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.
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.
Synthesis and purification of albumin-based nanoparticles crosslinked by radiation
2020 - RIELLO, F.N.; VARCA, G.H.; LIMA, C.S.; FREITAS, L.F.; FERREIRA, A.H.; LUGAO, A.B.
Protein-based nanoparticles have been proved a promissing alternative for the loading and delivery of chemotherapeutic agents, radiopharmaceutics and other drugs of interests, constituting a less toxic therapeutic option due to its biocompatibility and low or null side effects. The use of radiation to crosslink or form covalent bonds enables the controll of the crosslinking process, without the need for crosslinking agents, as well as provides sterilizations simultaneously, withouth generating toxic compounds or products. The present work targets the synthesis an purification of albumin-based nanocarrier crosslinked by gamma radiation for biomedical applications. For such purpose, albumin nanoparticles were synthesized using BSA at 20% ethanol (v/v) in 50 mM phosphate buffer on an ice bath prior to and after irradiation. Samples were exposed to gamma radiation at a minimun absrobed dose of 10 kGy at 5kGy.h-1 and purified using a SuperdexTM 200 Increase 10/300GL for isolating the crosslinked protein (high molecular weight) from the native BSA. After the purification, the fractions were characterized by electrophoresis, Uv, fluorescence and dynamic light scaterring. The nanoparticles were obtained in the range of 25-40 nm and purified into fractions of high molecular weight and the native ones. The high molecular weight fractions presented increased bityrosine levels if compared to the fraction corresponded to the native BSA. The yields of nanoparticle formation remains to be determined, but our results provided a clear evidence of the formation of radiation-crosslinked BSA nanoparticles and the role of bityrosine in the nanoparticle assembly.
Radiolabeled protein nanoparticles for cancer diagnosis
2020 - FERREIRA, A.H.; MARQUES, F.N.; SOUZA, L.E. de; VARCA, G.H.; REAL, C.C.; FARIA, D.d.; JUNQUEIRA, M.d.; LUGAO, A.B.; FREITAS, L.F.
Recent advances in nanomedicine and nanotechnology have expanded the development of multifunctional nanostructures which combine specificity, diagnostic and therapeutic functions in nanostructured complexes in order to overcome biological barriers that may hinder the selective and effective administration and uptake of drugs and diagnostic agents in tumor tissue. Nanoparticles have been used in nuclear medicine as nano-radiopharmaceuticals to carry PET and SPECT ?- and ?-emitting radioisotopes used in endoradiotherapy to specifically destroy tumor tissue. The aim of the present work was the study of radiolabeling of albumin (BSA-NPs) and papain (P-NPs) nanoparticles synthesized by gamma irradiation, with 99mTc and characterize their in vitro and in vivo properties as potential novel nano-radiopharmaceuticals. Electron microscopy and light scattering techniques show spherical shapes of nanoparticles and average diameter of 9.3 ± 1.9 nm for P-NPs and 25.1 ± 2.9 nm for BSA-NPs. The radiolabeling reached around 90% yield, and the 99mTc-BSA-NPs showed stability for 24 h in all assayed conditions, while 99mTc-P-NPs presented stability for 6 h in human serum. The biodistribution studies in healthy animals have shown different excretion profiles, 99mTc-P-NPs featured a renal excretion. On the other hand the 99mTc-BSA-NPs were found in the liver and spleen to a larger extent, undergoing hepatic excretion. In vitro studies showed promising internalization rates for both nanoparticles with 74% and 57.6% of total uptake in MDA-MB231 cells, respectively for 99mTc-P-NPs and 99mTc-BSA-NPs. In vivo studies in micro-SPECT/CT images also showed a high tumor uptake for both nanoparticles. The autoradiographic studies and immunohistochemistry assays revealed a high density of both papain and BSA nanoparticles in peripheral regions of tumor tissue and confirmed the efficacy of the developed nano-radioparmaceuticals for targeting breast cancer.