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Projeto de investigação
Research Institute for Medicines
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Natural inspired small organic molecules for targeting aquaporins as a novel therapeutic approach to pancreatic cancer
Publication . Jesus, Rita Rodrigues Fernandes de; Afonso, Carlos; Vale, João
Exploration of natural products for potential therapeutic use and asymmetric organic synthesis is
an interesting approach for natural product valorisation. Therefore, in the present work, two
projects were investigated: discovery of novel pharmacological agents for cancer treatment and
development of a new series of asymmetric catalysts.
Aquaporins (AQPs) are transmembrane proteins involved in metastatic and tumour growth
processes. Thus, their potential as a novel druggable cancer target prompted the study of AQPs
modulators, from natural sources. In this first project, two labdane diterpenes present in Cistus
Ladaniferus — Labdanolic acid (LA) and 6-oxocativic acid (OA) — were isolated and their
biological activity was studied in three different AQPs (AQP1, AQP3, AQP5), aiming to unleash a
new therapeutic application for cancer treatment. Through AQPs permeability assays using the
stopped flow technique, results indicated that both compounds were not promising for cancer
treatment, since a decrease in permeability is not depicted in any of the AQPs under study. In
addition, a linear total synthesis of OA from LA was investigated but without promising results.
Using another natural source —Lupinus albus L. — another family of natural products is
encountered: quinolizidine alkaloids. Lupanine and Sparteine are members of this family with
known pharmacological activity. Sparteine is mostly known for its use in asymmetric catalysis as
a chiral base. Considering the possibility of developing a new series of asymmetric catalysts with
increased enantioselectivity comparing to the already known chiral base sparteine, and based on
studies previously developed in our group, in this second project we envisioned the development
of a new series of asymmetric catalysts via functionalization of lupanine with a nitrile functional
group, through a yet unreported C-H activation electrochemical approach. In batch, 17-cyano rac-lupanine was obtained in high yield and selectivity, whereas in flow, further studies need to
be performed to improve reaction selectivity. Additionally, derivatizations of 17-cyano-rac lupanine and 17-cyano-rac-sparteine were investigated, yielding new synthetically useful
products. In the context of finding novel AQPs inhibitors, 17-cyano-rac-lupanine, 17-cyano-rac sparteine and the derivatives synthetized throughout this work were studied in three different
AQPs (AQP1, AQP3, AQP5) using the stopped flow technique. No promising results in regard to
cancer treatment were obtained.
Both projects will add insight to natural product utility.
The Use of Topical Emulsions containing Serotonergic Drugs to Modulate Skin Inflammation
Publication . Fonseca, Marta Pereira Torres Lopes da; Marto, Joana; Ribeiro, Helena
Psoriasis is a chronic, immune, and inflammatory skin disease characterized by the appearance of localized or generalized erythematous plaques on the skin. Currently there are several treatments, however, the use of topical treatments is often a challenge due to several factors such as the low rate of penetration of the drug into the skin, the necessary complementation with other treatments and the low adherence by patients. In this sense, this dissertation focused on the development of a topical treatment, namely the development of an oil-in-water (O/W) emulsion with physical-chemical and sensory characteristics appealing to the consumer and capable of performing the desired therapeutic function through the incorporation of antidepressant drugs of the selective serotonin reuptake inhibitor (ISRS) type. Thus, after pre-formulation studies, O/W emulsions prepared by a cold emulsification process were developed, optimized, and characterized. Different solvents were studied as well as the influence of different preservatives in the final properties of the O/W emulsions. The developed emulsions were characterized and selected through rheological tests, droplet size distribution tests and microscopy analysis. After the development of the emulsion (placebo), in vitro and in vivo tests were performed for the selection of the drug to be incorporated. Antidepressants drugs, such as, fluvoxamine maleate, escitalopram oxalate and sertraline hydrochloride were studied, and fluvoxamine maleate was selected because it presents more promising results in the improvement of psoriatic symptoms. The incorporation of fluvoxamine maleate led physical instability of the selected emulsion. Thus, it was necessary to change the composition of the emulsion until reaching physical stability, incorporating the HPMC polymer and replacing the agent thickening with Sepineo™ P 600. The physicochemical characterization of the final emulsion with or without fluvoxamine maleate, as well as the rheological behaviour and the microstructure analysis were part of the study. Both formulations present suitable topical physicochemical properties. In vivo biological efficacy (hydration, TEWL and moisture evaluation) and sensorial analysis were performed on placebo final emulsion. The application of placebo for 28 days improved the hydration and the skin barrier, and the results of sensorial analysis confirmed a good consumer acceptability. In conclusion, it was possible to develop an O/W emulsion containing an antidepressant drug, with the desired and appealing characteristics for possible consumers and with promising biological and therapeutic efficacy.
Polylactic acid 3D scaffolds as platforms for local-delivery and hyperthermia applications in bone tumours
Publication . Saraiva, Ana Sofia Domingues Santos; Bettencourt, Ana; Gonçalves, Lídia
The bone is one of the most frequent target sites of metastases. Presently, treatment management has a variety of limitations that need to be replaced by more effective strategies. In this context, three-dimensional (3D) printed scaffolds can be an adjuvant local therapy for bone metastases as well as accomplish several biological and mechanical requirements for bone regeneration with the additional possibility of design the architecture of the scaffold according to the patient’s needs. In this study, 3D-printed PLA scaffolds were multifunctionalized with: i) collagen (Col) and hydroxyapatite nanoparticles (nHA) aiming the promotion of bone regeneration, ii) magnetic nanoparticles (MNs) for magnetic hyperthermia purposes against bone tumour cells and iii) minocycline (MH) to prevent bone infection. The physicochemical properties, in vitro swelling ability, drug (MH) release, bioactivity, magnetic heating properties, antimicrobial properties and cell response of functionalized PLA scaffolds were investigated. Results showed that scaffolds were obtained with uniform square macroporous and a stable functionalization. Also, a properly low swelling ability for bone regeneration and bioactive properties specially with the presence of nHA was attained. MH functionalization resulted into an efficient antibacterial activity against Staphylococcus aureus, a pathogen often associated with bone-related infections, that was coupled with an adequate drug release profile leading to an effective prevention of bone infection. PLA scaffolds revealed to be no cytotoxic for cells (MG-63 osteoblasts) and had a higher osteogenic potential when loaded with nHA. SPIONs demonstrated magnetic heating ability, however at the tested concentrations did not reached hyperthermia temperatures (40-45ºC). Therefore, multifunctionalized 3D printed PLA scaffolds showed to be a promising strategy for bone regeneration associated with infection prevention and bone cancer treatment with the need to improve on the magnet heating ability of MNs to advance bone tumours management.
Antioxidant – loaded mucoadhesive nanoparticles for eye drug delivery: new strategy to reduce the oxidative stress
Publication . Cordeiro, Sandra Isabel Nunes; Marto, Joana; Gonçalves, Lídia
There are several techniques of drug delivery to treat ocular diseases, which can be invasive or non-invasive. In the area of the non-invasive techniques, new pharmaceutical strategies based on nanotechnology and mucoadhesive polymers are emerging approaches to reach an efficient treatment of ocular diseases. The aim of this work is to develop novel nanoparticle systems with mucoadhesive properties, intended to encapsulate antioxidant molecules and, aiming to reduce the generation of oxidative stress and consequently ocular diseases. To improve the retention time of antioxidant molecules on the surface of the eye, our strategy involves the use of nanoparticles composed by chitosan and hyaluronic acid, with known mucoadhesive properties.
In conclusion, CS/HA nanoparticles is a promising platform for antioxidants delivery in the eye by increasing its residence time and controlled drug delivery. In the future, in vitro experiments would be useful to elucidate the biodistribution of drugs after ophthalmic application and would be also useful the scale-up of the manufacturing processes using a Quality by Design approach.
Characterization of demyelination and possible microglia targeting using BASHY dyes
Publication . Pinto, Maria Vaz; Borralho, Adelaide
Unidades organizacionais
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
6817 - DCRRNI ID
Número da atribuição
UID/DTP/04138/2019