophage capture in a dose-dependent manner, which was validated through imaging. High content image analysis revealed that rifabutin induced a dose-dependent increase in phospholipid content of macrophages, which could be prevented by formulation in chondroitin sulfate microparticles. This work provides indications on the potential of chondroitin sulfate carriers to interact with macrophages, thus providing a platform for drug delivery in the context of macrophage intracellular diseases, namely tuberculosis.
- Hybrid nanosystems based on natural polymers as protein carriers for respiratory delivery: stability and toxicological evaluationPublication . Rodrigues, Susana; Cordeiro, Clara; Seijo, Begona; Remunan-Lopez, Carmen; Grenha, AnaChitosan/carrageenan/tripolyphosphate nanoparticles were previously presented as holding potential for an application in transmucosal delivery of macromolecules, with tripolyphosphate demonstrating to contribute for both size reduction and stabilisation of the nanoparticles. This work was aimed at evaluating the capacity of the nanoparticles as protein carriers for pulmonary and nasal transmucosal delivery, further assessing their biocompatibility pattern regarding that application. Nanoparticles demonstrated stability in presence of lysozyme, while freeze-drying was shown to preserve their characteristics when glucose or sucrose were used as cryoprotectants. Bovine serum albumin was associated to the nanoparticles, which were successfully microencapsulated by spray-drying to meet the aerodynamic requirements inherent to pulmonary delivery. Finally, a satisfactory biocompatibility profile was demonstrated upon exposure of two respiratory cell lines (Calu-3 and A549 cells) to the carriers. A negligible effect on cell viability along with no alterations on transepithelial electrical resistance and no induction of inflammatory response were observed. (C) 2015 Elsevier Ltd. All rights reserved.
- Chondroitin sulphate microparticles for tuberculosis treatment: a way to target macrophagesPublication . Rodrigues, Susana; Rosa Da Costa, Ana; Grenha, AnaTuberculosis remains a leading cause of death; therapeutic failure being mainly due to non-compliance with prolonged treatments, often associated with severe side-effects. New therapeutic strategies are demanded and, considering that the lung is the primary site of infection, direct lung delivery of antibiotics is an interesting and, possibly, effective approach. Therapeutic success in this context depends on suitable carriers that reach the alveoli where Mycobacterium hosts (macrophages) reside, as well as on their ability to promote macrophage capture and intracellular accumulation of drugs. In this work, we propose inhalable chondroitin sulphate microparticles produced by spray-drying and tailored to suitable aerodynamic properties to reach the alveoli. Macrophage targeting will be driven by microparticle size, which is favoured for carriers of 1-2 μm, and composition based on chondroitin sulphate, a glycosaminoglycan comprised of alternating units of sulphated N-acetylgalactosamine and glucuronic acid residues, the former recognized by macrophage receptors. Spray-drying of chondroitin sulphate in combination with two first-line antitubercular drugs (isoniazid and rifabutin) was successful with a satisfactory production yield (> 70%). Microparticles have Feret’s diameter of 1.6 μm, potentiating macrophage uptake. Chondroitin sulphate as solution or microparticulate form and drug-loaded microparticles appear to not have a cytotoxic effect on alveolar epithelial cells. A more extended biocompatibility/safety assessment of this formulation needs to be performed. Taking into account the general trend of the results obtained so far, good indications are given that encourage the continuation of the studies in order to establish the potential of these microparticles as inhalable carriers in tuberculosis treatment.