GUSTAVO HENRIQUE COSTAVARCA

GUSTAVO HENRIQUE COSTAVARCA

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Mucoadhesive drug delivery system with enhanced permeability capacity for intravesical therapy
2023 - LIMA, CAROLINE S.A. de; RIAL-HERMIDA, M.I.; FERREIRA, ARYEL H.; FREITAS, LUCAS F. de; VARCA, GUSTAVA H.C.; ALVAREZ-LORENZO, CARMEN; LUGAO, ADEMAR B.
Introduction and objective: Bladder cancer (BC) represents 3% of the new diagnosis of cancer. 70% of the patients present the non-muscle-invasive type of the disease [1]. This type of BC is usually treated by the transurethral resection of the visible tumor, followed by intravesical inmuno- or chemotherapy. The instillation of chemotherapy into the bladder is not totally efficient as it faces limitations such as short residence time and permeability restrictions of the bladder mucosa [2]. Thus, the main objective of this work was to develop drug delivery formulations for intravesical chemotherapy that enhance its residence time and permeation capacity. Methodology: Carboxymethylcellulose (CMC) and polyvinyl alcohol (PVA) polymers were used to prepare a physical hydrogel with mucoadhesive properties. Papain, a thiol proteolytic enzyme, was added to the formulations as a permeation enhancer. The mucoadhesive capacity of the formulation was evaluated by its interaction with mucin, bioadhesion strength and retention on bladder urothelium. Ex-vivo drug permeation was also elucidated using Franz cells to observe the papain effect. Results and discussion: The CMC + PVA formulations showed positive bioadhesion components, confirming their interaction with the urothelium. The significant decrease of ɳb in the formulation containing enzyme suggests that papain was cleaving the glycoproteins present in the mucin. On bioadhesion strength assays, the prepared formulations required a slightly higher detachment force than the control. In terms of work of adhesion, all formulations had values higher than those recorded for the control (p < 0.05), confirming that there were mucoadhesive interactions between the bladder tissue and the gels. Hydrogel retention assay revealed that the formulations had higher bioadhesion capacity than the control (FITC solution), especially after the third wash (15 mL). By drug permeation analysis, it was possible to observe that the lag time decreased for CMC + PVA hydrogels with and without papain in comparison to the control. At the timepoint of 2 h, the formulation containing papain presented the highest capacity of permeation. Conclusions: The biocompatible hydrogel containing papain as a permeability enhancer was an innovative approach for BC treatment to address the poor permeation of the tissue and short residence time. The formulation developed in this work could represent a very notable improvement in clinical practice, ensuring a longer retention time of the formulation in the bladder tissue, with a more sustained release of the drug and greater permeation capacity.
Mucoadhesive gellan gum-based and carboxymethyl cellulose -based hydrogels containing gemcitabine and papain for bladder cancer treatment
2023 - LIMA, CAROLINE S.A. de; RIAL-HERMIDA, MARIA I.; FREITAS, LUCAS F. de; PEREIRA-DA-MOTA, ANA F.; VIVERO-LOPEZ, MARIA; FERREIRA, ARYEL H.; KADŁUBOWSKI, SŁAWOMIR; VARCA, GUSTAVO H.C.; LUGAO, ADEMAR B.; ALVAREZ-LORENZO, CARMEN
Local treatment of bladder cancer faces several limitations such as short residence time or low permeation through urothelium tissue. The aim of this work was to develop patient-friendly mucoadhesive gel formulations combining gemcitabine and the enzyme papain for improved intravesical chemotherapy delivery. Hydrogels based on two different polysaccharides, gellan gum and sodium carboxymethylcellulose (CMC), were prepared with either native papain or papain nanoparticles (nanopapain) to explore for the first time their use as permeability enhancers through bladder tissue. Gel formulations were characterized regarding enzyme stability, rheological behavior, retention on bladder tissue and bioadhesion, drug release properties, permeation capacity, and biocompatibility. After 90 days of storage, the enzyme loaded in the CMC gels retained up to 83.5 ± 4.9 % of its activity in the absence of the drug, and up to 78.1 ± 5.3 with gemcitabine. The gels were mucoadhesive and the enzyme papain showed mucolytic action, which resulted in resistance against washing off from the urothelium and enhanced permeability of gemcitabine in the ex vivo tissue diffusion tests. Native papain shortened lag-time tissue penetration to 0.6 h and enhanced 2-fold drug permeability All formulations demonstrated pseudoplastic behavior and no irritability. Overall, the developed formulations have potential as an upgraded alternative to intravesical therapy for bladder cancer treatment.
Solubility study of Kraft lignin for the development of electrospun nanofibers
2022 - NOGUEIRA, K.M.; VARCA, J.O.; LIMA, C.S.; CRUZ, C.C. da; RIBEIRO, A.H.; FREITAS, L.F.; VARCA, G.H.; LUGAO, A.B.
Lignin is a high-volume byproduct of paper manufacturing which has been explored in many research fields, especially for the development of fiber and nanofiber for biomedical applications [1,2]. This work presents a solubility study performed through gravimetry for kraft lignin considering its application for the development of electrospun nanofibers [3]. In practical terms, lignin was solubilized in alkaline aqueous solution, dimethylformamide and dimethylsulfoxide, at concentrations of 10, 15 and 20% (w/v) and varying temperatures of 25, 50 and 75 ºC, under constant stirring. After solubilizing, the solution was filtered, and the insoluble fraction was dried in the oven at 100 ºC. At 25 ºC lignin was insoluble in all solvents tested, as predicted using Hansen solubility parameters. Although the increase in temperature promoted lignin solubilization in all solvents tested, at the highest temperature assayed, the solubilization was facilitated, presenting the smallest levels of the insoluble fraction. Lignin was soluble in all solvents tested, and optimum solubility conditions were achieved using 10% lignin solutions (w/v), without significant insoluble fraction, and therefore ideal concentration for the development of lignin based fibers.
A biological study of gelatin-PVA based scaffold functionalized with albumin for biomedical purposes
2022 - VARCA, J.O.; KLINGBEIL, F.; NOGUEIRA, K.M.; LIMA, C.S.; CRUZ, C.C. da; FREITAS, L.F.; VARCA, G.H.; MATHOR, M.B.; LUGAO, A.B.
Biomaterials have been designed for tissue reconstruction, bone regeneration and cell culture, and functionalized with presence of proteins, nanoparticles, peptides and other components to improve the biocompatibility for instance. This work shows a biological study of gelatin-PVA based scaffold with controlled pore size and functionalized with albumin for biomedical purposes. The in vitro study comprises cytotoxicity, cell adhesion and proliferation assessment. In practical terms, the gelatin-PVA scaffold crosslinked and sterilized by gamma radiation followed by freeze-drying was evaluated by cytotoxicity, adhesion and proliferation tests. The cytotoxicity results showed that the biomaterial produced was non-toxic, and adhesion and proliferation assays showed that the material was suitable for tissue engineering. The presence of albumin did not present a significant impact on the cell performance, at the assayed concentration.
Géis mucoadesivos para o tratamento do câncer de bexiga superficial
2022 - LIMA, C.S.; HERMIDA, M.R.; VARCA, G.C.; FREITAS, L.F.; LORENZO, C.A.; LUGAO, A.B.
A mucoadesividade tem sido estudada na área farmacêutica há mais de 50 anos e é uma propriedade explorada para aumentar o tempo de residência de um fármaco, bem como para melhorar a especificidade da entrega do ativo ao local desejado. Um sistema mucoadesivo que permite a absorção direta do fármaco e uma diminuição da taxa de excreção, consequentemente, tem-se uma maior biodisponibilidade do ativo associada à administração de doses menores, com menor frequência (Yan et al., 2017). O câncer de bexiga (CB) é uma das principais doenças que atacam o trato urinário e se dá pela proliferação anormal das células do tecido da parede interna da bexiga conhecida como urotélio (INCA, 2021). Sabe-se que o tratamento por quimioterapia intravesical do CB apresenta algumas limitações como a permeação do ativo no urotélio e o tempo de residência desse fármaco que é muito limitado devido ao efeito de diluição e lavagem da urina que acaba eliminando-o completamente. Dessa forma, o desenvolvimento de novos veículos mucoadesivos para o carreamento da quimioterapia pode ser uma opção de tratamento avançado (Kolawole et al., 2017). Neste trabalho, buscou-se preparar géis mucoadesivos a partir da goma gelana (0,1% m/v) e de uma blenda de carboximetilcelulose (2% m/v) e polivinil álcool (0,2% m/v), contendo um adjuvante para aumento de permeação (papaína), como potenciais alternativas para a quimioterapia intravesical. Foram realizados ensaios de reologia (frequency sweep para avaliação dos módulos de perda (G’’) e de armazenamento (G’)); força de adesão para estudo da capacidade de mucoadesão das formulações e, por fim, de citotoxidade em duas linhagens celulares, HUVEC (endotelial humana) e V79-4 (fibroblastos) . Os ensaios reológicos dos géis apresentam resultados característicos de comportamentos pseudoplásticos, isto é, com maior fluidez a altas frequências, e, portanto, com potencial para aplicação por seringa e cateter. Os ensaios de mucoadesão confirmaram que os polímeros escolhidos apresentam capacidade de interação com a mucina presente no urotélio, representando alternativas interessantes para o aumento do tempo de residência e da biodisponibilidade da terapia. Por fim, as formulações apresentaram pouca ou nenhuma toxicidade, mostrando potencial para aplicação biomédica.
Mucoadhesive polymers and their applications in drug delivery systems for the treatment of bladder cancer
2022 - LIMA, CAROLINE S.A. de; VARCA, JUSTINE P.R.O.; ALVES, VICTORIA M.; NOGUEIRA, KAMILA M.; CRUZ, CASSIA P.C.; RIAL-HERMIDA, M. ISABEL; KADLUBOWSKI, SLAWOMIR S.; VARCA, GUSTAVO H.C.; LUGAO, ADEMAR B.
Bladder cancer (BC) is the tenth most common type of cancer worldwide, affecting up to four times more men than women. Depending on the stage of the tumor, different therapy protocols are applied. Non-muscle-invasive cancer englobes around 70% of the cases and is usually treated using the transurethral resection of bladder tumor (TURBIT) followed by the instillation of chemotherapy or immunotherapy. However, due to bladder anatomy and physiology, current intravesical therapies present limitations concerning permeation and time of residence. Furthermore, they require several frequent catheter insertions with a reduced interval between doses, which is highly demotivating for the patient. This scenario has encouraged several pieces of research focusing on the development of drug delivery systems (DDS) to improve drug time residence, permeation capacity, and target release. In this review, the current situation of BC is described concerning the disease and available treatments, followed by a report on the main DDS developed in the past few years, focusing on those based on mucoadhesive polymers as a strategy. A brief review of methods to evaluate mucoadhesion properties is also presented; lastly, different polymers suitable for this application are discussed.
A mechanistic approach towards the formation of bityrosine in proteins by ionizing radiation
2021 - SOWINSKI, SEBASTIAN; VARCA, GUSTAVO H.C.; KADLUBOWSKI, SLAWOMIR; LUGAO, ADEMAR B.; ULANSKI, PIOTR
One of the methods of protein crosslinking used in the synthesis of protein-based nanoparticles is the formation of bityrosine bridges, which may be achieved by the recombination of phenoxyl-type radicals in irradiated protein solutions. Radiation-induced formation of phenoxyl radicals in tyrosine is promoted in presence of H+. In this work, kinetics of this process and the influence of pH were studied by pulse radiolysis measurements of a model peptide H-Gly-Tyr-Gly-OH (GYG), which may help to solve questions raised for bigger, more complex systems in comparable conditions. The main route of phenoxyl radicals formation consists of the addition reaction of hydroxyl radical to the phenol ring on the tyrosine side-chain and proton catalyzed water molecule elimination. A similar effect was observed in studies of tripeptide solutions containing phosphate buffer. The presented data include time-resolved optical spectroscopy of transient species formed under pulse electron beam irradiation and a comparison of the kinetics of the phenoxyl radicals formation in samples at various pH and in presence of phosphate buffer. The postulated mechanism and obtained values of rate constants of the formation and decay of transient species were additionally checked by simple probabilistic simulations.
The state of the art of theranostic nanomaterials for lung, breast, and prostate cancers
2021 - FREITAS, LUCAS F.; FERREIRA, ARYEL H.; THIPE, VELAPHI C.; VARCA, GUSTAVO H.C.; LIMA, CAROLINE S.A.; BATISTA, JORGE G.S.; RIELLO, FABIANE N.; NOGUEIRA, KAMILA; CRUZ, CASSIA P.C.; MENDES, GIOVANNA O.A.; RODRIGUES, ADRIANA S.; SOUSA, THAYNA S.; ALVES, VICTORIA M.; LUGAO, ADEMAR B.
The synthesis and engineering of nanomaterials offer more robust systems for the treatment of cancer, with technologies that combine therapy with imaging diagnostic tools in the so‐called nanotheranostics. Among the most studied systems, there are quantum dots, liposomes, polymeric nanoparticles, inorganic nanoparticles, magnetic nanoparticles, dendrimers, and gold nanoparticles. Most of the advantages of nanomaterials over the classic anticancer therapies come from their optimal size, which prevents the elimination by the kidneys and enhances their permeation in the tumor due to the abnormal blood vessels present in cancer tissues. Furthermore, the drug delivery and the contrast efficiency for imaging are enhanced, especially due to the increased surface area and the selective accumulation in the desired tissues. This property leads to the reduced drug dose necessary to exert the desired effect and for a longer action within the tumor. Finally, they are made so that there is no degradation into toxic byproducts and have a lower immune response triggering. In this article, we intend to review and discuss the state‐of‐the‐art regarding the use of nanomaterials as therapeutic and diagnostic tools for lung, breast, and prostate cancer, as they are among the most prevalent worldwide.
Hybrid gold-protein nanoparticles as radiosensitizers
2020 - FREITAS, L.F.; CRUZ, C.C. da; BATISTA, J.G.; VARCA, G.H.; LUGAO, A.B.; MATHOR, M.B.
Gold nanoparticles present unique optical properties which are dependent upon size and morphology, and consist on a differential interaction with radiation compared to the bulk material. Those nanoparticles can be modified in order to adjust their bioavailability and tissue-targeting, and one of the means to do so is by adsorbing one or more types of proteins onto their surface. Gamma radiation can be helpful in this regard, since it promotes intra- and intermolecular crosslinks in proteins and enables their adsorption onto the metallic nanoparticles’ surfaces. Here we present the results obtained for hybrid gold-protein nanoparticles as radiosensitizers. The nanoparticles were synthesized radiolytically by mixing 5 mmol L-1 NaAuCl4 with 1 mg mL-1 bovine serum albumin (BSA) or papain in the presence of 0.1 mol L-1 tert-butanol and 20% ethanol. The solutions were irradiated with 10 kGy in a multipurpose gamma irradiator (60Co source, 5 kGy per hour) for the radiolytic synthesis of the nanoparticles, and then the resulting red suspension was stored until use. 10^4 cells (MDA-MB-231 line) were seeded in 96-well plates and incubated with a 2:1 mixture of DMEM medium and nanoparticles suspension for 12 hours. Then, the wells were washed with sterile phosphate buffered saline, and fresh DMEM medium was added prior to irradiation in a gamma cell (60Co source, 0.6 kGy per hour) with 10, 30 and 50 Gy. 48 hours later, the cell viability was assessed by MTS assay. The results indicate that the radiation alone slightly stimulated the proliferation of the tumor cells, but this effect was more evident in the presence of gold-papain nanoparticles. The ablative effect due to radiosensitization was observed with 30 and 50 Gy for the cells incubated with gold-BSA nanoparticles, and 10 and 30 Gy for the cells incubated with gold-papain nanoparticles. This difference might be due to a more effective internalization or surface-attachment of nanoparticles when they are coated with papain, and one evidence for this assumption is the fact that the cell culture becomes red after the incubation with gold-papain nanoparticles. Therefore, protein-coated nanoparticles might be effective as radiosensitizers, depending on the coating and dose of radiation.
Influence of argon and nitrous oxide on the synthesis of PVP nanogels prepared by gamma radiation
2020 - BALOGH, T.S.; KADLUBOWSKI, S.; BONTURIM, E.; LUGAO, A.B.; VARCA, G.H.
Nanogels are innovative systems with great potential for use in chemotherapy, disease diagnosis, release of bioactive substances, vaccines, cell culture systems, biocatalysis, in the generation of bioactive scaffolds in regenerative medicine among other applications. The definition of this material can be directly derived from the definition of polymeric gel, that is, a two-component system consisting of a permanent three-dimensional network of linked polymer chains and solvent molecules filling the pores of this network. Its internal structure is similar to that of hydrogels however presents particle size range varying from 0 to 100 nm leading to several advantages. Nanogel production methods involve intramolecular crosslinking that can be achieved using ionizing radiation. This method avoids the addition of any additives allowing the reaction to be carried out in a pure polymer-solvent system and the production of nanogels for biomedical applications free from monomer and crosslinking agents or surfactants. In this work influence of argon and nitrous oxide on the formation of nanogels by gamma irradiation has been evaluated. The samples were prepared in duplicate in multipurpose cobalt-60 gamma irradiator using a 25 mM PVP solution. Samples were irradiated in argon and nitrous oxide conditions with doses from 1 kGy up to 25 kGy with 10 kGy/h dose rate. These samples were morphologically characterized using Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) as well as the pristine PVP solution. The mean particle size of the samples and the polydispersity index was performed in equipment Zetasizer Nano ZS - Malvern® and the determination of radius of gyration and molecular weight was performed in equipment Heleos - Wyatt®. It was observed in the conditions evaluated that saturation with argon or nitrous oxide promoted similar results except for 25 kGy dose. At this dose larger mean particle size and radius of gyration were observed in the sample saturated with nitrous oxide.