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Sarmento, Célia, Ana Rita C. Duarte, and Ana Rita Jesus. "Can (Natural) deep eutectic systems increase the efficacy of ocular therapeutics?" European Journal of Pharmaceutics and Biopharmaceutics. 198 (2024): 114276. AbstractWebsite

The eye is one of the most complex organs in the human body, with a unique anatomy and physiology, being divided into anterior and posterior segments. Ocular diseases can occur in both segments, but different diseases affect different segments. Glaucoma and cataracts affect the anterior segment, while macular degeneration and diabetic retinopathy occur in the posterior segment. The easiest approach to treat ocular diseases, especially in the anterior segment, is through the administration of topical eye drops, but this route presents many constraints, namely precorneal dynamic and static ocular barriers. On the other hand, the delivery of drugs to the posterior segment of the eye is far more challenging and is mainly performed by the intravitreal route. However, it can lead to severe complications such as retinal detachment, endophthalmitis, increased intraocular pressure and haemorrhage. The design of new drug delivery systems for the anterior segment is very challenging, but targeting the posterior one is even more difficult and little progress has been made. In this review we will discuss various strategies including the incorporation of additives in the formulations, such as viscosity, permeability, and solubility enhancers, namely based on Deep eutectic systems (DES). Natural deep eutectic systems (NADES) have emerged to solve several problems encountered in pharmaceutical industry, regarding the pharmacokinetic and pharmacodynamic properties of drugs. NADES can contribute to the design of advanced technologies for ocular therapeutics, including hydrogels and nanomaterials. Here in, we revise some applications of (NA)DES in the development of new drug delivery systems that can be translated into the ophthalmology field.

Viñas-Ospino, Adriana, Ana Rita Jesus, Alexandre Paiva, Maria J. Esteve, Ana Frígola, Jesús Blesa, and Daniel López-Malo. "Comparison of green solvents for the revalorization of orange by-products: Carotenoid extraction and in vitro antioxidant activity." Food Chemistry. 442 (2024): 138530. AbstractWebsite

Orange peels contain a considerable number of bioactive compounds such as carotenoids, that can be used as ingredients in high-value products. The aim of this study was to compare orange peel extracts obtained with different green solvents (vegetable oils, fatty acids, and deep eutectic solvents (DES)). In addition, the chemical characterization of a new hydrophobic DES formed by octanoic acid and l-proline (C8:Pro) was performed. The extracts were compared in terms of carotenoid extraction, antioxidant activity by three methods, color, and environmental impact. The results confirmed that the mixture of C8:Pro is a DES and showed the highest carotenoid extraction (46.01 µg/g) compared to hexane (39.28 µg/g). The antioxidant activity was also the highest in C8:Pro (2438.8 µM TE/mL). Finally, two assessment models were used to evaluate the greenness and sustainability of the proposed extractions. These results demonstrated the potential use of orange peels in the circular economy and industry.

Domingues, Luis, Ana Rita C. Duarte, and Ana Rita Jesus. "How Can Deep Eutectic Systems Promote Greener Processes in Medicinal Chemistry and Drug Discovery?" Pharmaceuticals. 17 (2024). AbstractWebsite

Chemists in the medicinal chemistry field are constantly searching for alternatives towards more sustainable and eco-friendly processes for the design and synthesis of drug candidates. The pharmaceutical industry is one of the most polluting industries, having a high E-factor, which is driving the adoption of more sustainable processes not only for new drug candidates, but also in the production of well-established active pharmaceutical ingredients. Deep eutectic systems (DESs) have emerged as a greener alternative to ionic liquids, and their potential to substitute traditional organic solvents in drug discovery has raised interest among scientists. With the use of DESs as alternative solvents, the processes become more attractive in terms of eco-friendliness and recyclability. Furthermore, they might be more effective through making the process simpler, faster, and with maximum efficiency. This review will be focused on the role and application of deep eutectic systems in drug discovery, using biocatalytic processes and traditional organic chemical reactions, as new environmentally benign alternative solvents. Furthermore, herein we also show that DESs, if used in the pharmaceutical industry, may have a significant effect on lowering production costs and decreasing the impact of this industry on the quality of the environment.

Jesus, Ana Rita, Alexandre Paiva, and Ana Rita C. Duarte. "Current developments and future perspectives on biotechnology applications of natural deep eutectic systems." 39 (2023): 100731. AbstractWebsite

Natural Deep Eutectic Systems (NADES) have emerged in the past years as alternative solvents to traditional organic solvents and ionic liquids. NADES are easy to produce, sustainable, biocompatible, eco-friendly, remarkable solubilizing agents, and highly task-specific. The outstanding properties of this new liquid media have attracted the attention of researchers in the last decade in many fields and biotechnology is probably one of the fields where NADES have gained more relevance. Nonetheless, the progress beyond the state of the art in this field is not yet fully explored. Most research papers regarding the use of NADES in biotechnology are related to their use as solubility enhancers for poorly soluble active ingredients, particularly for pharmaceutical applications. However, the applicability of NADES in applications such as cryopreservation, stabilization of proteins and DNA, as well as other biomedical applications, has only recently been explored and presents still a plethora of discoveries to be unravelled. The current developments in this scientific field and future perspectives will be discussed herein.

Silva, Ana B. P., Ana R. Jesus, Daniela A. S. Agostinho, José M. S. S. Esperança, Alexandre Paiva, Ana R. C. Duarte, and Patrícia M. Reis. "Using dicationic ionic liquids to upgrade the cytotoxicity and solubility of poorly water-soluble drugs." 3.1 (2023): 100052. AbstractWebsite

New dicationic ionic liquids (DcILs) based on carboxylic acid-derived, N-acetyl amino acid-derived or bromide anions, and ammonium cations were synthesized and characterized. DcILs were employed as co-solvents to improve the solubility of ibuprofen and ketoprofen belonging to BCS class II. These DcILs demonstrated to be less cytotoxic towards fibroblasts L929 cells and contributed to an augment in the solubility of both drugs when compared with monocationic ionic liquids (McILs). The cytotoxic profile of some of these ILs was established, and when the linker between two ammonium cations was an ether group or a short alkyl chain an IC50 higher than 200 mM for fibroblasts L929 cells was achieved. The anion structure showed to be a key factor in the solubility of both drugs, being the family of carboxylic acid-derived, the one that presented the most significant effect, followed by N-acetyl amino acid-derived and finally bromide. The two dimensional 1H1H– NOESY NMR spectra showed the interaction between the IL and the two oral drugs, responsible for the improvement of their solubility. The lipophilicity (logP) of ibuprofen and ketoprofen reduced in the presence of these new DcILs.

Barreira, António, Andreia F. M. Santos, Madalena Dionísio, Ana R. Jesus, Ana Rita C. Duarte, Željko Petrovski, Ana B. Paninho, Márcia G. Ventura, and Luis C. Branco. "Ionic Levothyroxine Formulations: Synthesis, Bioavailability, and Cytotoxicity Studies." International Journal of Molecular Sciences. 24 (2023). AbstractWebsite

Thyroid diseases affect a considerable portion of the population, with hypothyroidism being one of the most commonly reported thyroid diseases. Levothyroxine (T4) is clinically used to treat hypothyroidism and suppress thyroid stimulating hormone secretion in other thyroid diseases. In this work, an attempt to improve T4 solubility is made through the synthesis of ionic liquids (ILs) based on this drug. In this context, [Na][T4] was combined with choline [Ch]+ and 1-(2-hydroxyethyl)-3-methylimidazolium [C2OHMiM]+ cations in order to prepare the desired T4-ILs. All compounds were characterized by NMR, ATR-FTIR, elemental analysis, and DSC, aiming to check their chemical structure, purities, and thermal properties. The serum, water, and PBS solubilities of the T4-ILs were compared to [Na][T4], as well as the permeability assays. It is important to note an improved adsorption capacity, in which no significant cytotoxicity was observed against L929 cells. [C2OHMiM][T4] seems to be a good alternative to the commercial levothyroxine sodium salt with promising bioavailability.

Ferreira, Inês João, Filipe Oliveira, Ana Rita Jesus, Alexandre Paiva, and Ana Rita C. Duarte. "Current methodologies for the assessment of deep eutectic systems toxicology: Challenges and perspectives." 362 (2022): 119675. AbstractWebsite

Deep eutectic systems (DES) are a mixture of two or more components where at least one works as a hydrogen bond acceptor (HBA) and another as a hydrogen bond donor (HBD). DES most distinctive characteristic is the fact that the mixture possesses a lower melting point, when compared to the melting point of its individual components. These systems have emerged as a “greener alternative” to organic solvents, while also offering several advantages over other “green” solvents such as ionic liquids (IL). However, the number of studies concerning the real biodegradability and biocompatibility are scarce and the methodologies are scattered through different articles. Current state of the art provides several reports using different models, namely using prokaryotic and eukaryotic cells but also more complex models considering whole organisms, such as plants and animals, attempting to understand DES toxicity at different complexity levels. The currently used methodologies is very different among authors, thus the standardization is urgently needed. This review’s purpose is to summarize the available data about DES toxicity, biocompatibility and biodegradability, while also assembling the different methodologies used in an effort to pave the way so that standard guidelines for future research work are established.

Jesus, Ana Rita, Ana Rita C. Duarte, and Alexandre Paiva. "Use of natural deep eutectic systems as new cryoprotectant agents in the vitrification of mammalian cells." 12.1 (2022): 8095. AbstractWebsite

In this work we present the potential of Natural Deep Eutectic Systems (NADES) as new vitrification media for the cryopreservation of mammalian cells. Several NADES composed of natural metabolites were prepared and tested as CPAs in two cell lines, L929 and HacaT cells. After the harvesting, cells were mixed with the eutectic systems, and frozen directly into liquid nitrogen to achieve a vitreous state. Then, the cells were thawed and it was observed that NADES were able to exert a significant cryoprotective effect in L929 cells, when compared with DMSO or in the absence of a CPA. For HacaT cells, only a eutectic system showed a slightly improvement in cell survival, while DMSO caused complete cell death. Moreover, the thermal behaviour of the best systems was studied for further understanding the protective properties of NADES as CPAs, and have shown a significant difference in terms of Tm and Tc when compared with DMSO and water. Additionally, the results obtained showed that NADES can be maintained in the growth media after the thawing step, without compromising cell viability. In summary, we have shown the great potential of NADES to be used as CPAs for the cryopreservation of different cell types, using the vitrification method.