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1.
Int J Nanomedicine ; 16: 1405-1422, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33658780

RESUMO

Aim: Iridoid glycosides (IG) as the major active fraction of Syringa oblata Lindl. has a proven anti-inflammatory effect for ulcerative colitis (UC). However, its current commercial formulations are hampered by low bioavailability and unable to reach inflamed colon. To overcome the limitation, dual functional IG-loaded nanoparticles (DFNPs) were prepared to increase the residence time of IG in colon. The protective mechanism of DFNPs on DSS-induced colonic injury was evaluated in rats. Materials and Methods: We prepared DFNPs using the oil-in-water emulsion method. PLGA was selected as sustained-release polymer, and ES100 and EL30D-55 as pH-responsive polymers. The morphology and size distribution of NPs were measured by SEM and DLS technique. To evaluate colon targeting of DFNPs, DiR, was encapsulated as a fluorescent probe into NPs. Fluorescent distribution of NPs were investigated. The therapeutic potential and in vivo transportation of NPs in gastrointestinal tract were evaluated in a colitis model. Results: SEM images and zeta data indicated the successful preparation of DFNPs. This formulation exhibited high loading capacity. Drug release results suggested DFNPs released less than 20% at the first 6 h in simulated gastric fluid (pH1.2) and simulated small intestine fluid (pH6.8). A high amount of 84.7% sustained release from NPs in simulated colonic fluid (pH7.4) was beyond 24 h. DiR-loaded NPs demonstrated a much higher colon accumulation, suggesting effective targeting due to functionalization with pH and time-dependent polymers. DFNPs could significantly ameliorate the colonic damage by reducing DAI, macroscopic score, histological damage and cell apoptosis. Our results also proved that the potent anti-inflammatory effect of DFNPs is contributed by decrease of NADPH, gene expression of COX-2 and MMP-9 and the production of TNF-α, IL-17, IL-23 and PGE2. Conclusion: We confirm that DFNPs exert protective effects through inhibiting the inflammatory response, which could be developed as a potential colon-targeted system.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Colo/patologia , Glicosídeos Iridoides/uso terapêutico , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ácidos Polimetacrílicos/química , Animais , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana , Liberação Controlada de Fármacos , Fluorescência , Concentração de Íons de Hidrogênio , Glicosídeos Iridoides/sangue , Glicosídeos Iridoides/farmacocinética , Glicosídeos Iridoides/farmacologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos ICR , NADPH Oxidases/metabolismo , Nanopartículas/ultraestrutura , Tamanho da Partícula , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacos
2.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652632

RESUMO

The use of bioresorbable fracture fixation plates made of aliphatic polyesters have good potential due to good biocompatibility, reduced risk of stress-shielding, and eliminated need for plate removal. However, polyesters are ductile, and their handling properties are limited. We suggested an alternative, PLAMA (PolyLActide functionalized with diMethAcrylate), for the use as the matrix phase for the novel concept of the in situ curable bioresorbable load-bearing composite plate to reduce the limitations of conventional polyesters. The purpose was to obtain a preliminary understanding of the chemical and physical properties and the biological safety of PLAMA from the prospective of the novel concept. Modifications with different molecular masses (PLAMA-500 and PLAMA-1000) were synthesized. The efficiency of curing was assessed by the degree of convergence (DC). The mechanical properties were obtained by tensile test and thermomechanical analysis. The bioresorbability was investigated by immersion in simulated body fluid. The biocompatibility was studied in cell morphology and viability tests. PLAMA-500 showed better DC and mechanical properties, and slower bioresorbability than PLAMA-1000. Both did not prevent proliferation and normal morphological development of cells. We concluded that PLAMA-500 has potential for the use as the matrix material for bioresorbable load-bearing composite fracture fixation plates.


Assuntos
Fixação de Fratura/métodos , Fraturas Ósseas/terapia , Lactose/análogos & derivados , Poliésteres/farmacologia , Ácidos Polimetacrílicos/farmacologia , Implantes Absorvíveis/efeitos adversos , Placas Ósseas/efeitos adversos , Proliferação de Células/efeitos dos fármacos , Humanos , Lactose/química , Lactose/farmacologia , Teste de Materiais , Poliésteres/química , Ácidos Polimetacrílicos/química , Estresse Mecânico , Resistência à Tração , Suporte de Carga
3.
ACS Appl Mater Interfaces ; 13(2): 3089-3097, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33400490

RESUMO

Numerous efforts to fabricate antimicrobial surfaces by simple yet universal protocols with high efficiency have attracted considerable interest but proved to be particularly challenging. Herein, we designed and fabricated a series of antimicrobial polymeric coatings with different functions from single to multiple mechanisms by selectively utilizing diethylene glycol diglycidyl ether (PEGDGE), polylysine, and poly[glycidylmethacrylate-co-3-(dimethyl(4-vinylbenzyl)ammonium)propyl sulfonate] (poly(GMA-co-DVBAPS)) via straightforward mussel-inspired codeposition techniques. Bactericidal polylysine endowed the modified surfaces with a high ability (∼90%) to kill attached bacteria, while PEGDGE components with unique surface hydration prevented bacterial adhesion, avoiding the initial biofilm formation. Moreover, excellent salt-responsive poly(GMA-co-DVBAPS) enabled reactant polymeric coatings to change chain conformations from shrinkable to stretchable state and subsequently release >90% attached bacteria when treated with NaCl solution, even after repeated cycles. Therefore, the obtained polymeric coatings, polydopamine/poly(GMA-co-DVBAPS) (PDA/PDV), polydopamine/polylysine/poly(GMA-co-DVBAPS) (PDA/l-PDV), and polydopamine/polylysine/poly(GMA-co-DVBAPS)/diethylene glycol diglycidyl ether (PDA/l-PDV-PEGDGE), controllably realized functions from single and dual to multiple antimicrobial mechanisms, as evidenced by long-term antifouling activity to bacteria, high bactericidal efficiency, and salt-responsive bacterial regeneration performance with several bacterial killing-release cycles. This study not only contributes to mussel-inspired chemistry for polymeric coatings with controllable functions but also provides a series of reliable and highly efficient antimicrobial surfaces for potential biomedical applications.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Polímeros/química , Polímeros/farmacologia , Animais , Aderência Bacteriana/efeitos dos fármacos , Infecções Bacterianas/microbiologia , Infecções Bacterianas/prevenção & controle , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Bivalves/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Etilenoglicóis/química , Etilenoglicóis/farmacologia , Humanos , Indóis/química , Indóis/farmacologia , Polilisina/química , Polilisina/farmacologia , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Propriedades de Superfície
4.
ACS Appl Mater Interfaces ; 13(2): 2218-2229, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33406826

RESUMO

pH-sensitive hydrophobic segments have been certificated to facilitate siRNA delivery efficiency of amphiphilic polycation vehicles. However, optimal design concepts for these vehicles remain unclear. Herein, by studying the library of amphiphilic polycations mPEG-PAMA50-P(DEAx-r-D5Ay) (EAE5x/y), we concluded a multifactor matching concept (pKa values, "proton buffering capacities" (BCs), and critical micelle concentrations (CMCs)) for polycation vehicles to improve siRNA delivery efficiency in vitro and in vivo. We identified that the stronger BCs in a pH 5.5-7.4 subset induced by EAE548/29 (pKa = 6.79) and EAE539/37 (pKa = 6.20) are effective for siRNA delivery in vitro. Further, the stronger BCs occurred in a narrow subset of pH 5.5-6.5 and the lower CMC attributed to higher siRNA delivery capacity of EAE539/37 in vivo than EAE548/29 after intravenous administration and subcutaneous injection. More importantly, 87.2% gene knockdown efficacy was achieved by EAE539/37 via subcutaneous injection, which might be useful for an mRNA vaccine adjuvant. Furthermore, EAE539/37 also successfully delivered siRRM2 to tumor via intravenous administration and received highly efficient antitumor activity. Taken together, the suitable pKa values, strong BCs occurred in pH 5.5-6.5, and low CMCs were probably the potential solution for designing efficient polycationic vehicles for siRNA delivery.


Assuntos
Polieletrólitos/química , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Animais , Linhagem Celular , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , RNA Interferente Pequeno/genética
5.
AAPS PharmSciTech ; 22(1): 23, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33400042

RESUMO

Cannabidiol (CBD) and cannabigerol (CBG) are two active pharmaceutical ingredients, derived from cannabis plant. In the present study, CBD and CBG were formulated with polyvinyl(pyrrolidone) (PVP) and Eudragit L-100, using electrohydrodynamic atomization (electrospinning). The produced fibers were smooth and uniform in shape, with average fiber diameters in the range of 700-900 nm for PVP fibers and 1-5 µm for Eudragit L-100 fibers. The encapsulation efficiency for both CB and CBG was high (over 90%) for all formulations tested. Both in vitro release and disintegration tests of the formulations in simulated gastric fluids (SGF) and simulated intestinal fluids (SIF) indicated the rapid disintegration and dissolution of the fibers and the subsequent rapid release of the drugs. The study concluded that the electrospinning process is a fast and efficient method to produce drug-loaded fibers suitable for the per os administration of cannabinoids.


Assuntos
Canabidiol/administração & dosagem , Canabinoides/administração & dosagem , Nanofibras/química , Administração Oral , Canabidiol/química , Canabinoides/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Ácidos Polimetacrílicos/química , Povidona/química
6.
Biochim Biophys Acta Biomembr ; 1863(1): 183441, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810489

RESUMO

G protein coupled receptors (GPCRs) function as guanine nucleotide exchange factors (GEFs) at heterotrimeric G proteins, and conduct this role embedded in a lipid bilayer. Detergents are widely used to solubilise GPCRs for structural and biophysical analysis, but are poor mimics of the lipid bilayer and may be deleterious to protein function. Amphipathic polymers have emerged as promising alternatives to detergents, which maintain a lipid environment around a membrane protein during purification. Of these polymers, the polymethacrylate (PMA) polymers have potential advantages over the most popular styrene maleic acid (SMA) polymer, but to date have not been applied to purification of membrane proteins. Here we use a class A GPCR, neurotensin receptor 1 (NTSR1), to explore detergent-free purification using PMA. By using an NTSR1-eGFP fusion protein expressed in Sf9 cells, a range of solubilisation conditions were screened, demonstrating the importance of solubilisation temperature, pH, NaCl concentration and the relative amounts of polymer and membrane sample. PMA-solubilised NTSR1 displayed compatibility with standard purification protocols and millimolar divalent cation concentrations. Moreover, the receptor in PMA discs showed stimulation of both Gq and Gi1 heterotrimers to an extent that was greater than that for the detergent-solubilised receptor. PMA therefore represents a viable alternative to SMA for membrane protein purification and has a potentially broad utility in studying GPCRs and other membrane proteins.


Assuntos
Ácidos Polimetacrílicos/química , Receptores de Neurotensina , Detergentes/química , Humanos , Receptores de Neurotensina/biossíntese , Receptores de Neurotensina/química , Receptores de Neurotensina/isolamento & purificação , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Solubilidade
7.
Methods Mol Biol ; 2147: 45-54, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32840809

RESUMO

Thanks to their unique advantages, additive manufacturing technologies are revolutionizing almost all sectors of the industrial and academic worlds, including tissue engineering and regenerative medicine. In particular, 3D bioprinting is rapidly emerging as a first-choice approach for the fabrication-in one step-of advanced cell-laden hydrogel constructs to be used for in vitro and in vivo studies. This technique consists in the precise deposition layer-by-layer of sub-millimetric hydrogel strands in which living cells are embedded. A key factor of this process consists in the proper formulation of the hydrogel precursor solution, the so-called bioink. Ideal bioinks should be able, on the one side, to support cell growth and differentiation and, on the other, to allow the high-resolution deposition of cell-laden hydrogel strands. The latter feature requires the extruded solution to instantaneously undergo a sol-gel transition to avoid its collapse after deposition.To address this challenge, researchers are recently focusing their attention on the synthesis of several derivatives of natural biopolymers to enhance their printability. Here, we present an approach for the synthesis of photocurable derivatives of natural biopolymers-namely, gelatin methacrylate, hyaluronic acid methacrylate, chondroitin sulfate methacrylate, and PEGylated fibrinogen-that can be used to formulate tailored innovative bioinks for coaxial-based 3D bioprinting applications.


Assuntos
Biopolímeros/química , Bioimpressão/métodos , Ácidos Polimetacrílicos/síntese química , Impressão Tridimensional , Tecidos Suporte/química , Biopolímeros/efeitos da radiação , Bioimpressão/instrumentação , Sulfatos de Condroitina/química , Fibrinogênio/química , Gelatina/química , Humanos , Ácido Hialurônico/química , Hidrogéis/química , Tinta , Luz , Processos Fotoquímicos , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Propriedades de Superfície/efeitos da radiação , Engenharia Tecidual/instrumentação , Engenharia Tecidual/métodos
8.
J Chromatogr A ; 1628: 461481, 2020 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-32822998

RESUMO

A single-step copolymerization strategy was developed for the preparation of carbohydrate (glucose and maltose) functionalized monoliths using click reaction. Firstly, novel carbohydrate-functionalized methacrylate monomers were synthesized through Cu(I)-catalyzed 1,3-dipolar cycloaddition (alkyne-azide reaction) of terminal alkyne with azide of carbohydrate derivatives. The corresponding carbohydrate functionalized monolithic columns were then prepared through a single-step in-situ copolymerization. The physicochemical properties and performance of the fabricated monolithic columns were evaluated using scanning electron microscopy, Fourier-transform infrared spectroscopy, and nano-liquid chromatography. For the optimized monolithic column, satisfactory column permeability and good separation performance were demonstrated for polar compounds including nucleoside, phenolic compounds and benzoic acid derivatives. The monolithic column is also highly useful for selective and efficient enrichment of glycopeptides from human IgG tryptic digests. This study not only provided a novel hydrophilic column for separation and selective trapping of polar compounds, but also proposed a facile and efficient approach for preparing carbohydrate functionalized monoliths.


Assuntos
Carboidratos/química , Química Click/métodos , Carboidratos/síntese química , Glicopeptídeos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Polimerização , Ácidos Polimetacrílicos/síntese química , Ácidos Polimetacrílicos/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
9.
Phytomedicine ; 78: 153293, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32777486

RESUMO

BACKGROUND: Ulcerative colitis (UC) is an intricate enteric disease with a rising incidence that is closely related to mucosa-barrier destruction, gut dysbacteriosis, and immune disorders. Emodin (1,3,8-trihydroxy-6-methyl-9,10-anthraquinone, EMO) is a natural anthraquinone derivative that occurs in many Polygonaceae plants. Its multiple pharmacological effects, including antioxidant, immune-suppressive, and anti-bacteria activities, make it a promising treatment option for UC. However, its poor solubility, extensive absorption, and metabolism in the upper gastrointestinal tract may compromise its anti-colitis effects. PURPOSE: EMO was loaded in a colon-targeted delivery system using multifunctional biomedical materials and the enhanced anti-colitis effect involving mucosa reconstruction was investigated in this study. METHODS: EMO-loaded Poly (DL-lactide-co-glycolide)/EudragitⓇ S100/montmorillonite nanoparticles (EMO/PSM NPs) were prepared by a versatile single-step assembly approach. The colon-specific release behavior was characterized in vitro and in vivo, and the anti-colitis effect was evaluated in dextran sulfate sodium (DSS)-induced acute colitis in mice by weight loss, disease activity index (DAI) score, colon length, histological changes, and colitis biomarkers. The integrity of the intestinal mucosal barrier was evaluated through transwell co-culture model in vitro and serum zonulin-related tight junctions and mucin2 (MUC2) in vivo. RESULTS: EMO/PSM NPs with a desirable hydrodynamic diameter (~ 235 nm) and negative zeta potential (~ -31 mV) could prevent the premature drug release (< 4% in the first 6 h in vitro) in the upper gastrointestinal tract (GIT) and boost retention in the lower GIT and inflamed colon mucosa in vivo. Compared to free EMO-treatment of different doses in UC mice, the NPs could enhance the remedial efficacy of EMO in DAI decline, histological remission, and regulation of colitis indicators, such as myeloperoxidase (MPO), nitric oxide (NO), and glutathione (GSH). The inflammatory factors including induced nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-1ß were suppressed by EMO/PSM NPs at both mRNA and protein levels. The obtained NPs could also promote the regeneration of the mucosal barrier via reduced fluorescein isothiocyanate (FITC)-dextran leakage in the transwell co-culture model and decreased serum zonulin levels, which was demonstrated to be associated with the upregulated tight junctions (TJs)-related proteins (claudin-2, occludin, and zo-1) and MUC2 at mRNA level. Moreover, the NPs could contribute to attenuating the liver injury caused by free EMO under excessive immune inflammation. CONCLUSION: Our results demonstrated that EMO/PSM NPs could specifically release EMO in the diseased colon, and effectively enhance the anti-colitis effects of EMO related to intestinal barrier improvement. It can be considered as a novel potential alternative for oral colon-targeted UC therapy by increasing therapeutic efficacy and reducing side-effects.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Emodina/farmacologia , Nanoestruturas/química , Administração Oral , Animais , Células CACO-2 , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Emodina/administração & dosagem , Emodina/efeitos adversos , Emodina/farmacocinética , Glutationa , Humanos , Concentração de Íons de Hidrogênio , Mucosa Intestinal/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Mucina-2/genética , Nanoestruturas/administração & dosagem , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ácidos Polimetacrílicos/química , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/genética , Distribuição Tecidual
10.
AAPS PharmSciTech ; 21(7): 243, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32856144

RESUMO

The objective of this work was to develop taste-masked donut-shaped tablet formulations utilizing fused filament fabrication three-dimensional printing paired with hot-melt extrusion techniques. Caffeine citrate was used as the model drug for its bitter taste, and a 3-point bend test was performed to assess the printability of filaments. The stiffness constant was calculated to represent the printability by fitting the breaking distances and stress data into Hooke's law. The formulations without Eudragit E PO (F6) and with Eudragit E PO (F7) filaments exhibited the desired hardness with a "k" value of 48.30 ± 3.52 and 45.47 ± 3.51 g/mm3 (n = 10), respectively, and were successfully printed. The donut-shaped tablets were 3D printed with 10, 50, and 100% infill densities. In vitro dissolution studies were performed in simulated salivary fluid (pH 6.8, artificial saliva) to evaluate the taste-masking efficiency of the printed donuts. In the first minute, the concentrations of caffeine citrate observed in the dissolution media from all the printed donuts were less than the bitter threshold of caffeine citrate (0.25 mg/mL). Formulation F7, which contained Eudragit E PO copolymer, demonstrated better taste-masking efficiency than formulation F6. Furthermore, both formulations F6 and F7 demonstrated immediate drug release profiles in gastric medium (10% infill, > 80% release within 1 h). Taste-masked caffeine citrate formulations were successfully developed with donut shapes, which will enhance appeal in pediatric populations and increase compliance and patient acceptance of the dosage form.


Assuntos
Composição de Medicamentos/métodos , Tecnologia de Extrusão por Fusão a Quente/métodos , Impressão Tridimensional , Paladar/efeitos dos fármacos , Cafeína/química , Cafeína/farmacologia , Citratos/química , Citratos/farmacologia , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Excipientes/química , Excipientes/farmacologia , Humanos , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacologia , Comprimidos , Paladar/fisiologia
11.
Int J Nanomedicine ; 15: 3965-3980, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606658

RESUMO

Aim: Etoricoxib is a selective inhibitor of COX-2 enzyme. It is proposed as a potent anti-inflammatory drug intended for the control of irritable bowel syndrome. The current work aimed at developing etoricoxib-loaded nanoparticles for colon- targeting. Materials and Methods: PLGA nanoparticles were developed via nano-spray drying technique. The D-optimal design was adopted for the investigation of the influence of i) DL-lactide-coglycolide (PLGA) concentration, ii) polyvinylpyrrolidone K30 (PVP K30) concentration and iii) lactide:glycolide ratio in the copolymer chain on the yield%, the encapsulation efficiency (EE%), particle size (PS) and percentage of drug release after 2h (P2h), 4h (P4h) and 12h (P12h). To promote colon targeting of the systems, the best achieved system (M14) was either directly coated with poly(methacrylic acid-co-methyl methacrylate) [Eudragit®-S100] or loaded into hard gelatin capsules and the capsules were coated with poly(methacrylic acid-co-methyl methacrylate) (E-M14C). The pharmacokinetic parameters of etoricoxib following oral administration of E-M14C in healthy volunteers were assessed relative to commercial etoricoxib tablets. Results: M14 system was prepared using PLGA (0.5% w/v) at a lactide:glycolide ratio of 100:0, in the presence of PVP K30 (2% w/v). M14 system was nano-spherical particles of 488 nm size possessing promising yield% (63.5%) and EE% (91.2%). The percentage drug released after 2, 4 and 12 hours were 43.41%, 47.34 and 64.96%, respectively. Following M14-loading into hard gelatin capsules and coating with poly(methacrylic acid-co-methyl methacrylate) [Eudragit-S100], the respective P2h, P4h and P12h were 10.1%, 28.60% and 65.45%. Significant (p < 0.05) differences between the pharmacokinetic parameter of E-M14C in comparison with the commercial product were revealed with a delay in Tmax (from 2.5h to 6h), a prolongation in MRT0-∞ (from 24.4h to 34.7h) and an increase in the relative oral bioavailability (4.23 folds). Conclusion: E-M14C is a potential system for possible colon targeting of etoricoxib.


Assuntos
Colo/efeitos dos fármacos , Etoricoxib/farmacologia , Etoricoxib/farmacocinética , Voluntários Saudáveis , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ácidos Polimetacrílicos/química , Administração Oral , Adulto , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Colo/metabolismo , Liberação Controlada de Fármacos , Humanos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Adulto Jovem
12.
Macromol Rapid Commun ; 41(15): e2000260, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32648310

RESUMO

Polymerization-induced self-assembly has been demonstrated to be a powerful strategy for fabricating polymeric nanoparticles in the last two decades. However, the stringent requirements for the monomers greatly limit the chemical versatility of PISA-based functional nanoparticles and expanding the monomer family of PISA is still highly desirable. Herein, a camptothecin analogue (CPTM) is first used as the monomer in PISA. Prodrug nanoparticles with reduction-responsive camptothecin release behavior are fabricated at 10% solid concentration (100 mg g-1 ). Poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) and poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) are used as the macro RAFT agents to comediate the RAFT dispersion polymerization of CPTM in ethanol to produce the PHPMA/PDEAEMA-stabilized nanoparticles. The PDEAEMA chains become hydrophobic and are in the collapsed state at physiological pH values. In contrast, in the vicinity of an acidic tumor, the tertiary amine groups of PDEAEMA chains are rapidly protonated, leading to fast hydrophobic-hydrophilic transitions and charge reversal. Such fast charge-reversal results in enhanced cancer cell internalization of the prodrug nanoparticles, thus achieving superior anticancer efficacy.


Assuntos
Portadores de Fármacos/química , Nanopartículas/química , Pró-Fármacos/química , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Etanol/química , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Metacrilatos/química , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Nylons/química , Polimerização , Polímeros/química , Ácidos Polimetacrílicos/química , Água/química
13.
AAPS PharmSciTech ; 21(5): 189, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651739

RESUMO

The aim of this study was to investigate the influence of the production method and the polymeric carrier on the ability to generate and maintain the supersaturation of a poorly soluble drug in biorelevant medium. The amorphous solid dispersion of sulfamethoxazole, an antibacterial drug, was produced using two different polymers by spray-drying or hot melt extrusion methods. When Eudragit EPO was used, supersaturation was maintained up to 24 h for both techniques at all drug-polymer proportions. However, when Soluplus was employed in hot melt extrusion, a smaller amount of drug was dissolved when compared to the amorphous drug. The proportion of 3:7 drug-Eudragit EPO (w/w) produced by spray-drying presented a higher amount of drug dissolved in supersaturation studies and it was able to maintain the physical stability under different storage conditions throughout the 90-day evaluation. Supersaturation generation and system stability were found to be related to more effective chemical interaction between the polymer and the drug provided by the production method, as revealed by the 1D ROESY NMR experiment. Investigation of drug-polymer interaction is critical in supersaturating drug delivery systems to avoid crystallization of the drug and to predict the effectiveness of the system. Chemical compounds studied in this article: Sulfamethoxazole (PubChem CID: 4539) and Methacrylate copolymer - Eudragit EPO (PubChem CID: 65358).


Assuntos
Preparações Farmacêuticas/química , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Polivinil/química , Cristalização , Dessecação , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Interações Medicamentosas , Estabilidade de Medicamentos , Solubilidade
14.
Nat Commun ; 11(1): 3362, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620794

RESUMO

Intrinsically and fully stretchable active-matrix-driven displays are an important element to skin electronics that can be applied to many emerging fields, such as wearable electronics, consumer electronics and biomedical devices. Here, we show for the first time a fully stretchable active-matrix-driven organic light-emitting electrochemical cell array. Briefly, it is comprised of a stretchable light-emitting electrochemical cell array driven by a solution-processed, vertically integrated stretchable organic thin-film transistor active-matrix, which is enabled by the development of chemically-orthogonal and intrinsically stretchable dielectric materials. Our resulting active-matrix-driven organic light-emitting electrochemical cell array can be readily bent, twisted and stretched without affecting its device performance. When mounted on skin, the array can tolerate to repeated cycles at 30% strain. This work demonstrates the feasibility of skin-applicable displays and lays the foundation for further materials development.


Assuntos
Materiais Biomiméticos/química , Elastômeros/química , Transistores Eletrônicos , Dispositivos Eletrônicos Vestíveis , Eletroquímica , Éteres/química , Estudos de Viabilidade , Fluorcarbonetos/química , Luminescência , Teste de Materiais , Ácidos Polimetacrílicos/química , Pele
15.
Mar Drugs ; 18(4)2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32344610

RESUMO

This work aimed at improving the targeting and cytotoxicity of simvastatin (SMV) against colon cancer cells. SMV was encapsulated in chitosan polymers, followed by eudragit S100 microparticles. The release of SMV double coated microparticles was dependent on time and pH. At pH 7.4 maximum release was observed for 6 h. The efficiency of the double coat to target colonic tissues was confirmed using real-time X-ray radiography of iohexol dye. Entrapment efficiency and particle size were used in the characterization of the formula. Cytotoxicity of SMV microparticles against HCT-116 colon cancer cells was significantly improved as compared to raw SMV. Cell cycle analysis by flow cytomeric technique indicated enhanced accumulation of colon cancer cells in the G2/M phase. Additionally, a significantly higher cell fraction was observed in the pre-G phase, which highlighted enhancement of the proapoptotic activity of SMV prepared in the double coat formula. Assessment of annexin V staining was used for confirmation. Cell fraction in early, late and total cell death were significantly elevated. This was accompanied by a significant elevation of cellular caspase 3 activity. In conclusion, SMV-loaded chitosan coated with eudragit S100 formula exhibited improved colon targeting and enhanced cytotoxicity and proapoptotic activity against HCT-116 colon cancer cells.


Assuntos
Antineoplásicos/administração & dosagem , Quitosana/química , Neoplasias do Colo/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Sinvastatina/administração & dosagem , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Portadores de Fármacos/química , Células HCT116 , Humanos , Concentração de Íons de Hidrogênio , Masculino , Microesferas , Tamanho da Partícula , Ácidos Polimetacrílicos/química , Coelhos , Sinvastatina/farmacologia
16.
J Appl Oral Sci ; 28: e20190499, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348441

RESUMO

Enzymatic degradation of the hybrid layer can be accelerated by the activation of dentin metalloproteinases (MMP) during the bonding procedure. MMP inhibitors may be used to contain this process. Objective To evaluate the degree of conversion (DC%), dentin bond strength (µTBS) (immediate and after 1 year of storage in water), and nanoleakage of an experimental (EXP) and a commercial (SB) adhesive system, containing different concentrations of the MMP inhibitor GM1489: 0, 1 µM, 5 µM and 10 µM. Methodology DC% was evaluated by FT-IR spectroscopy. Dentin bond strength was evaluated by µTBS test. Half of beams were submitted to the µTBS test after 24 h and the other half, after storage for 1 year. From each tooth and storage time, 2 beams were reserved for nanoleakage testing. Data were analyzed using ANOVA and Tukey's test to compare means (α=0.05). Results All adhesive systems maintained the µTBS after 1 year of storage. Groups with higher concentrations of inhibitor (5 µM and 10 µM) showed higher µTBS values than groups without inhibitor or with 1 µM. The nanoleakage values of all groups showed no increase after 1 year of storage and values were similar for SB and EXP groups, in both storage periods. The inhibitor did not affect the DC% of the EXP groups, but the SB5 and SB10 groups showed higher DC% values than those of SB0 and SB1. Conclusions The incorporation of GM1489 in the adhesive systems had no detrimental effect on DC%. The concentrations of 5 µM GM1489 for SB and 5 µM or 10 µM for EXP provided higher µTBS than groups without GM1489, in the evaluation after 1 year of storage; whereas the concentration of inhibitor did not affect adhesive systems nanoleakage.


Assuntos
Cimentos Dentários/química , Dentina/química , Inibidores de Metaloproteinases de Matriz/química , Metacrilatos/química , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Análise de Variância , Colagem Dentária/métodos , Corrosão Dentária/métodos , Infiltração Dentária , Dentina/efeitos dos fármacos , Humanos , Teste de Materiais , Valores de Referência , Reprodutibilidade dos Testes , Espectroscopia de Infravermelho com Transformada de Fourier , Estatísticas não Paramétricas , Propriedades de Superfície , Resistência à Tração , Fatores de Tempo
17.
Biol Pharm Bull ; 43(4): 682-687, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238709

RESUMO

We previously showed that adhesive aggregates were formed when levofloxacin hydrate tablets and lansoprazole orally disintegrating (OD) tablets were suspended in water in the clinical context. In this study, we have clarified the factors causing aggregate formation, focusing on the role of pharmaceutical additives and electrostatic interaction. Co-suspension of enteric-coated proton pump inhibitor (PPI) esomeprazole magnesium hydrate with levofloxacin resulted in aggregate formation, whereas the non-enteric-coated PPI vonoprazan fumarate did not. A comparison of pharmaceutical additive in the two PPIs highlighted polysorbate 80 and methacrylic acid copolymer LD as candidates causing aggregation. When these pharmaceutical additives were added to levofloxacin, only methacrylic acid copolymer LD induced aggregate formation. Since levofloxacin is zwitterionic, we examined another zwitterionic ingredient, ampicillin sodium, and found that it also formed aggregates with methacrylic acid copolymer LD, while benzylpenicillin sodium, which is not zwitterionic, did not form aggregates. When we next examined a series of zwitterionic quinolone antimicrobial drugs, we found that ofloxacin, which is highly soluble, formed aggregates with lansoprazole OD tablets, whereas poorly soluble quinolone antimicrobial drugs did not form aggregates. Further, although cefepime hydrochloride and cephalexin did not form aggregates with methacrylic acid copolymer LD in tap water, aggregates were formed when a suspension of cefepime hydrochloride or cephalexin with methacrylic acid copolymer LD was adjusted to pH 7.0. Our results indicate that electrostatic interaction between zwitterionic ingredients and methacrylic acid copolymer LD can result in aggregate formation under conditions where the drug and methacrylic acid copolymer LD are both sufficiently soluble.


Assuntos
Ácidos Polimetacrílicos/química , Antibacterianos/química , Ciprofloxacino/química , Liberação Controlada de Fármacos , Ofloxacino/química , Eletricidade Estática , Compostos de Enxofre/química , Comprimidos com Revestimento Entérico , Tegafur/química , beta-Lactamas/química
18.
Talanta ; 212: 120778, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32113541

RESUMO

Tailor-made Escherichia coli (E. coli) receptors were created with microcontact imprinted technique and binding events of E. coli were carried out by a surface plasmon resonance (SPR) sensor in aqueous solution and in urine mimic in real time and label-free. N-methacryloyl-(l)-histidine methyl ester (MAH) was selected as a functional monomer to design tailor-made E. coli receptors on the polymeric film and during the formation of the polymeric film on a chip surface, Ag nanoparticles (AgNPs) were entrapped into the polymer mixture in order to lower the detection limit of biomimetic SPR based sensor. The polymeric film was characterized with atomic force microscopy (AFM), scanning electron microscopy (SEM), ellipsometer and contact angle measurements. Limit of detection (LOD) was found 0.57 CFU/mL and feasibility of the biomimetic sensor was investigated in urine mimic.


Assuntos
Técnicas de Tipagem Bacteriana/métodos , Escherichia coli/isolamento & purificação , Ácidos Polimetacrílicos/química , Ressonância de Plasmônio de Superfície/métodos , Infecções Urinárias/diagnóstico , Biomimética/métodos , Histidina/análogos & derivados , Histidina/química , Limite de Detecção , Nanopartículas Metálicas/química , Metacrilatos/química , Impressão Molecular , Prata/química , Urina/microbiologia
19.
Biomater Sci ; 8(8): 2264-2273, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32134074

RESUMO

Endometrial carcinoma is a kind of epithelial malignant tumor occurring in the endometrium with high incidence (nearly 200 000 people are diagnosed every year). At present, surgery is the main strategy for the treatment of endometrial carcinoma. However, in special cases such as serous, clear cell carcinoma and postoperative recurrences, chemotherapy is still essential and indispensable. The combined chemotherapy schemes of cisplatin, paclitaxel and doxorubicin (DOX) in clinical applications are unfortunately complicated and easily cause severe side effects. In recent years, with the development of nanotechnology, the targeted delivery of multi-chemotherapeutic drugs shows great advantages in reducing side effects and improving anticancer efficacy. Here, an ultra pH-sensitive nanovesicle based on polyethylene glycol-poly(diisopropylamino)ethyl methacrylate (PEG-PDPA) was fabricated. A chemotherapeutic drug (doxorubicin) and an anti-apoptotic Bcl-2 inhibitor (navitoclax) were co-encapsulated in the hydrophilic cavity and hydrophobic membrane of the vesicle, respectively. After accumulating in the tumor tissue via the enhanced permeability and retention (EPR) effect, the nanovesicles could be efficiently diffused in tumor cells by endocytosis and then rapidly release drugs in response to the lysosomal acidic environment, leading to an enhanced tumor-killing effect based on the combination therapy between DOX and the Bcl-2 inhibitor. The drug co-delivery system and microenvironment-triggered drug release may provide an efficient strategy for endometrial carcinoma therapy.


Assuntos
Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ácidos Polimetacrílicos/administração & dosagem , Sulfonamidas/administração & dosagem , Compostos de Anilina/química , Animais , Antineoplásicos/química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Linhagem Celular Tumoral , Doxorrubicina/química , Portadores de Fármacos/química , Humanos , Concentração de Íons de Hidrogênio , Camundongos Nus , Nanopartículas/química , Neoplasias/tratamento farmacológico , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Sulfonamidas/química
20.
Carbohydr Polym ; 236: 116021, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32172841

RESUMO

In this work, a facile click reaction strategy is employed to form hydrogels in situ with cytocompatibility, biodegradability, self-healing property and resistance to protein. The thiol-functionalized zwitterionic carboxybetaine methacrylate copolymer, which take part as a cross-linker in the "thiol-ene" click reaction with the methacrylated hyaluronic acid. The hydrogels are obtained under the physiological condition without the presence of any copper catalyst and UV light. The hydrogel consisting of zwitterionic component shows an obvious reduction in protein adsorption and cell adhesion and avoid non-targeted factor interference in the biological experiments. The hydrogels also demonstrate adjustable degradation behavior. Human mesenchymal stem cells (hMSCs) are easily encapsulated into the hydrogels and remains metabolically active, indicating the excellent biocompatibility of the hydrogels. Additionally, the result of the cytokine secretion assays (IL-6 and TNF-α) has shown that this clickable hydrogel can serve to suppress inflammatory reactions and is beneficial for in vivo applications. Based on the above results, this clickable hydrogel with excellent performance can be an amenable platform for 3D cell encapsulation.


Assuntos
Ácido Hialurônico/análogos & derivados , Hidrogéis/química , Ácidos Polimetacrílicos/química , Compostos de Sulfidrila/química , Animais , Adesão Celular/efeitos dos fármacos , Encapsulamento de Células/métodos , Sobrevivência Celular/efeitos dos fármacos , Química Click , Humanos , Ácido Hialurônico/síntese química , Ácido Hialurônico/toxicidade , Hidrogéis/síntese química , Hidrogéis/toxicidade , Interleucina-6/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Ácidos Polimetacrílicos/síntese química , Ácidos Polimetacrílicos/toxicidade , Células RAW 264.7 , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/toxicidade , Fator de Necrose Tumoral alfa/metabolismo
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