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.
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.
Development of natural polymeric microcapsules for antimicrobial drug delivery
2020 - LIMA, CAROLINE S.A. de; VARCA, GUSTAVO H.C.; COSTA, SIRLENE M. da; FERRAZ, HUMBERTO G.; SANTOS, ANA C. da S.; LOPES, PATRICIA S.; COSTA, SILGIA A. da
The goal of this work was the development of natural polymeric microcapsules for antimicrobial drug delivery – triclosan loaded alginate and chitosan-based microcapsules for potential coating applications in substrates such as textiles or plastics. Microcapsules containing 2.5% (w/w) or 3% (w/w) triclosan in both core and matrix were synthesized and evaluated by Fourier-transform infrared spectroscopy, scanning electron microscopy, confocal microscopy, differential scanning calorimetry, thermogravimetry, and antimicrobial activity. The microcapsules produced featured spherical and mostly irregularly-shaped surfaces composed by an alginate core in a chitosan outer matrix, as revealed by confocal microscopy, and antimicrobial activity against S. aureus and E. coli with inhibition halos up to 60 mm and 25 mm respectively, granted by a triclosan loading of 61.66%. The thermal analysis suggested that the polymers protected the active substance from temperature-induced degradation. In conclusion, these microcapsules may be applied toward antimicrobial functionalization of plastics, textiles and other materials.
Antimicrobial activity and physicochemical performance of a modified endodontic sealer
2020 - GONCALVES, FLAVIA; CAMPOS, LUIZA M. de P.; SANCHES, LUCIANA K.F.; SILVA, LARISSA T.S.; SANTOS, TAMIRIS M.R. dos; VARCA, GUSTAVO H.C.; LOPES, DIANA P.; COGO-MULLER, KARINA; PARRA, DUCLERC F.; BRAGA, ROBERTO R.; SANTOS, MARCELO dos; BOARO, LETICIA C.C.
Introduction: this study aimed to evaluate the antimicrobial and physicochemical properties of a commercial endodontic sealer modified by the addition of montmorillonite (MMT) nanoparticles loaded with two different drugs: chlorhexidine (CHX) or metronidazole (MET). Methods: 5 wt% MMT/CHX or MMT/MET nanoparticles were added to the sealer AH-Plus. The experimental materials were evaluated for drug release, antimicrobial activity, flow, flexural strength, and flexural modulus. Data were subjected to one-way ANOVA, Kruskal-Wallis, and Mann-Whitney tests. Results: The drug incorporation into MMT particles was 9% and 10% for CHX and MET, respectively. At 20 days after manipulation, 16.5% of the drug was released by the sealer with MMT/MET and 0.4% by MMT/CHX. The addition of both nanoparticles decreased the flow of materials, but they were still in compliance with ISO 6876-2012. The conversion, flexural strength, and flexural modulus of MMT/MET (87%, 37±7 MPa, 2.3 GPa) and MMT/CHX (78%, 29±2 MPa, 2.7 GPa) were similar in both groups but lower than in the control group (100%, 54±7 MPa, 4.0±0.7 GPa). Both experimental materials were able to form an inhibition halo for E. faecalis bacteria (CHX: 4.8±1.4 and MET: 4.0±1.6 mm), whereas the control group did not inhibit the microorganism. Conclusion: both formulations proposed as endodontic sealer presented effective antimicrobial activity and acceptable flow. The addition of MMT/CHX and MMT/MET particles decreased the conversion and mechanical properties, but further studies are required to clarify the clinical relevance of these properties.
Semi-solid pharmaceutical formulations for the delivery of papain nanoparticles
2020 - LIMA, CAROLINE S.A. de; VARCA, JUSTINE P.R.O.; NOGUEIRA, KAMILA M.; FAZOLIN, GABRIELA N.; FREITAS, LUCAS F. de; SOUZA, ELISEU W. de; LUGAO, ADEMAR B.; VARCA, GUSTAVO H.C.
Papain is a therapeutic enzyme with restricted applications due to associated allergenic reactions. Papain nanoparticles have shown to be safe for biomedical use, although a method for proper drug loading and release remains to be developed. Thus, the objective of this work was to develop and assess the stability of papain nanoparticles in a prototype semi-solid formulation suitable for dermatological or topical administrations. Papain nanoparticles of 7.0 ± 0.1 nm were synthesized and loaded into carboxymethylcellulose- and poly(vinyl alcohol)-based gels. The formulations were then assayed for preliminary stability, enzyme activity, cytotoxicity studies, and characterized according to their microstructures and protein distribution. The formulations were suitable for papain nanoparticle loading and provided a stable environment for the nanoparticles. The enzyme distribution along the gel matrix was homogeneous for all the formulations, and the proteolytic activity was preserved after the gel preparation. Both gels presented a slow release of the papain nanoparticles for four days. Cell viability assays revealed no potential cytotoxicity, and the presence of the nanoparticles did not alter the microstructure of the gel. The developed systems presented a potential for biomedical applications, either as drug delivery systems for papain nanoparticles and/or its complexes.
An updated review of macro, micro, and nanostructured hydrogels for biomedical and pharmaceutical applications
2020 - LIMA, CAROLINE S.A. de; BALOGH, TATIANA S.; VARCA, JUSTINE P.R.O.; VARCA, GUSTAVO H.C.; LUGAO, ADEMAR B.; CAMACHO-CRUZ, LUIS A.; BUCIO, EMILIO; KADLUBOWSKI, SLAWOMIR S.
Hydrogels are materials with wide applications in several fields, including the biomedical and pharmaceutical industries. Their properties such as the capacity of absorbing great amounts of aqueous solutions without losing shape and mechanical properties, as well as loading drugs of different nature, including hydrophobic ones and biomolecules, give an idea of their versatility and promising demand. As they have been explored in a great number of studies for years, many routes of synthesis have been developed, especially for chemical/permanent hydrogels. In the same way, stimuli-responsive hydrogels, also known as intelligent materials, have been explored too, enhancing the regulation of properties such as targeting and drug release. By controlling the particle size, hydrogel on the micro- and nanoscale have been studied likewise and have increased, even more, the possibilities for applications of the so-called XXI century materials. In this paper, we aimed to produce an overview of the recent studies concerning methods of synthesis, biomedical, and pharmaceutical applications of macro-, micro, and nanogels.
Enhancing the furosemide permeability by papain minitablets through a triple co-culture in vitro intestinal cell model
2020 - CORAZZA, FULVIO G.; ERNESTO, JULIA V.; NAMBU, FELIPE A.N.; CALIXTO, LEANDRO A.; VARCA, GUSTAVO H.C.; VIEIRA, DANIEL P.; LEITE-SILVA, VANIA R.; ANDREO-FILHO, NEWTON; LOPES, PATRICIA S.
The administration of medicines by the oral route is the most used approach for being very convenient. Although it is the most popular, this route also has absorption, and consequently, bioavailability limitations. In this sense, several pharmacotechnical strategies have been used to improve drug absorption, one of which is the use of permeation promoters. Papain is a very versatile plant enzyme that can be used as a permeation promoter of various active compounds. This study aimed to evaluate the safety of papain and the formulation of native papain minitablets to promote in vitro permeation of furosemide through an innovative biomimetic triple co-culture model of Caco-2, HT29-MTX, and Raji cells. Regarding permeation, furosemide and metaprolol concentrations are determined with HPLC; those are used to calculate Papp. Monolayer integrity was evaluated using TEER and Lucifer Yellow. In the presence of papain, TEER decreased two-fold and the Papp of furosemide increased six-fold. The results suggest that native papain minitablets can be used as therapeutic adjuvants to enhance the permeation of drugs significantly improving bioavailability.