Araraquara - FCF - Faculdade de Ciências Farmacêuticas

URI Permanente para esta coleçãohttps://hdl.handle.net/11449/253730

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Avaliação do potencial de nanopartículas de sílica mesoporosas funcionalizadas com cetuximabe para veiculação de docetaxel no tratamento do câncer de próstata
(Universidade Estadual Paulista (Unesp), 2024-07-29) Sábio, Rafael ; Chorilli, Marlus
O câncer de próstata (CP) é uma das doenças não contagiosas que mais atinge a população masculina no mundo. O tratamento com o quimioterápico docetaxel (DTX), embora apresente eficácia clínica, está associado ao desenvolvimento de resistência em estágios mais avançados da doença, além do fármaco apresentar baixa solubilidade aquosa e problemas relacionados à sua farmacocinética. Nanopartículas de sílica mesoporosas (NSMs) têm atraído grande interesse por apresentar alta estabilidade química, grande área superficial e poros de diâmetros e volumes ajustáveis, possibilitando a incorporação de grande quantidade de fármacos, protegendo-os de processos de desativação, degradação e liberação prematura atuando como um excelente nanocarreador. Além disso, a disponibilidade de hidroxilas em sua superfície permite a conjugação de moléculas como o anticorpo monoclonal cetuximabe (CTX) o qual se liga ao receptor EGFR (Enhanced Growth Factor Receptor) superexpresso em muitos tumores de próstata, representando uma estratégia em potencial para o tratamento do câncer de próstata em combinação ao DTX. Diante ao exposto, este projeto de pesquisa objetivou o desenvolvimento de nanoplataformas inteligentes baseadas em nanopartículas de sílica mesoporosas funcionalizadas com CTX para veiculação de DTX no tratamento do CP, visando contornar problemas como baixa internalização, ausência de controle da liberação do antineoplásico na região de interesse, diversos efeitos colaterais ao paciente e baixa eficácia dos tratamentos atuais. Para avaliação desses parâmetros, a caracterização dos materiais e validação das metodologias foram realizadas assim como os ensaios in vitro utilizando modelos de linhagens celulares PC3 e DU145, com o intuito de comprovar a eficácia dos novos nanocarreadores propostos. Os resultados evidenciaram a citotoxicidade dos nanossistemas NSM@DTX-CTX frente a linhagem DU145, com IC50 igual a 69,99 nM. Além disso, os valores calculados de internalização obtidos por citometria de fluxo para as NSM-FITC e NSM-FITC-CTX foram de 0,5 ± 0,1 % e 44,2 ± 5,2 %, respectivamente. Os resultados obtidos corroboram parte das análises de citotoxicidade realizadas além de destacar a importância do anticorpo CTX para promover rápida internalização nas células DU145 considerando 6 h de incubação. Portanto, as NSM@DTX-CTX compreendem nanoplataformas promissoras para continuação e otimização dos estudos in vitro visando a avaliação in vivo e, consequentemente, o tratamento do câncer de próstata.
Avaliação da atividade da micafungina incorporada em nanoemulsão frente a biofilme de Candida auris e Candida albicans e em modelo alternativo de Galleria mellonella
(Universidade Estadual Paulista (Unesp), 2023-07-12) Blanco, Ana Lígia ; Bauab, Taís Maria ; Faculdade de Ciências Farmacêuticas
Foi realizada a avaliação da atividade biológica do uso de uma nanoemulsão contendo micafungina sobre os biofilmes formados por C. auris e C. albicans, como uma alternativa aos tratamentos empregados atualmente. A nanoemulsão foi desenvolvida contendo como fase oleosa o ácido oleico, uma mistura de polioxietileno 20 cetil éter (Brij® 58) e fosfatidilcolina de soja na proporção 2:1 como sistema tensoativo e tampão fosfato (PBS) pH 7,4 como fase aquosa. Os ensaios biológicos mostram que a nanoemulsão com micafungina incorporada não apresentou atividade antifúngica frente à cepa clínica de C. auris, contudo, a solução com micafungina livre demonstrou atividade com uma CIM de 0,333 µg/mL. Para a cepa padrão de C. albicans foi obtido a mesma CIM de 0,0103 µg/mL tanto para nanoemulsão contendo micafungina quanto para a solução com este fármaco livre, evidenciando assim que há atividade fungicida da nanoemulsão contendo micafungina (NEMICA) para essa cepa utilizada. Nos ensaios em presença de sorbitol houve aumento dos valores de CIM de micafungina para as duas cepas utilizadas, elucidando o possível mecanismo de ação, enquanto que nos ensaios com exógenos de ergosterol não houve alteração dos valores de concentração inibitória. Não foi observada atividade antifúngica frente aos biofilmes das cepas utilizadas. Os resultados referentes ao índice de citotoxicidade (IC50) de micafungina, da formulação base (NE) e da nanoemulsão contendo micafungina (NEMICA) frente à linhagem celular L929 são de 60 µg/mL para a MICA e NEMICA, e 80 µg/mL para a formulação base. Quanto ao ensaio de toxicidade aguda em larvas de G. mellonella, as dosagens 5, 10, 25, 50 100, 200, 500, 1000 e 2000 mg/kg de micafungina livre e incorporada em nanoemulsão não foram capazes de induzir morte nas larvas utilizadas. Nos ensaios terapêuticos de infecção por C. auris e C. albicans em modelos alternativos in vivo de G. mellonella, para C. albicans, todos os grupos experimentais tiveram um perfil de sobrevida positivo após a infecção. Para C. auris, a maior porcentagem de sobrevida nos grupos 3 e 4 sugere que o tratamento com micafungina livre e incorporada foi capaz de previnir um número maior de mortes dos grupos amostrais, apontando uma possível ação sobre a infecção causada nas larvas.
Ionic liquids and deep eutectic solvents for the stabilization of biopharmaceuticals: a review
(Elsevier, 2024-01-08) Veríssimo, Nathalia Vieira Porphirio ; Mussagy, Cassamo Usemane ; Bento, Heitor Buzetti Simões ; Pereira, Jorge Fernando Brandão ; Santos-Ebinuma, Valéria de Carvalho ; Universidade de São Paulo ; Pontificia Universidad Católica de Valparaíso ; Universidade de Coimbra
Biopharmaceuticals have allowed the control of previously untreatable diseases. However, their low solubility and stability still hinder their application, transport, and storage. Hence, researchers have applied different compounds to preserve and enhance the delivery of biopharmaceuticals, such as ionic liquids (ILs) and deep eutectic solvents (DESs). Although the biopharmaceutical industry can employ various substances for enhancing formulations, their effect will change depending on the properties of the target biomolecule and environmental conditions. Hence, this review organized the current state-of-the-art on the application of ILs and DESs to stabilize biopharmaceuticals, considering the properties of the biomolecules, ILs, and DESs classes, concentration range, types of stability, and effect. We also provided a critical discussion regarding the potential utilization of ILs and DESs in pharmaceutical formulations, considering the restrictions in this field, as well as the advantages and drawbacks of these substances for medical applications. Overall, the most applied IL and DES classes for stabilizing biopharmaceuticals were cholinium-, imidazolium-, and ammonium-based, with cholinium ILs also employed to improve their delivery. Interestingly, dilute and concentrated ILs and DESs solutions presented similar results regarding the stabilization of biopharmaceuticals. With additional investigation, ILs and DESs have the potential to overcome current challenges in biopharmaceutical formulation.
Optimization of resveratrol used as a scaffold to design histone deacetylase (HDAC-1 and HDAC-2) inhibitors
(MDPI, 2022-10-13) Urias, Beatriz Silva ; Pavan, Aline Renata ; Albuquerque, Gabriela Ribeiro ; Prokopczyk, Igor Muccilo ; Alves, Tânia Mara Ferreira ; de Melo, Thais Regina Ferreira ; Sartori, Geraldo Rodrigues ; da Silva, João Hermínio Martins ; Man Chin, Chung ; Dos Santos, Jean Leandro ; Universidade Estadual Paulista (Unesp)
Histone deacetylases (HDAC) are epigenetic enzymes responsible for repressing gene expression through the deacetylation of histone lysine residues. Therefore, inhibition of HDACs has become an interesting approach for the treatment of several diseases, including cancer, hematology, neurodegenerative, immune diseases, bacterial infections, and more. Resveratrol (RVT) has pleiotropic effects, including pan-inhibition of HDAC isoforms; however, its ability to interfere with membranes requires additional optimization to eliminate nonspecific and off-target effects. Thus, to explore RVT as a scaffold, we designed a series of novel HDAC-1 and -2 inhibitors containing the 2-aminobenzamide subunit. Using molecular modeling, all compounds, except unsaturated compounds (4) and (7), exhibited a similar mode of interaction at the active sites of HDAC 1 and 2. The docking score values obtained from the study ranged from −12.780 to −10.967 Kcal/mol. All compounds were synthesized, with overall yields ranging from 33% to 67.3%. In an initial screening, compounds (4), (5), (7), and (20)–(26), showed enzymatic inhibitory effects ranging from 1 to 96% and 6 to 93% against HDAC-1 and HDAC-2, respectively. Compound (5), the most promising HDAC inhibitor in this series, was selected for IC50 assays, resulting in IC50 values of 0.44 µM and 0.37 µM against HDAC-1 and HDAC-2, respectively. In a panel of selectivity against HDACs 3–11, compound (5) presented selectivity towards Class I, mainly HDAC-1, 2, and 3. All compounds exhibited suitable physicochemical and ADMET properties as determined using in silico simulations. In conclusion, the optimization of the RVT structure allows the design of selective HDAC inhibitors, mainly targeting HDAC-1 and HDAC-2 isoforms.
Vascular effects of the fetal hemoglobin inducer agent 3-(1,3-dioxoisoindolin-2-yl) benzyl nitrate
(MDPI, 2022-10-24) Terroni, Barbara ; de Moraes, Luis Henrique Oliveira ; Pavan, Aline Renata ; Rodrigues, Gerson Jhonatan ; Dos Santos, Jean Leandro ; Universidade Estadual Paulista (Unesp)
Vascular endothelium is a protective layer of cells lining the lumen of blood vessels that plays important roles by releasing factors responsible for controlling the vascular tone, regulating the expression of pro-inflammatory cytokines, and expressing adhesion molecules involved in vascular hemostasis. Imbalance of vascular properties leads to endothelial dysfunction (ED) and cardiovascular damage. Some diseases, such as sickle cell anemia, are characterized by ED with reduction in the levels of nitric oxide (NO). Previously, we have shown that the fetal hemoglobin inducer agent 3-(1,3-dioxoisoindolin-2-yl) benzyl nitrate (Lapdesf-4c) could act as NO donor, inhibiting platelet aggregation and reducing the inflammation associated with SCA. However, the vascular effect of this compound was not yet studied. Herein, we evaluated the effects of Lapdesf-4c in vascular reactivity experiments using aortic rings from male Wistar rats (300 g/90 days). We have found that Lapdesf-4c induced vasodilation in the presence (E+) or absence of endothelium (E−) with an average of EMax values of 101.8 ± 3.33% and 111.8 ± 3.21%. The mechanism of action was studied using 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ), L-NG-nitroarginine methyl ester (L-NAME), and hydroxocobalamin. The EMax values for those pathways were hydroxocobalamin (30.6 ± 2.21%), ODQ (4.75 ± 0.51%), and L-NAME (109 ± 3.65), suggesting that Lapdesf-4c exhibits NO-dependent mechanisms. Lapdesf-4c was able to prevent angiotensin-induced ED after incubation of aorta rings for 1 h. We found based on the concentration–effect curve using acetylcholine (ACh) that pEC50 values for the control, Ang II, and combination of (Ang II + Lapdesf-4c) were 6.73, 6.46, and 7.15, respectively. In conclusion, Lapdesf-4c has emerged as a new drug candidate that can promote vasodilation and act as a protective agent against ED, being useful to prevent vascular damage.
Editorial: Epigenetic therapy against cancer: toward new molecular targets and technologies
(2023-01-01) Sousa, Ângela ; Soares, Christiane P. ; Chin, Chung Man ; Trisciuoglio, Daniela ; Valdes-Mora, Fatima ; University of Beira Interior ; Universidade Estadual Paulista (UNESP) ; UNION of the Colleges of the GREAT LAKES (UNILAGO) ; Sapienza University of Rome ; Children’s Cancer Institute Australia Randwick ; Garvan Institute of Medical Research Darlinghurst
Preface
(2022-01-01) de Sousa, Ângela Maria Almeida ; Soares, Christiane Pienna ; Chorilli, Marlus ; University of Beira Interior ; Universidade Estadual Paulista (UNESP)
Three-dimensional culture models: emerging platforms for screening the antitumoral efficacy of nanomedicines
(2023-03-01) Tofani, Larissa Bueno ; Luiz, Marcela Tavares ; Paes Dutra, Jessyca Aparecida ; Abriata, Juliana Palma ; Chorilli, Marlus ; Universidade de São Paulo (USP) ; Universidade Estadual Paulista (UNESP)
Nanomedicines have been investigated for delivering drugs to tumors due to their ability to accumulate in the tumor tissues. 2D in vitro cell culture has been used to investigate the antitumoral potential of nanomedicines. However, a 2D model cannot adequately mimic the in vivo tissue conditions because of the lack of cell-cell interaction, a gradient of nutrients and the expression of genes. To overcome this limitation, 3D cell culture models have emerged as promising platforms that better replicate the complexity of native tumors. For this purpose, different techniques can be used to produce 3D models, including scaffold-free, scaffold-based and microfluidic-based models. This review addresses the principles, advantages and limitations of these culture methods for evaluating the antitumoral efficacy of nanomedicines.
Intranasal in situ gelling liquid crystal for delivery of resveratrol ameliorates memory and neuroinflammation in Alzheimer's disease
(2023-07-01) Fonseca-Santos, Bruno ; Cazarin, Camila André ; da Silva, Patrícia Bento ; dos Santos, Kaio Pini ; da Rocha, Márcia Cristina Oliveira ; Báo, Sônia Nair ; De-Souza, Márcia Maria ; Chorilli, Marlus ; Universidade Estadual Paulista (UNESP) ; Universidade Federal da Bahia (UFBA) ; Postgraduate in Pharmaceutical Sciences ; University of Brasilia (UnB)
Alzheimer's disease (AD) is an illness that affects people aged 65 or older and affects around 6.5 million in the United States. Resveratrol is a chemical obtained from natural products and it exhibits biological activity based on inhibiting the formation, depolymerization of the amyloid, and decreasing neuroinflammation. Due to the insolubility of this compound; its incorporation in surfactant-based systems was proposed to design an intranasal formulation. A range of systems has been produced by mixing oleic acid, CETETH-20 and water. Polarised light microscopy (PLM), small angle x-ray scattering (SAXS) and transmission electron microscopy (TEM) confirm the initial liquid formulation (F) presented as microemulsion (ME). After dilution, the gelled systems were characterized as hexagonal mesophase and they showed feasibility proprieties. Pharmacological assays performed after intranasal administration showed the ability to improve learning and memory in animals, as well as remission of neuroinflammation via inhibition of interleukin.
A receptor-mediated landscape of druggable and targeted nanomaterials for gliomas
(2023-06-01) Di Filippo, Leonardo Delello ; de Carvalho, Suzana Gonçalves ; Duarte, Jonatas Lobato ; Luiz, Marcela Tavares ; Paes Dutra, Jessyca Aparecida ; de Paula, Geanne Aparecida ; Chorilli, Marlus ; Conde, João ; Universidade Estadual Paulista (UNESP) ; Universidade NOVA de Lisboa
Gliomas are the most common type of brain cancer, and among them, glioblastoma multiforme (GBM) is the most prevalent (about 60% of cases) and the most aggressive type of primary brain tumor. The treatment of GBM is a major challenge due to the pathophysiological characteristics of the disease, such as the presence of the blood-brain barrier (BBB), which prevents and regulates the passage of substances from the bloodstream to the brain parenchyma, making many of the chemotherapeutics currently available not able to reach the brain in therapeutic concentrations, accumulating in non-target organs, and causing considerable adverse effects for the patient. In this scenario, nanocarriers emerge as tools capable of improving the brain bioavailability of chemotherapeutics, in addition to improving their biodistribution and enhancing their uptake in GBM cells. This is possible due to its nanometric size and surface modification strategies, which can actively target nanocarriers to elements overexpressed by GBM cells (such as transmembrane receptors) related to aggressive development, drug resistance, and poor prognosis. In this review, an overview of the most frequently overexpressed receptors in GBM cells and possible approaches to chemotherapeutic delivery and active targeting using nanocarriers will be presented.
Hybrid Membranes of the Ureasil-Polyether Containing Glucose for Future Application in Bone Regeneration
(2023-05-01) da Silva, Camila Garcia ; Monteiro, João Rodrigues ; Oshiro-Júnior, João Augusto ; Chiavacci, Leila Aparecida ; Universidade Estadual Paulista (UNESP) ; State University of Paraiba (UEPB)
The application of mesenchymal stem cells (MSC) in bone tissue regeneration can have unpredictable results due to the low survival of cells in the process since the lack of oxygen and nutrients promotes metabolic stress. Therefore, in this work, polymeric membranes formed by organic–inorganic hybrid materials called ureasil-polyether for modified glucose release were developed in order to overcome the problems posed by a of lack of this nutrient. Thus, membranes formed by polymeric blend of polypropylene oxide (PPO4000) and polyethylene oxide (PEO500) with 6% glucose incorporation were developed. Physical–chemical characterization techniques were performed, as well as tests that evaluated thermal properties, bioactivity, swelling, and release in SBF solution. The results of the swelling test showed an increase in membrane mass correlated with an increase in the concentration of ureasil-PEO500 in the polymeric blends. The membranes showed adequate resistance when subjected to the application of a high compression force (15 N). X-ray diffraction (XRD) evidenced peaks corresponding to orthorhombic crystalline organization, but the absence of glucose-related peaks showed characteristics of the amorphous regions of hybrid materials, likely due to solubilization. Thermogravimetry (TG) and differential scanning calorimetry (DSC) analyses showed that the thermal events attributed to glucose and hybrid materials were similar to that seen in the literature, however when glucose was incorporated into the PEO500, an increase in rigidity occurs. In PPO400, and in the blends of both materials, there was a slight decrease in Tg values. The smaller contact angle for the ureasil-PEO500 membrane revealed the more hydrophilic character of the material compared to other membranes. The membranes showed bioactivity and hemocompatibility in vitro. The in vitro release test revealed that it is possible to control the release rate of glucose and the kinetic analysis revealed a release mechanism characteristic of anomalous transport kinetics. Thus, we can conclude that ureasil-polyether membranes have great potential to be used as a glucose release system, and their future application has the potential to optimize the bone regeneration process.
Exploring the Hidden World of Vectors of Chagas Disease: A Fascinating Look at the Taxonomic Aspects of the Psammolestes Genus (Hemiptera, Triatominae)
(2023-05-01) de Oliveira, Jader ; Alevi, Kaio Cesar Chaboli ; Almeida, Carlos Eduardo ; Olaia, Nicoly ; Cacini, Gustavo Lázari ; Galvão, Cleber ; Herrera, Heitor Miraglia ; Santos, Filipe Martins ; Rosa, João Aristeu da ; Universidade de São Paulo (USP) ; Pavilhão Rocha Lima ; Universidade Federal do Rio de Janeiro (UFRJ) ; Universidade Estadual Paulista (UNESP) ; Universidade Católica Dom Bosco
Chagas disease (CD) is a neglected illness affecting approximately seven million individuals, with vector transmission occurring via triatomine bugs. The Rhodniini tribe comprises 24 species, grouped into the Rhodnius and Psammolestes genera. Given the importance of accurately identifying CD vectors, the taxonomy of Psammolestes spp. was revisited using morphological and morphometric data. Specimens of P. tertius, P. coreodes, and P. arthuri were collected, and the morphological characteristics of the head, thorax, abdomen, and eggs were analyzed. Morphometric studies of eggs were also conducted. Dichotomous keys allowing for the differentiation of Psammolestes spp. were elaborated based on adult insect and egg morphological characteristics. Through these studies, it was possible to differentiate the three Psammolestes species and confirm that this genus should not be classified under the Rhodnius genus, contributing to Rhodniini taxonomy.
New Palladium(II) Complexes Containing Methyl Gallate and Octyl Gallate: Effect against Mycobacterium tuberculosis and Campylobacter jejuni
(2023-05-01) Silva, Raphael Tristão Cruvinel ; Guidotti-Takeuchi, Micaela ; Peixoto, Jéssica Laura Miranda ; Demarqui, Fernanda Manaia ; Mori, Ananda Paula ; Dumont, Carolyne Ferreira ; Ferreira, Gabriella Rayane Aparecida ; Pereira, Gabriele de Menezes ; Rossi, Daise Aparecida ; Corbi, Pedro Paulo ; Pavan, Fernando Rogério ; Rezende Júnior, Celso de Oliveira ; Melo, Roberta Torres de ; Guerra, Wendell ; Universidade Federal de Uberlândia (UFU) ; Universidade Estadual Paulista (UNESP) ; Universidade Estadual de Campinas (UNICAMP)
This work describes the preparation, characterization and antimicrobial activity of four palladium(II) complexes, namely, [Pd(meg)(1,10-phen)] 1, [Pd(meg)(PPh3)2] 2, [Pd(og)(1,10-phen)] 3 and [Pd(og)(PPh3)2] 4, where meg = methyl gallate, og = octyl gallate, 1,10-phen = 1,10-phenanthroline and PPh3 = triphenylphosphine. As to the chemical structures, spectral and physicochemical studies of 1–4 indicated that methyl or octyl gallate coordinates a palladium(II) ion through two oxygen atoms upon deprotonation. A chelating bidentate phenanthroline or two triphenylphosphine molecules complete the coordination sphere of palladium(II) ion, depending on the complex. The metal complexes were tested against the Mycobacterium tuberculosis H37Rv strain and 2 exhibited high activity (MIC = 3.28 μg/mL). As to the tests with Campylobacter jejuni, complex 1 showed a significant effect in reducing bacterial population (greater than 7 log CFU) in planktonic forms, as well as in the biomass intensity (IBF: 0.87) when compared to peracetic acid (IBF: 1.11) at a concentration of 400 μg/mL. The effect provided by these complexes has specificity according to the target microorganism and represent a promising alternative for the control of microorganisms of public health importance.
Pharmacological, toxicological and phytochemical analysis of Spondias dulcis parkinson
(2023-01-01) Fernandes, Felipe Hugo Alencar ; Soares, Sabrina da Silva ; Bekbolatova, Elmira ; Boylan, Fábio ; Salgado, Hérida Regina Nunes ; Universidade Estadual Paulista (UNESP) ; UNIFACISA Centro Universitário ; Heidelberg University ; JSC National Medical University ; Trinity College Dublin
Spondias dulcis Parkinson have been used in traditional medicine in Asia, Oceania, and South America, for different diseases conditions and as a functional food. The scientific literature described as different potential pharmacology such as antioxidant, anti-inflammatory, antimicrobial, thrombolytic and enzymatic inhibitor. This study aimed to: (1) establish the pharmacological activity in intestinal motility in vivo and antioxidant activity in vitro; (2) perform the acute toxicology test in mouse; (3) characterize the phytochemical profile based on counter-current chromatography (CCC) and NMR analysis. The results revealed a laxative effect of S. dulcis extract and a high antioxidant activity (IC50 = 5.10 for DPPH assay and 14.14 for hydrogen peroxide scavenging test). No side effects were observed in the oral acute toxicity test for a dose up to 2000 mg/kg. The chemical profile was identified by CCC and NMR, and the comparison of the data obtained with previous literature revealed the presence of the flavonoid rutin (Quercetin-3-O-rutinoside) in the extract.
Synthesis and Anti-Mycobacterium tuberculosis Activity of Imidazo[2,1-b][1,3]oxazine Derivatives against Multidrug-Resistant Strains
(2023-01-01) Fernandes, Guilherme F. S. ; Manieri, Karyn F. ; Bonjorno, Andressa F. ; Campos, Debora L. ; Ribeiro, Camila M. ; Demarqui, Fernanda M. ; Ruiz, Daniel A. G. ; Nascimento-Junior, Nailton M. ; Denny, William A. ; Thompson, Andrew M. ; Pavan, Fernando R. ; Dos Santos, Jean L. ; Universidade Estadual Paulista (UNESP) ; The University of Auckland ; University College London
The emergence of multidrug-resistant strains of M. tuberculosis has raised concerns due to the greater difficulties in patient treatment and higher mortality rates. Herein, we revisited the 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine scaffold and identified potent new carbamate derivatives having MIC90 values of 0.18–1.63 μM against Mtb H37Rv. Compounds 47–49, 51–53, and 55 exhibited remarkable activity against a panel of clinical isolates, displaying MIC90 values below 0.5 μM. In Mtb-infected macrophages, several compounds demonstrated a 1-log greater reduction in mycobacterial burden than rifampicin and pretomanid. The compounds tested did not exhibit significant cytotoxicity against three cell lines or any toxicity to Galleria mellonella. Furthermore, the imidazo[2,1-b][1,3]oxazine derivatives did not show substantial activity against other bacteria or fungi. Finally, molecular docking studies revealed that the new compounds could interact with the deazaflavin-dependent nitroreductase (Ddn) in a similar manner to pretomanid. Collectively, our findings highlight the chemical universe of imidazo[2,1-b][1,3]oxazines and their promising potential against MDR-TB.
Evaluation of photodynamic therapy on nanoparticles and films loaded-nanoparticles based on chitosan/alginate for curcumin delivery in oral biofilms
(2023-06-15) Silvestre, Amanda Letícia Polli ; dos Santos, Aline Martins ; de Oliveira, Analú Barros ; Ferrisse, Túlio Morandin ; Brighenti, Fernanda Lourenção ; Meneguin, Andréia Bagliotti ; Chorilli, Marlus ; Universidade Estadual Paulista (UNESP)
Nanoparticles and nanoparticle-loaded films based on chitosan/sodium alginate with curcumin (CUR) are promising strategies to improve the efficacy of antimicrobial photodynamic therapy (aPDT) for the treatment of oral biofilms. This work aimed to develop and evaluate the nanoparticles based on chitosan and sodium alginate encapsulated with CUR dispersed in polymeric films associated with aPDT in oral biofilms. The NPs were obtained by polyelectrolytic complexation, and the films were prepared by solvent evaporation. The photodynamic effect was evaluated by counting Colony Forming Units (CFU/mL). Both systems showed adequate characterization parameters for CUR release. Nanoparticles controlled the release of CUR for a longer period than the nanoparticle-loaded films in simulated saliva media. Control and CUR-loaded nanoparticles showed a significant reduction of 3 log10 CFU/mL against S. mutans biofilms, compared to treatment without light. However, biofilms of S. mutans showed no photoinactivation effect using films loaded with nanoparticles even in the presence of light. These results demonstrate the potential of chitosan/sodium alginate nanoparticles associated with aPDT as carriers for the oral delivery of CUR, offering new possibilities to improve the treatment of dental caries and infections. This work will contribute to advances in the search for innovative delivery systems in dentistry.
Karyotype Evolution in Triatominae (Hemiptera, Reduviidae): The Role of Chromosomal Rearrangements in the Diversification of Chagas Disease Vectors
(2023-04-01) Reis, Yago Visinho dos ; de Oliveira, Jader ; Madeira, Fernanda Fernandez ; Ravazi, Amanda ; Oliveira, Ana Beatriz Bortolozo de ; Bittinelli, Isadora da Silva ; Delgado, Luiza Maria Grzyb ; de Azeredo-Oliveira, Maria Tercília Vilela ; Rosa, João Aristeu da ; Galvão, Cleber ; Alevi, Kaio Cesar Chaboli ; Universidade Estadual Paulista (UNESP) ; Universidade de São Paulo (USP) ; Instituto Oswaldo Cruz (FIOCRUZ)
Several cytogenetic studies have already been performed in Triatominae, such that different karyotypes could be characterized (ranging from 2n = 21 to 25 chromosomes), being the changes in the number of chromosomes related mainly to fusion and fission events. These changes have been associated with reproductive isolation and speciation events in other insect groups. Thus, we evaluated whether different karyotypes could act in the reproductive isolation of triatomines and we analyzed how the events of karyotypic evolution occurred along the diversification of these vectors. For this, experimental crosses were carried out between triatomine species with different karyotypes. Furthermore, based on a phylogeny with 88 triatomine taxa (developed with different molecular markers), a reconstruction of ancestral karyotypes and of anagenetic and cladogenetic events related to karyotypic alterations was performed through the ChromoSSE chromosomal evolution model. All crosses performed did not result in hybrids (prezygotic isolation in both directions). Our modeling results suggest that during Triatominae diversification, at least nine cladogenetic events may be associated with karyotype change. Thus, we emphasize that these alterations in the number of chromosomes can act as a prezygotic barrier in Triatominae (karyotypic isolation), being important evolutionary events during the diversification of the species of Chagas disease vectors.
Development, characterization and in vitro cytotoxicity of kaempferol-loaded nanostructured lipid carriers in glioblastoma multiforme cells
(2023-06-01) Nicoleti, Luisa Ribeiro ; Di Filippo, Leonardo Delello ; Duarte, Jonatas Lobato ; Luiz, Marcela Tavares ; Sábio, Rafael Miguel ; Chorilli, Marlus ; Universidade Estadual Paulista (UNESP)
Glioblastoma multiforme is the most common and most aggressive human brain cancer. GBM treatment is still a challenge because many drugs are not able to cross the blood-brain barrier, in addition to the increasing resistance to currently available chemotherapy. New therapeutic alternatives are emerging, and, in this context, we highlight kaempferol, a flavonoid with remarkable anti-tumor activity but with limited bioavailability due to its strong lipophilic property. A promising tool to improve the biopharmaceutical properties of molecules such as kaempferol is the use of drug-delivery nanosystems, such as nanostructured lipid carriers (NLC), which can facilitate the dispersion and delivery of highly lipophilic molecules. The present work aimed at the development and characterization of kaempferol-loaded NLC (K-NLC) and the evaluation of its biological properties using in vitro models. The K-NLC showed an average size of 120 nm, zeta potential of − 21 mV, and polydispersity index of 0.099. The K-NLC presented high kaempferol encapsulation efficiency (93%), a drug loading of 3.58%, and a sustained kaempferol release profile for up to 48 h. In addition to presenting a 7-fold increase in kaempferol cytotoxicity, its encapsulation in NLC promoted a cellular uptake of 75%, which corroborates with increased cytotoxicity in U-87MG cells, as observed. Together, these data reinforce the promising antineoplastic properties of kaempferol in addition to the key role of NLC as a platform for the efficient delivery of lipophilic drugs to neoplastic cells, which improved their uptake and therapeutic efficacy in glioblastoma multiforme cells.
New Technological Approaches for Dental Caries Treatment: From Liquid Crystalline Systems to Nanocarriers
(2023-03-01) Luiz, Marcela Tavares ; di Filippo, Leonardo Delello ; Dutra, Jessyca Aparecida Paes ; Viegas, Juliana Santos Rosa ; Silvestre, Amanda Letícia Polli ; Anselmi, Caroline ; Duarte, Jonatas Lobato ; Calixto, Giovana Maria Fioramonti ; Chorilli, Marlus ; Universidade Estadual Paulista (UNESP) ; Universidade do Porto
Dental caries is the most common oral disease, with high prevalence rates in adolescents and low-income and lower-middle-income countries. This disease originates from acid production by bacteria, leading to demineralization of the dental enamel and the formation of cavities. The treatment of caries remains a global challenge and the development of effective drug delivery systems is a potential strategy. In this context, different drug delivery systems have been investigated to remove oral biofilms and remineralize dental enamel. For a successful application of these systems, it is necessary that they remain adhered to the surfaces of the teeth to allow enough time for the removal of biofilms and enamel remineralization, thus, the use of mucoadhesive systems is highly encouraged. Among the systems used for this purpose, liquid crystalline systems, polymer-based nanoparticles, lipid-based nanoparticles, and inorganic nanoparticles have demonstrated great potential for preventing and treating dental caries through their own antimicrobial and remineralization properties or through delivering drugs. Therefore, the present review addresses the main drug delivery systems investigated in the treatment and prevention of dental caries.
Hybrid Magnetic Lipid-Based Nanoparticles for Cancer Therapy
(2023-03-01) Luiz, Marcela Tavares ; Dutra, Jessyca Aparecida Paes ; Viegas, Juliana Santos Rosa ; de Araújo, Jennifer Thayanne Cavalcante ; Tavares Junior, Alberto Gomes ; Chorilli, Marlus ; Universidade Estadual Paulista (UNESP) ; Universidade do Porto
Cancer is one of the major public health problems worldwide. Despite the advances in cancer therapy, it remains a challenge due to the low specificity of treatment and the development of multidrug resistance mechanisms. To overcome these drawbacks, several drug delivery nanosystems have been investigated, among them, magnetic nanoparticles (MNP), especially superparamagnetic iron oxide nanoparticles (SPION), which have been applied for treating cancer. MNPs have the ability to be guided to the tumor microenvironment through an external applied magnetic field. Furthermore, in the presence of an alternating magnetic field (AMF) this nanocarrier can transform electromagnetic energy in heat (above 42 °C) through Néel and Brown relaxation, which makes it applicable for hyperthermia treatment. However, the low chemical and physical stability of MNPs makes their coating necessary. Thus, lipid-based nanoparticles, especially liposomes, have been used to encapsulate MNPs to improve their stability and enable their use as a cancer treatment. This review addresses the main features that make MNPs applicable for treating cancer and the most recent research in the nanomedicine field using hybrid magnetic lipid-based nanoparticles for this purpose.

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