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1.
J Appl Crystallogr ; 56(Pt 5): 1381-1391, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37791357

RESUMO

A Monte Carlo (MC) method was introduced into a state-of-the-art model used to analyse small-angle X-ray scattering (SAXS) data of SBA-15, an ordered mesoporous material with many applications. With this new procedure, referred to herein as the SBA-15+MC model, it is possible to retrieve the size distribution of the mesopores, D(r), in a free modelling approach. To achieve this, two main points were addressed: (i) based on previous implementations, the method was adapted to work with long core-shell cylinders; (ii) since the MC model requires longer processing times, strategies to speed up the calculations were developed, which included a simplified version of the original model used to analyse SAXS data of SBA-15 (referred to as the SBA-15 model) as well as the determination of several structural features from the SAXS curve prior to the fit. The new model was validated with simulated data and later used to fit experimental SAXS curves of SBA-15. The obtained results show that the SBA-15 model only works well because the mesopore size distribution of SBA-15 is narrow, whereas the new approach can be successfully used in cases where D(r) is wider and/or has a more complex profile, such as SBA-15 with expanded mesopores. Even though a specific SAXS example was chosen to prove the model, the strategies presented herein are general and suitable for inclusion in other models aimed at the analysis of SBA-15 and similar ordered mesoporous materials.

2.
Biologicals ; 80: 18-26, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36414490

RESUMO

Routine immunization against diphtheria and tetanus has drastically reduced the incidence of these diseases worldwide. Anti-diphtheria/tetanus vaccine has in general aluminum salt as adjuvant in its formulation that can produce several adverse effects. There is a growing interest in developing new adjuvants. In this study, we evaluated the efficiency of SBA-15 as an adjuvant in subcutaneous immunization in mice with diphtheria (dANA) and tetanus (tANA) anatoxins as well as with the mixture of them (dtANA). The tANA molecules and their encapsulation in SBA-15 were characterized using Small-Angle X-ray Scattering (SAXS), Dynamical Light Scattering (DLS), Nitrogen Adsorption Isotherm (NAI), Conventional Circular Dichroism (CD)/Synchrotron Radiation Circular Dichroism (SRCD) Spectroscopy, and Tryptophan Fluorescence Spectroscopy (FS). The primary and secondary antibody response elicited by subcutaneous immunization of High (HIII) and Low (LIII) antibody responder mice with dANA, tANA, or dtANA encapsulated in the SBA-15 were determined. We demonstrated that SBA-15 increases the immunogenicity of dANA and tANA antigens, especially when administered in combination. We also verified that SBA-15 modulates the antibody response of LIII mice, turning them into high antibody responder. Thus, these results suggest that SBA-15 may be an effective adjuvant for different vaccine formulations.


Assuntos
Difteria , Tétano , Camundongos , Animais , Imunidade Humoral , Espalhamento a Baixo Ângulo , Difração de Raios X , Difteria/prevenção & controle , Tétano/prevenção & controle , Toxoide Tetânico , Dióxido de Silício/farmacologia , Adjuvantes Imunológicos/farmacologia , Imunização Secundária/métodos , Anticorpos Antibacterianos
3.
Pharmaceutics ; 14(9)2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36145723

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. Curcumin-loaded mesoporous silica nanoparticles (MSN-CCM) can overcome the drawbacks related to the free curcumin (CCM) clinical application, such as water insolubility and low bioavailability, besides acting over the main causes associated to AD. A thermo-responsive hydrogel is an interesting approach for facilitating the administration of the nanosystem via a nasal route, as well as for overcoming mucociliary clearance mechanisms. In light of this, MSN-CCM were dispersed in the hydrogel and evaluated through in vitro and in vivo assays. The MSNs and MSN-CCM were successfully characterized by physicochemical analysis and a high value of the CCM encapsulation efficiency (EE%, 87.70 ± 0.05) was achieved. The designed thermo-responsive hydrogel (HG) was characterized by rheology, texture profile analysis, and ex vivo mucoadhesion, showing excellent mechanical and mucoadhesive properties. Ex vivo permeation studies of MSN-CCM and HG@MSN-CCM showed high permeation values (12.46 ± 1.08 and 28.40 ± 1.88 µg cm-2 of CCM, respectively) in porcine nasal mucosa. In vivo studies performed in a streptozotocin-induced AD model confirmed that HG@MSN-CCM reverted the cognitive deficit in mice, acting as a potential formulation in the treatment of AD.

4.
IUCrJ ; 9(Pt 1): 11-20, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-35059205

RESUMO

This article summarizes developments attained in oral vaccine formulations based on the encapsulation of antigen proteins inside porous silica matrices. These vaccine vehicles show great efficacy in protecting the proteins from the harsh acidic stomach medium, allowing the Peyer's patches in the small intestine to be reached and consequently enhancing immunity. Focusing on the pioneering research conducted at the Butantan Institute in Brazil, the optimization of the antigen encapsulation yield is reported, as well as their distribution inside the meso- and macroporous network of the porous silica. As the development of vaccines requires proper inclusion of antigens in the antibody cells, X-ray crystallography is one of the most commonly used techniques to unveil the structure of antibody-combining sites with protein antigens. Thus structural characterization and modelling of pure antigen structures, showing different dimensions, as well as their complexes, such as silica with encapsulated hepatitis B virus-like particles and diphtheria anatoxin, were performed using small-angle X-ray scattering, X-ray absorption spectroscopy, X-ray phase contrast tomography, and neutron and X-ray imaging. By combining crystallography with dynamic light scattering and transmission electron microscopy, a clearer picture of the proposed vaccine complexes is shown. Additionally, the stability of the immunogenic complex at different pH values and temperatures was checked and the efficacy of the proposed oral immunogenic complex was demonstrated. The latter was obtained by comparing the antibodies in mice with variable high and low antibody responses.

5.
Mol Pharm ; 18(9): 3401-3417, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34482696

RESUMO

The need of pharmacological strategies to preclude breast cancer development motivated us to develop a non-aqueous microemulsion (ME) capable of forming a depot after administration in the mammary tissue and uptake of interstitial fluids for prolonged release of the retinoid fenretinide. The selected ME was composed of phosphatidylcholine/tricaprylin/propylene glycol (45:5:50, w/w/w) and presented a droplet diameter of 175.3 ± 8.9 nm. Upon water uptake, the ME transformed successively into a lamellar phase, gel, and a lamellar phase-containing emulsion in vitro as the water content increased and released 30% of fenretinide in vitro after 9 days. Consistent with the slow release, the ME formed a depot in cell cultures and increased fenretinide IC50 values by 68.3- and 13.2-fold in MCF-7 and T-47D cells compared to a solution, respectively. At non-cytotoxic concentrations, the ME reduced T-47D cell migration by 75.9% and spheroid growth, resulting in ∼30% smaller structures. The depot formed in vivo prolonged a fluorochrome release for 30 days without producing any sings of local irritation. In a preclinical model of chemically induced carcinogenesis, ME administration every 3 weeks for 3 months significantly reduced (4.7-fold) the incidence of breast tumors and increased type II collagen expression, which might contribute to limit spreading. These promising results support the potential ME applicability as a preventive therapy of breast cancer.


Assuntos
Anticarcinógenos/administração & dosagem , Neoplasias da Mama/prevenção & controle , Fenretinida/administração & dosagem , Neoplasias Mamárias Experimentais/prevenção & controle , Animais , Anticarcinógenos/farmacocinética , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Emulsões , Feminino , Fenretinida/farmacocinética , Humanos , Concentração Inibidora 50 , Células MCF-7 , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , Metilnitrosoureia/administração & dosagem , Metilnitrosoureia/toxicidade , Camundongos , Ratos
6.
Drug Deliv Transl Res ; 10(6): 1810-1828, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32803561

RESUMO

In this study, the development and the performance of a new targeted liquid crystalline nanodispersion (LCN) by the attachment of cell-penetrating peptides (CPP) onto their surfaces to improve skin delivery of lipoic acid (LA) were evaluated. For that, the synthesis and characterization of this new platform as well as its spatiotemporal analysis from in vitro and in vivo topical application were explored and extensively discussed in this paper. The TAT or D4 peptides were chosen as CPP due to specific target strategies by the charge grouping on the skin surface or target the overexpressed epidermal growth factor receptor (EGFR) of cell membrane of keratinocytes, respectively. Thus, the nanoparticle characterization results when taken together suggested that designed LCNs maintained their hexagonal phase structure, nanoscale particle size, and low polydispersity index even after drug, lipopolymers, and peptide additions, which are proved to be favorable for topical skin delivery. There were no statistical differences among the LCNs investigated, except for superficial charge of LCN conjugated with TAT which may have altered the LCN zeta potential due to cationic charge of TAT amino acid sequence compared with D4. The cumulative amounts of LA retained into the skin were determined to be even higher coming from the targeted LCNs. Moreover, the exogenous antioxidant application of the LA from the LCNs can prevent ROS damage, which was demonstrated by this study with the less myeloperoxidase (MPO) activity and decrease in cytokine levels (TNF-alpha and IL-1ß) generated by the oxidative stress modulation. Together, the data presented highlights the potential of these targeted LCNs, and overall, opens new frontiers for preclinical trials.


Assuntos
Anti-Inflamatórios , Peptídeos Penetradores de Células , Nanopartículas , Pele/efeitos da radiação , Ácido Tióctico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Masculino , Camundongos , Absorção Cutânea , Ácido Tióctico/administração & dosagem , Ácido Tióctico/farmacologia , Raios Ultravioleta
7.
J Pharm Sci ; 107(3): 870-878, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29108729

RESUMO

Celecoxib (CXB) is a widely used anti-inflammatory drug that also acts as a chemopreventive agent against several types of cancer, including skin cancer. As the long-term oral administration of CXB has been associated with severe side effects, the skin delivery of this drug represents a promising alternative for the treatment of skin inflammatory conditions and chemoprevention of skin cancer. We prepared and characterized liquid crystalline systems based on glyceryl monooleate and water containing penetration enhancers which were primarily designed to promote skin delivery of CXB. Analysis of their phase behavior revealed the formation of cubic and hexagonal phases depending on the systems' composition. The systems' structure and composition markedly affected the in vitro CXB release profile. Oleic acid reduced CXB release rate, but association oleic acid/propylene glycol increased the drug release rate. The developed systems significantly reduced inflammation in an aerosil-induced rat paw edema model. The systems' composition and liquid crystalline structure influenced their anti-inflammatory potency. Cubic phase systems containing oleic acid/propylene glycol association reduced edema in a sustained manner, indicating that they modulate CXB release and permeation. Our findings demonstrate that the developed liquid crystalline systems are potential carriers for the skin delivery of CXB.


Assuntos
Celecoxib/química , Glicerídeos/química , Cristais Líquidos/química , Pele/metabolismo , Administração Cutânea , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Celecoxib/farmacologia , Química Farmacêutica/métodos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Masculino , Ácido Oleico/química , Permeabilidade/efeitos dos fármacos , Propilenoglicol/química , Ratos , Ratos Wistar , Absorção Cutânea/efeitos dos fármacos , Absorção Cutânea/fisiologia , Solubilidade/efeitos dos fármacos , Água/química
8.
Eur J Pharm Sci ; 74: 103-17, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25917525

RESUMO

The development of delivery systems able to complex and release siRNA into the cytosol is essential for therapeutic use of siRNA. Among the delivery systems, local delivery has advantages over systemic administration. In this study, we developed and characterized non-viral carriers to deliver siRNA locally, based on polyethylenimine (PEI) as gene carrier, and a self-assembling drug delivery system that forms a gel in situ. Liquid crystalline formulations composed of monoglycerides (MO), PEI, propylene glycol (PG) and 0.1M Tris buffer pH 6.5 were developed and characterized by polarized light microscopy, Small Angle X-ray Scattering (SAXS), for their ability to form inverted type liquid crystalline phases (LC2) in contact with excess water, water absorption capacity, ability to complex with siRNA and siRNA release. In addition, gel formation in vivo was determined by subcutaneous injection of the formulations in mice. In water excess, precursor fluid formulations rapidly transformed into a viscous liquid crystalline phase. The presence of PEI influences the liquid crystalline structure of the LC2 formed and was crucial for complexing siRNA. The siRNA was released from the crystalline phase complexed with PEI. The release rate was dependent on the rate of water uptake. The formulation containing MO/PEI/PG/Tris buffer at 7.85:0.65:76.5:15 (w/w/w/w) complexed with 10 µM of siRNA, characterized as a mixture of cubic phase (diamond-type) and inverted hexagonal phase (after contact with excess water), showed sustained release for 7 days in vitro. In mice, in situ gel formation occurred after subcutaneous injection of the formulations, and the gels were degraded in 30 days. Initially a mild inflammatory process occurred in the tissue surrounding the gel; but after 14 days the tissue appeared normal. Taken together, this work demonstrates the rational development of an in situ gelling formulation for local release of siRNA.


Assuntos
Celulite (Flegmão)/prevenção & controle , Técnicas de Transferência de Genes/efeitos adversos , Polietilenoimina/química , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Terapêutica com RNAi/efeitos adversos , Substâncias Viscoelásticas/química , Animais , Celulite (Flegmão)/induzido quimicamente , Celulite (Flegmão)/imunologia , Celulite (Flegmão)/patologia , Feminino , Géis , Glicerídeos/efeitos adversos , Glicerídeos/química , Injeções Subcutâneas , Camundongos Endogâmicos BALB C , Monoglicerídeos/efeitos adversos , Monoglicerídeos/química , Polietilenoimina/efeitos adversos , Propilenoglicol/efeitos adversos , Propilenoglicol/química , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/química , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Solubilidade , Tela Subcutânea/efeitos dos fármacos , Tela Subcutânea/imunologia , Tela Subcutânea/patologia , Substâncias Viscoelásticas/efeitos adversos , Viscosidade , Água/análise
9.
Einstein (Säo Paulo) ; 9(4)out.-dec. 2011. ilus, graf
Artigo em Inglês, Português | LILACS, SES-SP | ID: lil-612022

RESUMO

Objective: To evaluate the applicability of SBA-15 silica as an adjuvant in immunizations with purified particles of the viral protein HBsAg, the main component of hepatitis B vaccine, Butang®, produced by Instituto Butantan. Methods: BALB/c mice orally or subcutaneously received 0.5 mug of HBsAg adsorbed/encapsulated to SBA-15 or adsorbed to Al(OH)3. To assess the secondary immune response, a subcutaneous booster was administered 30 days after the first immunization. Individual serum and fecal samples of each group were periodically collected for specific antibody titration by ELISA. Results: Analysis of secretory IgA showed that mice orally primed with HBsAg on SBA-15 had increased levels of specific antibodies in primary and secondary immune responses. Specific serum IgA and IgG titers in HBsAg:SBA-15-orally immunized mice reached higher levels after the booster, demonstrating the effectiveness of oral vaccination with the use of silica. All immunized groups showed higher IgG1 levels. Conclusion: Our results clearly indicate the promising use of SBA-15 as an adjuvant, especially in oral immunizations.


Objetivo: Demonstrar a aplicabilidade da sílica do tipo SBA-15 como adjuvante nas imunizações com a proteína recombinante HBsAg do vírus da hepatite B, principal componente da vacina Butang® produzida pelo Instituto Butantan. Métodos: Camundongos BALB/c receberam, pela via oral ou subcutânea, 0,5 mig do HbsAg adsorvido/encapsulado à SBA-15 ou adsorvido ao Al(OH)3. Para avaliar a resposta imune secundária, uma dose de reforço foi administrada subcutaneamente 30 dias após a primeira imunização. Amostras individuais de soro e fezes foram coletadas periodicamente para titulação de anticorpos específicos por ELISA. Resultados: A análise de IgA secretada mostrou que camundongos imunizados pela via oral com HbsAg em SBA-15 apresentaram aumento nos níveis de anticorpos específicos nas respostas primária e secundária. Ainda, após o reforço, observaram-se maiores níveis de IgA e IgG séricas anti-HBsAg no grupo preparado com HBsAg:SBA-15 pela via oral. Todos os grupos imunizados apresentaram maior produção de IgG1. Conclusão: Os resultados indicam o uso promissor da sílica SBA-15 como adjuvante, especialmente nas imunizações pela via oral.


Assuntos
Adjuvantes Imunológicos , Hepatite B , Memória Imunológica
10.
Einstein (Sao Paulo) ; 9(4): 436-41, 2011 Dec.
Artigo em Inglês, Português | MEDLINE | ID: mdl-26761242

RESUMO

OBJECTIVE: To evaluate the applicability of SBA-15 silica as an adjuvant in immunizations with purified particles of the viral protein HBsAg, the main component of hepatitis B vaccine, Butang®, produced by Instituto Butantan. METHODS: BALB/c mice orally or subcutaneously received 0.5 µg of HBsAg adsorbed/encapsulated to SBA-15 or adsorbed to Al(OH)3. To assess the secondary immune response, a subcutaneous booster was administered 30 days after the first immunization. Individual serum and fecal samples of each group were periodically collected for specific antibody titration by ELISA. RESULTS: Analysis of secretory IgA showed that mice orally primed with HBsAg on SBA-15 had increased levels of specific antibodies in primary and secondary immune responses. Specific serum IgA and IgG titers in HBsAg:SBA-15-orally immunized mice reached higher levels after the booster, demonstrating the effectiveness of oral vaccination with the use of silica. All immunized groups showed higher IgG1 levels. CONCLUSION: Our results clearly indicate the promising use of SBA-15 as an adjuvant, especially in oral immunizations.

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