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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.
- Dual on–off and off–on switchable oligoaziridine biosensorPublication . Raje, Vivek; Morgado, Patrícia I.; Ribeiro, MP.; Correia, Ilídio Joaquim Sobreira; Bonifácio, Vasco; Branco, Paula S.; Ricardo, Ana AguiarA water-soluble biocompatible aziridine-based biosensor with pendant anthracene units was synthesized by radicalar polymerization of N-substituted aziridines in supercritical carbon dioxide. The binding ability of the sensor towards a series of metal ions was examined by comparing the fluorescence intensities of the solutions before and after the addition of 100 equivalents of a solution of the metal ion chloride salt. A fast, simple and highly optical sensitive dual behavior, “off–on” and “on–off” response, was observed after the biosensor was exposed to the metal cations in aqueous solution. Zinc presented the highest fluorescence enhancement (turn-on) and copper presented the highest fluorescence quenching (turn-off). The response time was found to be instantaneous and the detection limit was achieved even in the presence of excess metal cation competitors. By using immunofluorescence microscopy it was also shown that oligoaziridine acts as an “on–off” probe through highly sensitive (detection limit of 1.6 nM), selective and reversible binding to copper anions under physiologic conditions using living Human Fibroblast cells. The stoichiometry for the reaction of the biosensor with Cu2+ was determined by a Job plot and indicates the formation of an oligoaziridine-Cu2+ 1:2 adduct.
- Biocompatible Polyurea Dendrimers with pH‐Dependent FluorescencePublication . Restani, Rita; Morgado, Patrícia I.; Ribeiro, MP.; Correia, I.J.; Ricardo, Ana Aguiar; Bonifácio, VascoBiocompatible and biodegradable water‐soluble dendrimers comprising ureas within the interior and amino groups on the periphery were synthesized in supercritical carbon dioxide (dendrimer of generation 1 shown in picture). This novel class of dendrimers shows a pH‐dependent intrinsic blue fluorescence at very low concentrations, which makes them potential polymeric fluorescent cell markers.
- Biocompatible oligo-oxazoline crosslinkers: Towards advanced chitosans for controlled dug releasePublication . Lopes, Mafalda; Restani, Rita; Carvalho, Marco António Paulo de; Correia, I.J.; Ricardo, Ana Aguiar; Bonifácio, VascoChitosan, a natural and abundant biopolymer has been long explored as a biocompatible material for the preparation of drug delivery devices. This strategy has been mostly accomplished using chemically crosslinked chitosan leading to more stable scaffolds. However, crosslinking has been shown to reduce both biocompatibility and swelling. In this work chitosan was crosslinked with novel biocompatible crosslinkers, based on oligo-oxazolines and glycidyl methacrylate copolymers, leading to patches with a very high swelling capacity. Dexamethasone therapeutics is strongly enhanced by a controlled release administration. This study shows that oligo-oxazoline-crosslinked chitosan is a suitable biomaterial for loading and controlled release of dexamethasone.
- Polyurea dendrimer for efficient cytosolic siRNA deliveryPublication . Restani, Rita; Conde, João; Baptista, Pedro; Cidade, Maria Teresa Varanda; Bragança, Ana; Morgado, Jorge; Correia, Ilídio Joaquim Sobreira; Ricardo, Ana Aguiar; Bonifácio, VascoThe design of small interfering RNA (siRNA) delivery materials showing efficacy in vivo is at the forefront of nanotherapeutics research. Polyurea (PURE-type) dendrimers are ‘smart’ biocompatible 3D polymers that unveil a dynamic and elegant back-folding mechanism involving hydrogen bonding between primary amines at the surface and tertiary amines and ureas at the core. Similarly, to a biological proton pump, they are able to automatically and reversibly transform their conformation in response to pH stimulus. Here, we show that PURE-G4 is a useful gene silencing platform showing no cellular toxicity. As a proof of concept we investigated the PURE-G4-siRNA dendriplex, which was shown to be an attractive platform with high transfection efficacy. The simplicity associated with the complexation of siRNA with polyurea dendrimers makes them a powerful tool for efficient cytosolic siRNA delivery.
- 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.
- Natural melanin: A potential pH-responsive drug release devicePublication . Araújo, Marco; Viveiros, Raquel; Correia, Tiago R.; Correia, Ilídio Joaquim Sobreira; Bonifácio, Vasco; Casimiro, Teresa; Ricardo, Ana AguiarThis work proposes melanin as a new nanocarrier for pH-responsive drug release. Melanin is an abundant natural polymer that can be easily extracted from cuttlefish as nanoparticles with a suitable size range for drug delivery. However, despite its high potentiality, the application of this biopolymer in the pharmaceutical and biomedical fields is yet to be explored. Herein, melanin nanoparticles were impregnated with metronidazole, chosen as model antibiotic drug, using supercritical carbon dioxide. The drug release profile was investigated at acidic and physiologic pH, and the dominant mechanism was found to follow a non-Fickian transport. Drug release from melanin shows a strong pH dependency, which allied to its biocompatibility and lack of cytotoxicity envisages its potential application as nanocarrier in formulations for colon and intestine targeted drug delivery.
- 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.