FABIO FERNANDO ALVES DA SILVA

FABIO FERNANDO ALVES DA SILVA

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Radiosynthesis standardization and preclinical assessment of the [68Ga]Ga-DOTA-Ubiquicidin29-41
2024 - MIRANDA, ANA C.C.; FUSCALDI, LEONARDO L.; MEJIA, JORGE; SILVA, FABIO F.A. da; TURATO, WALTER M.; MENDONCA, FERNANDA F.; NOGUEIRA, SOLANGE A.; OSAWA, AKEMI; YAMAGA, LILIAN Y.I.; MALAVOLTA, LUCIANA; BARBOZA, MARYCEL F. de
Human bacterial infections significantly contribute to the increase in healthcare-related burdens. This scenario drives the study of novel techniques for the early and precise diagnosis of infectious processes. Some alternatives include Nuclear Medicine- and Molecular Imaging-based strategies. However, radiopharmaceuticals that are available for routine assessments are not specific to differentiating infectious from aseptic inflammatory processes. In this context, [Ga-68]Ga-DOTA-Ubiquicidin(29-41) was synthesized using an automated module and radiochemical; in vivo and in vitro studies were performed. The radiopharmaceutical remained stable in saline (up to 180 min) and in rodent serum (up to 120 min) with radiochemical purities > 99 and 95%, respectively. Partition coefficient and serum protein binding at 60 min were determined (-3.63 +/- 0.17 and 44.06 +/- 1.88%, respectively). Ex vivo biodistribution, as well as in vivo microPET/CT images in mice, showed rapid blood clearance with renal excretion and reduced uptake in other organs in Staphylococcus aureus-infected animals. Higher uptake was observed in the target as compared to the non-target tissue (p < 0.0001) at 60 min post administration. The presented in-human clinical case demonstrates uptake of the radiopharmaceutical by Staphyloccocus aureus bacteria. These results indicate the potential of [Ga-68]Ga-DOTA-Ubiquicidin(29-41) as a radiopharmaceutical that can be obtained in a hospital radiopharmacy for the diagnosis of infectious processes using PET/CT.
Radioactive gold nanoparticles coated with BSA
2024 - BARBEZAN, ANGELICA B.; ROSERO, WILMMER A.A.; VIEIRA, DANIEL P.; RIGO, MARIA E.Z.; SILVA, GIOVANA D. da; RODRIGUES, ALEX A.; ALMEIDA, LUIS F. de; SILVA, FABIO F.A. da; RIVERA, ANDY G.; SILVA, NATANAEL G. da; BERNARDES, EMERSON S.; ZEITUNI, CARLOS A.; ROSTELATO, MARIA E.C.M.
Background: Nanotechnology has revolutionized medicine, especially in oncological treatments. Gold nanoparticles (AuNPs) stand out as an innovative alternative due to their biocompatibility, potential for surface modification, and effectiveness in radiotherapeutic techniques. Given that prostate cancer ranks as one of the leading malignancies among men, there's a pressing need to investigate new therapeutic approaches. Methods: AuNPs coated with bovine serum albumin (BSA) were synthesized and their cytotoxicity was assessed against prostate tumor cell lines (LNCaP and PC-3), healthy prostate cells (RWPE-1), and endothelial control cells (HUVEC) using the MTS/PMS assay. For in vivo studies, BALB/C Nude mice were employed to gauge the therapeutic efficacy, biodistribution, and hematological implications post-treatment with BSA-coated AuNPs. Results: The BSA-coated AuNPs exhibited cytotoxic potential against PC-3 and LNCaP lines, while interactions with RWPE-1 and HUVEC remain subjects for further scrutiny. Within animal models, a diverse therapeutic response was observed, with certain instances indicating complete tumor regression. Biodistribution data emphasized the nanoparticles' affinity towards particular organs, and the majority of hematological indicators aligned with normative standards. Conclusions: BSA-coated AuNPs manifest substantial promise as therapeutic tools in treating prostate cancer. The present research not only accentuates the nanoparticles' efficacy but also stresses the imperative of optimization to ascertain both selectivity and safety. Such findings illuminate a promising trajectory for avant-garde therapeutic modalities, holding substantial implications for public health advancements.
Evaluation of MCP anticancer activity using molecular imaging
2023 - SILVA, FABIO F.A. da
MCP is a polysaccharide found abundantly in the plant's primary wall and shows activity in several areas of the food industry and nutrition, serving in food production, improving intestinal flow, reducing cholesterol, and being an important nutritional compound. MCP can also act as an anti-tumorigenic molecule in several types of tumors, in addition to avoiding chemoresistance, modulating the immune system, and preventing renal disease caused by radiotherapy and chemotherapy in cancer treatments. This study was divided into three main parts. In the first part, a review was carried out to study the biological activity of MCP and its contribution to cancer therapy, demonstrating treatment doses, types of MCP used, and experimental design, providing a critical view of the exposed data and its relationship with galectin-3 and other theories regarding its mechanisms. In the second part, we radiolabeled MCP with 99mTc and verified the biodistribution and pharmacokinetics of MCP-99mTc orally and intravenously (IV) administrated. First, the structure and monosaccharide composition of MCP were studied, and it was demonstrated that there is a diversity of monosaccharides and molecular weights within the MCP structure and that MCP30 and MCP3 fractions are rich in galactose. Next, we studied the inhibition and binding affinity of MCP for galectin-3 and demonstrated that MCP partially binds Gal-3 and that MCP3 shows an inhibition capacity at a concentration of 25 mg/ml. We radiolabeled MCP with 99mTc and verified its stability in saline in different pH, plasma, and in vivo. MCP-99mTc has a low gastrointestinal absorption (5.27x10-6 % total radioactivity counts) and gastrointestinal elimination when administered via oral and renal and hepatobiliary elimination when administered via IV. Finally, the blood compartment distribution assay showed that MCP-99mTc has a high affinity for plasma proteins and blood cells in C57BL/6 Lgals3 +/+ mice, and this affinity was partially lost when galectin-3 was deleted in C57BL/6 Lgals3 -/- mice. The pharmacokinetic assay showed that MCP-99mTc elimination speed was greater in the C57BL/6 Lgals3-/- mice than in the C57BL/6 Lgals3 +/+, indicating that a lack of galectin-3 increases MCP elimination. In the third part, we analyzed the behavior of MCP-99mTc in animals with SKOV-3 and MKN45 tumors using molecular imaging. First, we demonstrated that cell binding and internalization of MCP were only partially influenced by Galectin-3 expression in vitro using SKOV-3 scrambled and SKOV-3 shRNAGal3 cells (knockdown of Gal-3 expression). Next, we showed that MCP (20 mg/kg) exhibited anticancer activity in a SKOV-3 cell tumor xenograft model, reducing tumor growth by 48.5% and tumor weight by 50% when administered intravenously; however, oral administration of MCP (200 mg/kg) did not show an anticancer effect. Subsequently, we demonstrated that MCP-99mTc reached the tumor and bound to regions of necrosis in the SKOV-3 cell tumor xenograft model when administered intravenously. Finally, we demonstrated that IV administration of MCP (10 mg/kg) in mice with SKOV-3 tumors (lower expression of Gal-3) and MKN45 tumors (greater expression of Gal-3) reduced tumor growth by 58.7% and 35.4%, respectively, and reduced the tumor weight by 51.7% and 30.7 %, respectively. Furthermore, in both tumor xenografts, MCP-99mTc reached the tumor at the same proportion. These results demonstrate that MCP-99mTc radiolabeling is an important tool for studying the anticancer activity of MCP. We also showed that the data do not corroborate the hypothesis of the direct pharmacological effect of MCP exclusively targeting Gal-3, thus contributing to the knowledge of MCP anticancer activity.
Plant-derived polyphenolic compounds
2023 - ROSALES, THIECLA K.O.; SILVA, FABIO F.A. da; BERNARDES, EMERSON S.; FABI, JOAO P.
Plant-derived polyphenols are naturally occurring compounds widely distributed in plants. They have received greater attention in the food and pharmaceutical industries due to their potential health benefits, reducing the risk of some chronic diseases due to their antioxidant, anti-inflammatory, anticancer, cardioprotective, and neuro-action properties. Polyphenolic compounds orally administered can be used as adjuvants in several treatments but with restricted uses due to chemical instability. The review discusses the different structural compositions of polyphenols and their influence on chemical stability. Despite the potential and wide applications, there is a need to improve the delivery of polyphenolics to target the human intestine without massive chemical modifications. Oral administration of polyphenols is unfeasible due to instability, low bioaccessibility, and limited bioavailability. Nano-delivery systems based on polysaccharides (starch, pectin, chitosan, and cellulose) have been identified as a viable option for oral ingestion, potentiate biological effects, and direct-controlled delivery in specific tissues. The time and dose can be individualized for specific diseases, such as intestinal cancer. This review will address the mechanisms by which polysaccharides-based nanostructured systems can protect against degradation and enhance intestinal permeation, oral bioavailability, and the potential application of polysaccharides as nanocarriers for the controlled and targeted delivery of polyphenolic compounds.
Selection of aptamers against the Jagged-1 protein
2022 - SILVA, F.F.A. da; SANTOS, S.N. dos; PEREIRA, J.P.M.; GUSHIKEN JUNIOR, D.S.; CARNEIRO, M.A.P.; NASCIMENTO, I.C.C.; ULRICH, A.H.; BERNARDES, E.S.
The breast cancer is one of the biggest public health problems in the world, being the main female type of cancer that affects the population. The Jagged-1 protein plays an important role in the biology and development of cancer, influencing angiogenesis, growth of neoplastic cells, tumor stem cells, epithelial mesenchymal transition, metastatic processes and resistance to therapies in various types of cancer. In this project, our aim was to select an aptamer for JAG1 ligand using an aptamer library that could be used as a radiopharmaceutical for PET/SPECT/CT diagnosis of tumors that express JAG1. Our work showed that MDA-MB-231-JAG1 cells overexpress more mRNA and JAG1 protein than control cells (MDA-MB-231-Control). We also selected aptamers with high affinity for MDA-MB-231-JAG1 cells that could be a useful tool for the development of new radiopharmaceuticals for the diagnosis and treatment of tumors that overexpress JAG1.
Uncovering the role of modified citrus pectin in cancer
2022 - SILVA, FABIO A. da; BERNARDES, EMERSON S.
Background: Modified citrus pectin (MCP) is a polysaccharide consisting of galacturonic acid with anti-cancer activity that can act synergistically with other treatments to reduce tumor growth, stimulate programmed cell death and reduce the number of metastases. In addition, MCP prevents acute and severe renal syndromes caused by radiation/chemotherapy. All of these effects were reported to be due to MCP ability to specifically inhibit Galectin-3 protein functions. Aims: The aim of this work was to evaluate the anticancer effect of MCP in a Balb/c nude mice xenograft model of ovarian cancer. Methods: The human ovary cancer cell line, SKOV-3, was subcutaneously injected in Balb/c nude mice and tumor growth was monitored daily with a caliper. When tumors reached 250-300 mm3, 20 mg/kl of MCP was administered intravenously (I.V.) in a daily based for 21 days. Tumor growth and mice weight were monitored daily. Additionally, MCP was radiolabeled with 99m-technetium (99m-Tc) with the incubation of MCP (2.5 mg) in saline with SnCl2 (4 mg/ ml), HCl (0.01 M), NaOH (0.01 M) and 99mTc (129,5 MBq) at pH=7 for 30 min. The radiochemical purity was determined by iTLC-SG with acetone and ethanol/NH3/H2O (1:2:5). 99mTc-MCP (37 MBq) was administrated I.V. in Balb/C nude mice bearing SKOV-3 tumors and after 1, 2 and 4 hours, SPECT/CT image was acquired (Albira SI Buker). Ex-vivo biodistribution studies were performed after the I.V. injection of 10 MBq of 99mTc-MCP for 1-hour. The % of injected dose per gram (%ID/g) of tissues of interest was calculated. The tumors were removed, fixed, cut and used for autoradiography studies and stained with hematoxylin and eosin (H&E) to verify hypoxic regions. Results: The I.V. administration of MCP was able to significantly reduce SKOV-3 tumor growth (52% tumor volume reduction) in comparison with the non-treated group, after 21 of treatment. Our biodistribution studies showed that 99mTc-MCP was mainly found in kidneys, bladder and liver of mice (%ID/g = 12.25, 38.57 and 5.71, respectively), and was able to reach the tumor (%ID/g = 0.765 ± 0.045) 1-hour after I.V. administration. 99mTc-MCP accumulation in the tumor site was visualized by μSPECT/CT imaging 1 hour after I.V. administration. The autoradiography and stained (H&E) study demonstrated a correlation between MCP and regions of tumor necrosis. Because of MCP high accumulation in kidneys, renal toxicity was also evaluated. We were able to find that MCP doesn’t induce renal toxicity when administered in a daily base at a concentration of 20 mg/Kg. Conclusion: In this work we demonstrated that a daily treatment of MCP was able to reduce tumor growth of ovarian tumor xenografts (SKOV-3 cells) without showing renal toxicity. We found too that MCP can reach the tumor site, binding mainly in regions of necrosis. However, other studies are needed to unravel the mechanisms of action that act on the antitumor effect of MCP.
Selection of aptamers against Jagged-1 protein
2021 - SILVA, F.F.A. da; SANTOS, S.N. dos; GUSHIKEN JUNIOR, D.S.; CARNEIRO, M.A.P.; BERNARDES, E.S.
Radiochemistry and pharmacokinetics of Pectin (MCP)
2020 - SILVA, FABIO F.A. da; SANTOS, SOFIA N. dos; PIJEIRA, MARTHA S.O.; BERNARDES, EMERSON S.