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2019
Sutradhar, M, Alegria ECBA, Ferretti F, Raposo LR, Guedes da Silva FMC, Baptista PV, Fernandes AR, Pombeiro AJL.  2019.  Antiproliferative activity of heterometallic sodium and potassium-dioxidovanadium(V) polymers, 2019. Journal of Inorganic Biochemistry. 200:110811. AbstractWebsite

The syntheses of the heterometallic sodium and potassium-dioxidovanadium 2D polymers, [NaVO2(1κNOO’;2κO”-L)(H2O)]n (1) and [KVO2(1κNOO’;2κO’;3κO”-L)(EtOH)]n (2) (where the κ notation indicates the coordinating atoms of the polydentate ligand L) derived from (3,5-di-tert-butyl-2-hydroxybenzylidene)-2-hydroxybenzohydrazide (H2L) are reported. The polymers were characterized by IR, NMR, elemental analysis and single crystal X-ray diffraction analysis. The antiproliferative potential of 1 and 2 was examined towards four human cancer cell lines (ovarian carcinoma, A2780, colorectal carcinoma, HCT116, prostate carcinoma, PC3 and breast adenocarcinoma, MCF-7cell lines) and normal human fibroblasts. Complex 1 and 2 showed the highest cytotoxic activity against A2780 cell line (IC50 8.2 and 11.3 μM, respectively) with 1 > 2 and an IC50 in the same range as cisplatin (IC50 3.4 μM; obtained in the same experimental conditions) but, interestingly, with no cytotoxicity to healthy human fibroblasts for concentrations up to 75 μM. This high cytotoxicity of 1 in ovarian cancer cells and its low cytotoxicity in healthy cells demonstrates its potential for further biological studies. Our results suggest that both complexes induce ovarian carcinoma cell death via apoptosis and autophagy, but autophagy is the main biological cause of the reduction of viability observed and that ROS (reactive oxygen species) may play an important role in triggering cell death.

Oliveira, H, Roma-Rodrigues C, Santos A, Veigas B, Brás N, Faria A, Calhau C, de Freitas V, Baptista PV, Mateus N, Fernandes AR, Fernandes I.  2019.  GLUT1 and GLUT3 involvement in anthocyanin gastric transport- Nanobased targeted approach, 2019. Scientific Reports. 9(1):789. AbstractWebsite

Anthocyanins may protect against a myriad of human diseases. However few studies have been conducted to evaluate their bioavailability so their absorption mechanism remains unclear. This study aimed to evaluate the role of two glucose transporters (GLUT1 and GLUT3) in anthocyanins absorption in the human gastric epithelial cells (MKN-28) by using gold nanoparticles to silence these transporters. Anthocyanins were purified from purple fleshed sweet potatoes and grape skin. Silencing of GLUT1 and/or GLUT3 mRNA was performed by adding AuNP@GLUT1 and/or AuNP@GLUT3 to MKN-28 cells. Downregulation of mRNA expression occurred concomitantly with the reduction in protein expression. Malvidin-3-O-glucoside (Mv3glc) transport was reduced in the presence of either AuNP@GLUT1 and AuNP@GLUT3, and when both transporters were blocked simultaneously. Peonidin-3-(6′-hydroxybenzoyl)-sophoroside-5-glucoside (Pn3HBsoph5glc) and Peonidin-3-(6′-hydroxybenzoyl-6″-caffeoyl)-sophoroside-5-glucoside (Pn3HBCsoph5glc) were assayed to verify the effect of the sugar moiety esterification at glucose B in transporter binding. Both pigments were transported with a lower transport efficiency compared to Mv3glc, probably due to steric hindrance of the more complex structures. Interestingly, for Pn3HBCsoph5glc although the only free glucose is at C5 and the inhibitory effect of the nanoparticles was also observed, reinforcing the importance of glucose on the transport regardless of its position or substitution pattern. The results support the involvement of GLUT1 and GLUT3 in the gastric absorption of anthocyanins.

Roma-Rodrigues, C, Pombo I, Raposo L, Pedrosa P, Fernandes AR, Baptista PV.  2019.  Nanotheranostics Targeting the Tumor Microenvironment, 2019. Front. Bioeng. Biotechnol.. 7:197. AbstractWebsite

Cancer is considered the most aggressive malignancy to humans, and definitely the major cause of death worldwide. Despite the different and heterogenous presentation of the disease, there are pivotal cell elements involved in proliferation, differentiation, and immortalization, and ultimately the capability to evade treatment strategies. This is of utmost relevance when we are just beginning to grasp the complexity of the tumor environment and the molecular “evolution” within. The tumor micro-environment (TME) is thought to provide for differentiation niches for clonal development that results in tremendous cancer heterogeneity. To date, conventional cancer therapeutic strategies against cancer are failing to tackle the intricate interplay of actors within the TME. Nanomedicine has been proposing innovative strategies to tackle this TME and the cancer cells that simultaneously provide for biodistribution and/or assessment of action. These nanotheranostics systems are usually multi-functional nanosystems capable to carry and deliver active cargo to the site of interest and provide diagnostics capability, enabling early detection, and destruction of cancer cells in a more selective way. Some of the most promising multifunctional nanosystems are based on gold nanoparticles, whose physic-chemical properties have prompt for the development of multifunctional, responsive nanomedicines suitable for combinatory therapy and theranostics. Herein, we shall focus on the recent developments relying on the properties of gold nanoparticles as the basis for nanotheranostics systems against the heterogeneity within the TME.

Veigas, B, Matias A, Calmeiro T, Fortunato E, Fernandes AR, Baptista PV.  2019.  Antibody modified gold nanoparticles for fast colorimetric screening of rheumatoid arthritis. Analyst. 144:3613-3619.: The Royal Society of Chemistry AbstractWebsite

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation and one of the main causes of chronic disability worldwide with high prevalence in the ageing population. RA is characterized by autoantibody production{,} synovial inflammation and bone destruction{,} and the most accepted biomarker is rheumatoid factor (RF) autoantibodies. In this work{,} we developed a low-cost approach for the detection and quantification of the RF marker. This colorimetric immunosensor is based on gold nanoprobe crosslinking that results in extensive aggregation in the presence of the pentameric IgM RF. Aggregation of the nanoconjugates yields a color change from red to purple that can be easily observed by the naked eye. The interaction between nanoconjugates and the specific target was confirmed via dynamic light scattering (DLS){,} Raman spectroscopy and atomic force microscopy (AFM) imaging. This conceptual system shows a LOD of 4.15 UA mL−1 IgM RF (clinical threshold is set for 20 IU mL−1). The one-step biosensor strategy herein proposed is much faster than conventional detection techniques{,} without the need for secondary antibodies{,} additional complex washing or signal amplification protocols. To the best of our knowledge this is the first report on target induced aggregation of gold nanoprobes for quantitative colorimetric autoantibody detection.

Jesus, AR, Soromenho MRC, Raposo LR, Esperança JMSS, Baptista PV, Fernandes AR, Reis PM.  2019.  Enhancement of water solubility of poorly water-soluble drugs by new biocompatible N-acetyl amino acid N-alkyl cholinium-based ionic liquids. European Journal of Pharmaceutics and Biopharmaceutics. 137:227-232. AbstractWebsite

The major challenge of the pharmaceutical industry is to find potential solvents for poorly water-soluble drug molecules. Ionic liquids (ILs) have attracted this industry as (co-) solvents due to their unique physicochemical and biological properties. Herein, a straightforward approach for the enhancement of the water solubility of paracetamol and sodium diclofenac is presented, using new biocompatible N-acetyl amino acid N-alkyl cholinium-based ionic liquids as co-solvents (0.2–1 mol%). These new ionic liquids were able to increase the water solubility of these drugs up to four times that in pure water or in an inorganic salt solution. In the presence of these ILs, the drugs lipophilicity (log P was not significantly changed for paracetamol, but for sodium diclofenac it was possible to decrease significantly its lipophilicity. Concerning cytotoxicity in human dermal fibroblasts it was observed that ILs did not show a significant toxicity, and were able to improve cell viability compared with the respective precursors.

Santos, MM, Raposo LR, Carrera GVSM, Costa A, Dionísio M, Baptista PV, Fernandes AR, Branco LC.  2019.  Ionic Liquids and Salts from Ibuprofen as Promising Innovative Formulations of an Old Drug. ChemMedChem. 14:907-911., Number 9 AbstractWebsite

Abstract Herein we report the synthesis of novel ionic liquids (ILs) and organic salts by combining ibuprofen as anion with ammonium, imidazolium, or pyridinium cations. The methodology consists of an acid–base reaction of neutral ibuprofen with cation hydroxides, which were previously prepared by anion exchange from the corresponding halide salts with Amberlyst A-26(OH). In comparison with the parent drug, these organic salts display higher solubility in water and biological fluids and a smaller degree of polymorphism, which in some cases was completely eliminated. With the exception of [C16Pyr][Ibu] and [N1,1,2,2OH1][Ibu], the prepared salts did not affect the viability of normal human dermal fibroblasts or ovarian carcinoma (A2780) cells. Therefore, these ibuprofen-based ionic liquids may be very promising lead candidates for the development of effective formulations of this drug.

Kourmentza, C, Araujo D, Sevrin C, Roma-Rodriques C, Ferreira JL, Freitas F, Dionisio M, Baptista PV, Fernandes AR, Grandfils C, Reis MAM.  2019.  Occurrence of non-toxic bioemulsifiers during polyhydroxyalkanoate production by Pseudomonas strains valorizing crude glycerol by-product. Bioresource Technology. 281:31-40. AbstractWebsite

While screening for polyhydroxyalkanoate (PHA) producing strains, using glycerol rich by-product as carbon source, it was observed that extracellular polymers were also secreted into the culture broth. The scope of this study was to characterize both intracellular and extracellular polymers, produced by Pseudomonas putida NRRL B-14875 and Pseudomonas chlororaphis DSM 50083, mostly focusing on those novel extracellular polymers. It was found that they fall into the class of bioemulsifiers (BE), as they showed excellent emulsion stability against different hydrocarbons/oils at various pH conditions, temperature and salinity concentrations. Cytotoxicity tests revealed that BE produced by P. chlororaphis inhibited the growth of highly pigmented human melanoma cells (MNT-1) by 50% at concentrations between 150 and 200 μg/mL, while no effect was observed on normal skin primary keratinocytes and melanocytes. This is the first study reporting mcl-PHA production by P. putida NRRL B-14785 and bioemulsifier production from both P. putida and P. chlororaphis strains.

Das, K, Datta A, Massera C, Roma-Rodrigues C, Barroso M, Baptista PV, Fernandes AR.  2019.  Structural aspects of a trimetallic CuII derivative: cytotoxicity and anti-proliferative activity on human cancer cell lines. Journal of Coordination Chemistry. 72:920-940., Number 5-7: Taylor & Francis AbstractWebsite
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Almeida, J, Roma-Rodrigues C, Mahmoud AG, da Silva FGMC, Pombeiro AJL, Martins LMDRS, Baptista PV, Fernandes AR.  2019.  Structural characterization and biological properties of silver(I) tris(pyrazolyl)methane sulfonate. Journal of Inorganic Biochemistry. 199:110789. AbstractWebsite

The water-soluble 1D helical coordination polymer [Ag(Tpms)]n (1) [Tpms = tris(pyrazolyl)methane sulfonate, −O3SC(pz)3; pz = pyrazolyl] was synthesized and fully characterized, its single-crystal X-ray diffraction analysis revealing the ligand acting as a bridging chelate N3-donor ligand. The antiproliferative potential of 1 was performed on two human tumour cell lines, A2780 and HCT116, and in normal fibroblasts, with a much higher effect in the former cell line (IC50 of 0.04 μM) as compared to the latter cell line and to normal fibroblasts. Compound 1 does not alter cell cycle progression but interferes with the adherence of A2780 cells triggering cell apoptosis. Apoptosis appears to occur via the extrinsic pathway (no changes in mitochondria membrane potential, reactive oxygen species (ROS) and pro-apoptotic (B-cell lymphoma 2 (BCL-2) associated protein (BAX))/anti-apoptotic (BCL-2) ratio) being this hypothesis also supported by the presence of silver mainly in the supernatants of A2780 cells. Results also indicated that cell death via autophagy was triggered. Proteomic analysis allowed us to confirm that compound 1 is able to induce a stress response in A2780 cells that is related with its antiproliferative activity and the trigger of apoptosis.

Pedrosa, P, Corvo LM, Ferreira-Silva M, Martins P, Carvalheiro MC, Costa PM, Martins C, Martins LMDRS, Baptista PV, Fernandes AR.  2019.  Targeting Cancer Resistance via Multifunctional Gold Nanoparticles. International Journal of Molecular Sciences. 20, Number 21 AbstractWebsite

Resistance to chemotherapy is a major problem facing current cancer therapy, which is continuously aiming at the development of new compounds that are capable of tackling tumors that developed resistance toward common chemotherapeutic agents, such as doxorubicin (DOX). Alongside the development of new generations of compounds, nanotechnology-based delivery strategies can significantly improve the in vivo drug stability and target specificity for overcoming drug resistance. In this study, multifunctional gold nanoparticles (AuNP) have been used as a nanoplatform for the targeted delivery of an original anticancer agent, a Zn(II) coordination compound [Zn(DION)2]Cl2 (ZnD), toward better efficacy against DOX-resistant colorectal carcinoma cells (HCT116 DR). Selective delivery of the ZnD nanosystem to cancer cells was achieved by active targeting via cetuximab, NanoZnD, which significantly inhibited cell proliferation and triggered the death of resistant tumor cells, thus improving efficacy. In vivo studies in a colorectal DOX-resistant model corroborated the capability of NanoZnD for the selective targeting of cancer cells, leading to a reduction of tumor growth without systemic toxicity. This approach highlights the potential of gold nanoformulations for the targeting of drug-resistant cancer cells.

Roma-Rodrigues, C, Mendes R, Baptista PV, Fernandes AR.  2019.  Targeting Tumor Microenvironment for Cancer Therapy. International Journal of Molecular Sciences. 20, Number 4 AbstractWebsite

Cancer development is highly associated to the physiological state of the tumor microenvironment (TME). Despite the existing heterogeneity of tumors from the same or from different anatomical locations, common features can be found in the TME maturation of epithelial-derived tumors. Genetic alterations in tumor cells result in hyperplasia, uncontrolled growth, resistance to apoptosis, and metabolic shift towards anaerobic glycolysis (Warburg effect). These events create hypoxia, oxidative stress and acidosis within the TME triggering an adjustment of the extracellular matrix (ECM), a response from neighbor stromal cells (e.g., fibroblasts) and immune cells (lymphocytes and macrophages), inducing angiogenesis and, ultimately, resulting in metastasis. Exosomes secreted by TME cells are central players in all these events. The TME profile is preponderant on prognosis and impacts efficacy of anti-cancer therapies. Hence, a big effort has been made to develop new therapeutic strategies towards a more efficient targeting of TME. These efforts focus on: (i) therapeutic strategies targeting TME components, extending from conventional therapeutics, to combined therapies and nanomedicines; and (ii) the development of models that accurately resemble the TME for bench investigations, including tumor-tissue explants, “tumor on a chip” or multicellular tumor-spheroids.

2018
McCully, M, Conde J, V. Baptista P, Mullin M, Dalby MJ, Berry CC.  2018.  Nanoparticle-antagomiR based targeting of miR-31 to induce osterix and osteocalcin expression in mesenchymal stem cells, 2018/02/14. PLOS ONE. 13(2):e0192562-.: Public Library of Science AbstractWebsite

Mesenchymal stem cells are multipotent adult stem cells capable of generating bone, cartilage and fat, and are thus currently being exploited for regenerative medicine. When considering osteogenesis, developments have been made with regards to chemical induction (e.g. differentiation media) and physical induction (e.g. material stiffness, nanotopography), targeting established early transcription factors or regulators such as runx2 or bone morphogenic proteins and promoting increased numbers of cells committing to osteo-specific differentiation. Recent research highlighted the involvement of microRNAs in lineage commitment and terminal differentiation. Herein, gold nanoparticles that confer stability to short single stranded RNAs were used to deliver MiR-31 antagomiRs to both pre-osteoblastic cells and primary human MSCs in vitro. Results showed that blocking miR-31 led to an increase in osterix protein in both cell types at day 7, with an increase in osteocalcin at day 21, suggesting MSC osteogenesis. In addition, it was noted that antagomiR sequence direction was important, with the 5 prime reading direction proving more effective than the 3 prime. This study highlights the potential that miRNA antagomiR-tagged nanoparticles offer as novel therapeutics in regenerative medicine.

Pedrosa, P, Mendes R, Cabral R, Martins LMDRS, Baptista PV, Fernandes AR.  2018.  Combination of chemotherapy and Au-nanoparticle photothermy in the visible light to tackle doxorubicin resistance in cancer cells, 2018. Scientific Reports. 8(1):11429. AbstractWebsite

Despite great advances in the fight against cancer, traditional chemotherapy has been hindered by the dose dependent adverse side effects that reduce the usable doses for effective therapy. This has been associated to drug resistance in tumor cells that often cause relapse and therapy failure. These drawbacks have been tackled by combining different therapeutic regiments that prevent drug resistance while decreasing the chemotherapy dose required for efficacious ablation of cancer. In fact, new metallic compounds have been in a continuous development to extend the existing chemotherapy arsenal for these combined regimens. Here, we demonstrate that combination of a metallic compound (TS265), previously characterized by our group, with photothermy circumvents cells resistant to Doxorubicin (DOX). We first engendered a colorectal carcinoma cell line (HCT116) highly resistant to DOX, whose viability was diminished after administration of TS265. Cancer cell death was potentiated by challenging these cells with 14 nm spherical gold nanoparticles followed by laser irradiation at 532 nm. The combination of TS265 with photothermy lead to 65% cell death of the DOX resistant cells without impacting healthy cells. These results support the use of combined chemotherapy and photothermy in the visible spectrum as an efficient tool for drug resistant tumors.

Ribeiro, APC, Anbu S, Alegria ECBA, Fernandes AR, Baptista PV, Mendes R, Matias AS, Mendes M, Guedes da Silva MFC, Pombeiro AJL.  2018.  Evaluation of cell toxicity and DNA and protein binding of green synthesized silver nanoparticles, 2018. Biomedicine & Pharmacotherapy. 101:137-144. AbstractWebsite

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Alves, PU, Vinhas R, Fernandes AR, Birol SZ, Trabzon L, Bernacka-Wojcik I, Igreja R, Lopes P, Baptista PV, Águas H, Fortunato E, Martins R.  2018.  Multifunctional microfluidic chip for optical nanoprobe based RNA detection – application to Chronic Myeloid Leukemia, 2018. Scientific Reports. 8(1):381. AbstractWebsite

Many diseases have their treatment options narrowed and end up being fatal if detected during later stages. As a consequence, point-of-care devices have an increasing importance for routine screening applications in the health sector due to their portability, fast analyses and decreased cost. For that purpose, a multifunctional chip was developed and tested using gold nanoprobes to perform RNA optical detection inside a microfluidic chip without the need of molecular amplification steps. As a proof-of-concept, this device was used for the rapid detection of chronic myeloid leukemia, a hemato-oncological disease that would benefit from early stage diagnostics and screening tests. The chip passively mixed target RNA from samples, gold nanoprobes and saline solution to infer a result from their final colorimetric properties. An optical fiber network was used to evaluate its transmitted spectra inside the chip. Trials provided accurate output results within 3 min, yielding signal-to-noise ratios up to 9 dB. When compared to actual state-of-art screening techniques of chronic myeloid leukemia, these results were, at microscale, at least 10 times faster than the reported detection methods for chronic myeloid leukemia. Concerning point-of-care applications, this work paves the way for other new and more complex versions of optical based genosensors.

Cordeiro, M, Otrelo-Cardoso AR, Svergun DI, Konarev PV, Lima JC, Santos-Silva T, Baptista PV.  2018.  Optical and Structural Characterization of a Chronic Myeloid Leukemia DNA Biosensor, 2018. ACS Chemical BiologyACS Chemical Biology. 13(5):1235-1242.: American Chemical Society AbstractWebsite
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Daniela, P, Margarida F, Gabriela M, Catarina R‐R, V. BP, R. FA, Sónia B, Luísa CA, M. ACA, M. FL, S. BP.  2018.  Synthesis, Cytotoxicity Evaluation in Human Cell Lines and in Vitro DNA Interaction of a Hetero‐Arylidene‐9(10H)‐Anthrone, 2018. European Journal of Organic ChemistryEuropean Journal of Organic Chemistry. 2018(4):545-549.: Wiley-Blackwell AbstractWebsite

A new and never before reported hetero?arylidene?9(10H)?anthrone structure (4) was unexpectedly isolated on reaction of 1,2?dimethyl?3?ethylimidazolium iodide (2) and 9?anthracenecarboxaldehyde (3) under basic conditions. Its structure was unequivocally confirmed by X?ray crystallography. No cytotoxicity in human healthy fibroblasts and in two different cancer cell lines was observed, indicating its applicability in biological systems. Compound 4 interacts with CT?DNA by intercalation between the adjacent base pairs of DNA with a high binding affinity [Kb = 2.0?(±0.20)???105 m?1], which is 10?? higher than that described for doxorubicin [Kb = 3.2?(±0.23)???104 m?1]. Furthermore, compound 4 quenches the fluorescence emission of a GelRed?CT?DNA system with a quenching constant (KSV) of 3.3?(±0.3)???103 m?1 calculated by the Stern?Volmer equation.

Vinhas, R, Fernandes AR, Baptista PV.  2018.  Molecular Diagnostics of Chronic Myeloid Leukemia - precision medicine via gold nanoparticles. In CDx and precision medicine for hematologic malignancies. (Il-Jin Kim, Ed.).:205-230.: PanStanford Publishing
Vinhas, R, Lourenço A, Santos S, Lemos M, Ribeiro P, de Sousa AB, Baptista PV, Fernandes AR.  2018.  A novel BCR-ABL1 mutation in a patient with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia. :8589—8598.: OncoTargets and Therapy
Vinhas, R, Louren{\c c}o A, Santos S, Ribeiro P{\'ıcia, Silva M, de Sousa AB, Baptista PV, Fernandes AR.  2018.  A double Philadelphia chromosome-positive chronic myeloid leukemia patient, co-expressing P210BCR-ABL1 and P195BCR-ABL1 isoforms. Haematologica. : Haematologica AbstractWebsite

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Baptista, PV.  2018.  Gold nanoprobe-based non-crosslinking hybridization for molecular diagnostics: an update. Expert Review of Molecular Diagnostics. 18:767-773., Number 9: Taylor & Francis AbstractWebsite
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Svahn, N, Moro AJ, Roma-Rodrigues C, Puttreddy R, Rissanen K, Baptista PV, Fernandes AR, Lima JC, Rodríguez L.  2018.  The Important Role of the Nuclearity, Rigidity, and Solubility of Phosphane Ligands in the Biological Activity of Gold(I) Complexes. Chemistry – A European Journal. 24:14654-14667., Number 55 AbstractWebsite

Abstract A series of 4-ethynylaniline gold(I) complexes containing monophosphane (1,3,5-triaza-7-phosphaadamantane (pta; 2), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (3), and PR3, with R=naphthyl (4), phenyl (5), and ethyl (6)) and diphosphane (bis(diphenylphosphino)acetylene (dppa; 7), trans-1,2-bis(diphenylphosphino)ethene (dppet; 8), 1,2-bis(diphenylphosphino)ethane (dppe; 9), and 1,3-bis(diphenylphosphino)propane (dppp; 10)) ligands have been synthesized and their efficiency against tumor cells evaluated. The cytotoxicity of complexes 2–10 was evaluated in human colorectal (HCT116) and ovarian (A2780) carcinoma as well as in normal human fibroblasts. All the complexes showed a higher antiproliferative effect in A2780 cells, with the cytotoxicity decreasing in the following order 5>6=9=10>8>2>4>7>3. Complex 4 stands out for its very high selectivity towards ovarian carcinoma cells (IC50=2.3 μm) compared with colorectal carcinoma and normal human fibroblasts (IC50>100 μm), which makes this complex very attractive for ovarian cancer therapy. Its cytotoxicity in these cells correlates with the induction of the apoptotic process and an increase of intracellular reactive oxygen species (ROS). The effects of the nuclearity, rigidity, and solubility of these complexes on their biological activity were also analyzed. X-ray crystal structure determination allowed the identification of short N−H⋅⋅⋅π contacts as the main driving forces for the three-dimensional packing in these molecules.

Baptista, PV, McCusker MP, Carvalho A, Ferreira DA, Mohan NM, Martins M, Fernandes AR.  2018.  Nano-Strategies to Fight Multidrug Resistant Bacteria—“A Battle of the Titans”. Frontiers in Microbiology. 9:1441. AbstractWebsite

Infectious diseases remain one of the leading causes of morbidity and mortality worldwide. The WHO and CDC have expressed serious concern regarding the continued increase in the development of multidrug resistance among bacteria. Therefore, the antibiotic resistance crisis is one of the most pressing issues in global public health. Associated with the rise in antibiotic resistance is the lack of new antimicrobials. This has triggered initiatives worldwide to develop novel and more effective antimicrobial compounds as well as to develop novel delivery and targeting strategies. Bacteria have developed many ways by which they become resistant to antimicrobials. Among those are enzyme inactivation, decreased cell permeability, target protection, target overproduction, altered target site/enzyme, increased efflux due to over-expression of efflux pumps, among others. Other more complex phenotypes, such as biofilm formation and quorum sensing do not appear as a result of the exposure of bacteria to antibiotics although, it is known that biofilm formation can be induced by antibiotics. These phenotypes are related to tolerance to antibiotics in bacteria. Different strategies, such as the use of nanostructured materials, are being developed to overcome these and other types of resistance. Nanostructured materials can be used to convey antimicrobials, to assist in the delivery of novel drugs or ultimately, possess antimicrobial activity by themselves. Additionally, nanoparticles (e.g., metallic, organic, carbon nanotubes, etc.) may circumvent drug resistance mechanisms in bacteria and, associated with their antimicrobial potential, inhibit biofilm formation or other important processes. Other strategies, including the combined use of plant-based antimicrobials and nanoparticles to overcome toxicity issues, are also being investigated. Coupling nanoparticles and natural-based antimicrobials (or other repurposed compounds) to inhibit the activity of bacterial efflux pumps; formation of biofilms; interference of quorum sensing; and possibly plasmid curing, are just some of the strategies to combat multidrug resistant bacteria. However, the use of nanoparticles still presents a challenge to therapy and much more research is needed in order to overcome this. In this review, we will summarize the current research on nanoparticles and other nanomaterials and how these are or can be applied in the future to fight multidrug resistant bacteria.

Restani, RB, Pires RF, Tolmatcheva A, Cabral R, Baptista PV, Fernandes AR, Casimiro T, Bonifácio VDB, Aguiar-Ricardo A.  2018.  POxylated Dendrimer-Based Nano-in-Micro Dry Powder Formulations for Inhalation Chemotherapy. ChemistryOpen. 7:772-779., Number 10 AbstractWebsite

Abstract POxylated polyurea dendrimer (PUREG4OOx48)-based nanoparticles were loaded with paclitaxel (PTX) and doxorubicin (DOX) and micronized with chitosan (CHT) by using supercritical CO2-assisted spray drying (SASD). Respirable, biocompatible, and biodegradable dry powder formulations (DPFs) were produced to effectively transport and deliver the chemotherapeutics with a controlled rate to the deep lung. In vitro studies performed with the use of the lung adenocarcinoma cell line showed that DOX@PUREG4OOx48 nanoparticles were much more cytotoxic than the free drug. Additionally, the DPFs did not show higher cytotoxicity than the respective nanoparticles, and DOX-DPFs showed a higher chemotherapeutic effect than PTX formulations in adenocarcinoma cells.

2017
Vinhas, R, Mendes R, Fernandes AR, Baptista PV.  2017.  Nanoparticles—Emerging Potential for Managing Leukemia and Lymphoma, 2017. Front. Bioeng. Biotechnol. 5:79. AbstractWebsite

Nanotechnology has become a powerful approach to improve the way we diagnose and treat cancer. In particular, nanoparticles possess unique features for enhanced sensitivity and selectivity for earlier detection of circulating cancer biomarkers. In vivo, nanoparticles enhance the therapeutic efficacy of anticancer agents when compared to conventional chemotherapy, improving vectorization and delivery, and helping to overcome drug resistance. Nanomedicine has been mostly focused on solid cancers due to take advantage from the enhanced permeability and retention (EPR) effect experienced by tissues in the close vicinity of tumors, which enhance nanomedicine’s accumulation and, consequently, improve efficacy. Nanomedicines for leukemia and lymphoma, where EPR effect is not a factor, are addressed differently from solid tumors. Nevertheless, nanoparticles have provided innovative approaches to simple and non-invasive methodologies for diagnosis and treatment in liquid tumors. In this review, we consider the state of the art on different types of nanoconstructs for the management of liquid tumors, from pre-clinical studies to clinical trials. We also discuss the advantages of nanoplatforms for theranostics and the central role played by nanoparticles in this combined strategy.