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- Nano‐in‐Micro POxylated Polyurea Dendrimers and Chitosan Dry Powder Formulations for Pulmonary DeliveryPublication . Restani, Rita; Silva, A. Sofia; Pires, Rita; Cabral, Renato; Correia, Ilídio Joaquim Sobreira; Casimiro, Teresa; Bonifácio, Vasco; Ricardo, Ana AguiarPulmonary administration offers excellent advantages over conventional drug delivery routes, including increasing therapeutics bioavailability, and avoiding long‐term safety issues. Formulations of nano‐in‐micro dry powders for lung delivery are engineered using (S)‐ibuprofen as a model drug. These biodegradable formulations comprise nanoparticles of drug‐loaded POxylated polyurea dendrimers coated with chitosan using supercritical‐fluid‐assisted spray drying. The formulations are characterized in terms of morphology, particle‐size distribution, in vitro aerodynamic particle pulmonary distribution, and glutathione‐S‐transferase assay. It is demonstrated that ibuprofen‐loaded nanoparticles can be successfully incorporated into microspheres with adequate aerodynamic properties, mass median aerodynamic diameter (1.86–3.83 μm), and fine particle fraction (28%–45%), for deposition into the deep lung. The (S)‐ibuprofen dry powder formulations show enhanced solubility, high swelling behavior and a sustained drug release at physiologic pH. Also, POxylated polyureas decrease the (S)‐ibuprofen toxic effect on cancer cellular growth. The 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium (MTS) assays show no significant cytotoxicity on the metabolic activity of human lung adenocarcinoma ephithelial (A549) cell line for the lowest concentration (1 × 10−3 m), even for longer periods of contact with the cells (up to 120 h), and in the normal human dermal fibroblasts cell line the toxic effect is also reduced.
- Novel Methodology Based on Biomimetic Superhydrophobic Substrates to Immobilize Cells and Proteins in Hydrogel Spheres for Applications in Bone RegenerationPublication . Lima, Ana; Batista, Patrícia Sofia Pinhanços; Valente, Tiago António Martins; Silva, A. Sofia; Correia, Ilídio Joaquim Sobreira; Mano, JoãoCell-based therapies for regenerative medicine have been characterized by the low retention and integration of injected cells into host structures. Cell immobilization in hydrogels for target cell delivery has been developed to circumvent this issue. In this work mesenchymal stem cells isolated from Wistar rats bone marrow (rMSCs) were immobilized in alginate beads fabricated using an innovative approach involving the gellification of the liquid precursor droplets onto biomimetic superhydrophobic surfaces without the need of any precipitation bath. The process occurred in mild conditions preventing the loss of cell viability. Furthermore, fibronectin (FN) was also immobilized inside alginate beads with high efficiency in order to mimic the composition of the extracellular matrix. This process occurred in a very fast way (around 5 min), at room temperature, without aggressive mechanical strengths or particle aggregation. The methodology employed allowed the production of alginate beads exhibiting a homogenous rMSCs and FN distribution. Encapsulated rMSCs remained viable and were released from the alginate for more than 20 days. In vivo assays were also performed, by implanting these particles in a calvarial bone defect to evaluate their potential for bone tissue regeneration. Microcomputed tomography and histological analysis results showed that this hybrid system accelerated bone regeneration process. The methodology employed had a dual role by preventing cell and FN loss and avoiding any contamination of the beads or exchange of molecules with the surrounding environment. In principle, the method used for cell encapsulation could be extended to other systems aimed to be used in tissue regeneration strategies.
- Design and production of new nanodevices for future application in cancer therapyPublication . Silva, Ana Sofia Matias da; Correia, Ilídio Joaquim SobreiraNanotechnology is a multidisciplinary area of research that involves different knowledgements from, like life sciences, engineering and medicine. It has been used for different applications such as molecular imaging, molecular diagnosis and also targeted therapy. So far, ddifferent nanoscale devices have been produced, among them, inorganic nanoparticles, dendrimes, lipossomes, polymeric micelles, polymeric nanoparticles, nanotubes and nanofibers are some of the examples. Some of these particles exhibit unique optical and electrical properties allowing their course identification and precise location in the body. Gold nanoparticles are an example of inorganic particles with exceptional physico-chemical properties that demonstrate a huge potential for biomedicine applications. The present study aimed to produce gold nanoparticles by two different methods: the citrate reduction method developed by Frens in 1973 (method 1), and its functionalization with oligoaziridine, developed by the colleagues from Universidade Nova de Lisboa, as a capping agent (method 2). This second method relies on the fact that gold nanoparticles can be prepared in water directly by the complexation of the alkylamine molecules that act as reducing agents and consequently stabilizes gold nanoparticles. Moreover, gold nanoparticles produced by method 1 were also grafted with homofunctional maleimide poly(ethylene glycol) and then capped with oligoaziridine and the same parameters mentioned above were also evaluated. The cytotoxicity and cell internalization of the different nanoparticles herein produced, was evaluated through in vitro studies. The use of this new biosensor allow us to confirm the entry of the produced nanoparticles into cells opening new sights for the use of these particles as drug/gene delivery agents and/or as a new method for optimal imaging when methodologies like X-ray computed tomography or magnetic resonance cannot be used.
- Design of oligoaziridine-PEG coatings for efficient nanogold cellular biotaggingPublication . Silva, A. Sofia; Bonifácio, Vasco; Raje, Vivek; Branco, Paula S.; Machado, Paulo Filipe Brito; Correia, Ilídio Joaquim Sobreira; Ricardo, Ana AguiarGold nanoparticles (AuNPs) are the most investigated nanomaterials for theragnosis applications. In a research field where live cell assays, as well as the tracking of nanomaterials into a cell's environment, are of extremely importance, water-soluble AuNPs have been intensively studied to overcome the toxic effects exerted by coatings. Unfortunately, AuNPs fluorescent tagging often fails due to self-quenching and a careful design must be carried out to maintain optoelectronic properties and biocompatibility. In this work, the synthesis of fluorescent gold nanoprobes, able to enter the cell's environment (biotags) and target the cell nucleus, was designed and the particles tracked by confocal laser scanning microscopy. The coating of AuNPs with maleimide poly(ethylene glycol) and fluorescent oligoaziridine biocompatible oligomers, resulted in robust, optically active biotags that open novel insights into cancer theragnosis.
- Biomaterials for drug delivery patchesPublication . Santos, Lúcia; Correia, I.J.; Silva, A. Sofia; Mano, JoãoThe limited efficiency of conventional drugs has been instigated the development of new and more effective drug delivery systems (DDS). Transdermal DDS, are associated with numerous advantages such its painless application and less frequent replacement and greater flexibility of dosing, features that triggered the research and development of such devices. Such systems have been produced using either biopolymer; or synthetic polymers. Although the first ones are safer, biocompatible and present a controlled degradation by human enzymes or water, the second ones are the most currently available in the market due to their greater mechanical resistance and flexibility, and non-degradation over time. This review highlights the most recent advances (mainly in the last five years) of patches aimed for transdermal drug delivery, focusing on the different materials (natural, synthetic and blends) and latest designs for the development of such devices, emphasizing also their combination with drug carriers that enable enhanced drug solubility and a more controlled release of the drug over the time. The benefits and limitations of different patches formulations are considered with reference to their appliance to transdermal drug delivery. Furthermore, a record of the currently available patches on the market is given, featuring their most relevant characteristics. Finally, a list of most recent/ongoing clinical trials regarding the use of patches for skin disorders is detailed and critical insights on the current state of patches for transdermal drug delivery are also provided.
- Aerosolizable gold nano-in-micro dry powder formulations for theragnosis and lung deliveryPublication . Silva, A. Sofia; Sousa, Ana M. L.; Cabral, Renato; Silva, Marta; Sequeira, Clarinda Costa; Miguel, Sónia; Bonifácio, Vasco; Casimiro, Teresa; Correia, I.J.; Ricardo, Ana AguiarFunctionalized gold nanoparticles (AuNPs) have been widely investigated as promising multifunctional nanosystems for the theragnosis of lung cancer, the most common and prominent cause of cancer death worldwide. Nevertheless, nanoparticles are not in appropriate sizes for an accurate deep lung delivery and the lack of locally and effective delivery of therapeutic biomolecules to the deep lungs is, in fact, the major cause of low therapeutic outcome. Herein we incorporate, for the first time, AuNPs into respirable microparticles. AuNPs were functionalized with biocompatible oligo(2-oxazoline)-based optically stable fluorescent coatings, and conjugated with a laminin peptide (YIGSR) for targeted lung cancer delivery. These POxylated AuNPs were then incorporated into a chitosan matrix by a clean process, supercritical CO2-assisted spray drying (SASD), yielding nano-in-micro clean ultrafine dry powder formulations. The engineered formulations present the adequate morphology and flowability to reach the deep lung, with aerodynamic sizes ranging 3.2–3.8 μm, and excellent fine particle fraction (FPF) (FPF of 47% for CHT-bearing targeted AuNPs). The optimal biodegradation and release profiles enabled a sustained and controlled release of the embedded nanoparticles, with enhanced cellular uptake, opening new prospects for future lung theragnosis.
- Nanogold POxylation: towards always-on fluorescent lung cancer targetingPublication . Silva, A. Sofia; Silva, Marta; Miguel, Sónia P.; Bonifácio, Vasco; Correia, Ilídio Joaquim Sobreira; Ricardo, Ana AguiarGold nanoparticles (GNPs) are one of most investigated nanomaterials for lung cancer diagnosis and therapy (theragnosis). For imaging purposes, GNPs are often tagged with fluorescent probes, but unfortunately the associated plasmon resonance effect leads to fluorescence self-quenching, thus precluding accurate localization. In this study, biocompatible GNPs targeted with a laminin fragment were successfully engineered using fluorescent oligo-oxazolines produced in supercritical carbon dioxide. The architecture and properties of the POxylated constructs were fully characterized and confocal laser scanning microscopy measurements demonstrated a higher cellular uptake into A549 lung cancer cells through an active targeting mechanism.