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.
Evaluation of thermal and radiation stability of EPDM in the presence of some algal powders
2022 - ZAHARESCU, TRAIAN; MATEESCU, CARMEN; DIMA, ANDREEA; VARCA, GUSTAVO H.C.
In this paper, ecological-friendly materials based on ethylene–propylene–diene terpolymer (EPDM) with improved thermal and radiation stabilities by Chlorella vulgaris (CV) and Spirulina platensis (SP) powders were investigated by complementary procedures: FTIR spectroscopy and isothermal and nonisothermal chemiluminescence (CL). The stabilization potential of microalgae was evaluated at several degrees of γ-radiolysis by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, while the polymer resistances were studied on a large range of algal concentrations (1, 3, 5 and 10 mass%). The carbonyl and hydroxyl indices of all degraded EPDM formulations were found to be two times smaller in the presence of algal powders, if compared to the pristine material. Some dissimilarities between the oxidation development in pristine and modified EPDM appeared, especially in unirradiated samples. The activation energies required for the oxidation of EPDM and the lifetime of these samples at various temperatures between room temperature and 100 °C were calculated. The antioxidant compounds existing in the studied microalgae proved a significant influence on the stability of EPDM, mainly in the presence of SP, which was confirmed by the activation energies calculated from our CL results. The investigation of cycling thermal degradation revealed the obvious contribution of additives towards delaying EPDM ageing.
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.
Antimicrobial materials and devices for biomedical applications
2020 - LOPEZ-SAUCEDO, FELIPE; FLORES-ROJAS, GUADALUPE G.; VARCA, JUSTINE P.R.O.; VARCA, GUSTAVO H.C.; BUCIO, EMILIO
Bioaccumulation in sanitary devices, caused by opportunistic pathogens, intervenes negatively in the recovery of a patient since these are able to provoke a mild or life-threatening infection. Thus, surfaces of certain materials such as gauzes, catheters, sutures, etc., which are adjacent or directly exposed to a healing zone, are prone to become sites for the growth, proliferation, and spread of pathogenic microorganisms. Although in surgical or healing processes, sterile materials are usually applied, the time of contact with biological interfaces is long enough to make the sterilization but not enough to control and prevent an infection since pathogens abound in the surroundings. Air, water, and soil can be potential vectors, without considering those factors related to iatrogenesis that also play a role in the opportunities for the patient's recovery. Within this context, engineered materials are currently being developed and explored towards devices and biomaterials with improved design, performance, duration, biocompatibility aiming to be safer for the user. The surface functionalization of materials with antimicrobial agents is a highlighted alternative to overcome this issue. This chapter addresses current antimicrobial materials, as well as strategies for obtaining antimicrobial surfaces and coating as well as their properties. In addition, the safety assessment of biomedical applications and international standards are discussed.