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1.
Int J Pharm ; 577: 119093, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32004682

RESUMO

Gellan gum was chemically modified by the reaction with methacrylic anhydride to produce derivatives with 6, 14 and 49% methacrylation. The structure and substitution degrees of these derivatives were confirmed by 1H NMR- and FTIR-spectroscopy. These derivatives are more hydrophobic compared to pristine gellan and form turbid solutions in water. In vitro study performed with formulations of sodium fluorescein containing gellan gum and its methacrylated derivatives indicated that methacrylation enhances their retention on bovine conjunctival mucosa. In vivo experiments with the formulations of pilocarpine hydrochloride containing gellan gum and methacrylated derivatives have demonstrated that all polymers enhance the drug effect significantly, but best performance is observed for the polysaccharide with 6% methacrylation.


Assuntos
Túnica Conjuntiva/metabolismo , Mióticos/administração & dosagem , Pilocarpina/administração & dosagem , Polissacarídeos Bacterianos/química , Adesividade , Animais , Bovinos , Química Farmacêutica , Portadores de Fármacos/química , Feminino , Fluoresceína/química , Géis , Interações Hidrofóbicas e Hidrofílicas , Masculino , Metacrilatos/química , Metacrilatos/metabolismo , Mióticos/química , Mióticos/metabolismo , Membrana Mucosa/metabolismo , Pilocarpina/química , Coelhos
2.
Sci Rep ; 9(1): 13621, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541129

RESUMO

Cerebral malaria pathogenesis involves vascular dysfunction with low nitric oxide (NO) bioavailability, vasoconstriction and impaired vasodilation, leading to ischemia, tissue hypoxia and ultimately death. Cerebral blood flow (CBF) involves NO and other pathways, including arachidonic acid (AA)-derived metabolites. Here we show that mice with experimental cerebral malaria (ECM) by P. berghei ANKA showed marked decreases in CBF (as assessed by laser speckle contrast imaging - LSCI) and that administration of L-arginine supplementation (50 mg/kg) and/or of the thromboxane synthase inhibitor Ozagrel (100 mg/kg) induced immediate increases in CBF. L-arginine in combination with artesunate (32 mg/kg) induced immediate reversal of brain ischemia in the short-term (1 hour), but the effect subsided after 3 and 6 hours. Neither L-arginine nor Ozagrel reversed blood brain barrier breakdown. Mice with ECM showed brain levels of selected AA-derived metabolites with a vasoconstrictor profile, with increased levels of 8-isoprostanes, 20-HETE and 14,15-DHET, whereas mice infected with a non-ECM-inducing strain of P. berghei (NK65) showed a vasodilator profile, with normal levels of 20-HETE and 14,15-DHET and increased levels of PGE2. L-arginine is capable of partially reversing cerebral ischemia and AA metabolites may play a role in the cerebrovascular dysfunction in ECM.


Assuntos
Arginina/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Malária Cerebral/patologia , Animais , Arginina/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/patologia , Suplementos Nutricionais , Feminino , Malária Cerebral/metabolismo , Metacrilatos/metabolismo , Metacrilatos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium berghei/efeitos dos fármacos , Tromboxano-A Sintase/antagonistas & inibidores , Tromboxano-A Sintase/metabolismo , Tromboxanos/antagonistas & inibidores , Tromboxanos/metabolismo , Vasoconstrição/efeitos dos fármacos
3.
Colloids Surf B Biointerfaces ; 181: 989-993, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31382350

RESUMO

Saccharomyces cerevisiae immobilized in electrospun Pluronic F127 dimethacrylate (FDMA) was successfully employed for the production of ethanol in an immobilized cell reactor. Yeast cells were immobilized into fibers formed through the process of electrospinning and cross-linking. The threads had an average diameter of 0.88 µm and were used in continuous-flow immobilized cell reactors. The immobilized cell reactors were able to maintain a high ethanol yield of >90% from day 4 through to the end of the time course at day 14. The reactor was able to achieve a maximum ethanol yield of 94.3%. This study shows that the use of electrospinning is a promising method for continuous ethanol production through immobilized cell-based continuous flow reactors.


Assuntos
Reatores Biológicos , Células Imobilizadas/metabolismo , Etanol/metabolismo , Metacrilatos/metabolismo , Poloxâmero/metabolismo , Saccharomyces cerevisiae/metabolismo , Etanol/química , Fermentação , Metacrilatos/química , Tamanho da Partícula , Poloxâmero/química , Propriedades de Superfície
4.
Eye Contact Lens ; 45(5): 340-345, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31441829

RESUMO

OBJECTIVES: This report aimed to explore whether certain inflammatory mediators were absorbed, extracted, or bound by various contact lens materials. METHODS: Comfilcon A, balafilcon A, omafilcon A, and etafilcon A were soaked in 500 and 100 pg/mL of interleukin-8 (IL-8), matrix metalloproteinase-9 (MMP-9), or interleukin-1 receptor antagonist (IL-1Ra), and also in combined solutions of inflammatory mediators (500 pg/mL or 100 pg/mL) separately. Lenses were then extracted in 1:1 2% trifluoroacetic acid:acetonitrile. The extracted and residual concentrations of inflammatory mediators were determined using enzyme-linked immunosorbent assays. Absorbed (control-residual) and firmly bound (absorbed-extracted) concentrations were calculated for analysis. RESULTS: More MMP-9 was absorbed by omafilcon A (466±9 pg/mL) than balafilcon A (P=0.006; 437±11 pg/mL) or etafilcon A (P=0.001; 428±13 pg/mL) when soaked in 500 pg/mL, but no differences in 100 pg/mL. More MMP-9 remained firmly bound to omafilcon A (P=0.03; 174±3 pg/mL), comfilcon A (P=0.049; 168±34 pg/mL), and balafilcon A (P=0.01; 186±14 pg/mL) than etafilcon A (128±22 pg/mL). There were no differences in IL-8 absorption between lenses; however, more IL-8 remained firmly bound to omafilcon A (P=0.01; 336±25 pg/mL) than etafilcon A (106±133 pg/mL) when soaked in 500 pg/mL. No differences were found in concentrations of absorbed or firmly bound IL-1Ra between materials. When the mediators were combined, IL-8 was absorbed more in etafilcon A (P=0.03) than in other lens materials, but the absorbed IL-8 did not remain firmly bound. CONCLUSIONS: The uptake and extraction of inflammatory mediators from contact lenses was affected by competitive binding between the mediators.


Assuntos
Lentes de Contato Hidrofílicas , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-8/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Ligação Competitiva , Ensaio de Imunoadsorção Enzimática , Hidrogéis/metabolismo , Mediadores da Inflamação , Metacrilatos/metabolismo , Ligação Proteica , Silicones/metabolismo
5.
Protoplasma ; 256(5): 1375-1383, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31079230

RESUMO

In order to gain more insight into the involvement of mitochondrial complex III in the Cd-induced stress, we studied the effect of complex III inhibitors, antimycin A (AA), and myxothiazol (MYXO), on the Cd-induced ROS and NO generation in the barley root tip. Short-term exposure of barley roots to either MYXO or AA provoked a dose-dependent increase in both H2O2 and NO formation. In contrast to H2O2 generation, an enhanced superoxide formation in the transition zone of the root was a characteristic feature of AA-treated roots. MYXO and AA co-treatment had an additive effect on the amount of both H2O2 and NO formed in roots. On the other hand, AA-induced superoxide formation was markedly reversed in roots co-treated with MYXO. Both AA and MYXO exacerbated the Cd-mediated H2O2 or NO generation in the root tip. On the contrary, while AA also exacerbated the Cd-induced superoxide generation, MYXO dose-dependently attenuated it. These data provide strong evidence that ROS generation, a very early symptom of Cd toxicity in roots, is originated in mitochondria. Cd, similarly to AA, generates superoxide by blocking the mitochondrial electron transport chain (ETC) at complex III. In turn, the site of Cd-induced NO generation is not associated with complex III, but ROS formed in mitochondria at this third complex of ETC are probably responsible for enhanced NO generation in barley root under Cd stress.


Assuntos
Antimicina A/metabolismo , Cádmio/metabolismo , Hordeum/química , Peróxido de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Raízes de Plantas/química , Superóxidos/metabolismo , Metacrilatos/metabolismo , Tiazóis/metabolismo
6.
J Biomater Sci Polym Ed ; 30(11): 895-918, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31039085

RESUMO

Three-dimensional (3 D) hydrogel scaffolds are an attractive option for tissue regeneration applications because they allow for cell migration, fluid exchange, and can be synthesized to closely mimic the physical properties of the extracellular matrix environment. The material properties of hydrogels play a vital role in cellular migration and differentiation. In light of this, in-depth understanding of material properties is required before such scaffolds can be used to study their influence on cells. Herein, various blends and thicknesses of poly (ethylene glycol) dimethacrylate (PEGDMA) hydrogels were synthesized, flash frozen, and dried by lyophilization to create scaffolds with multiscale porosity. Environmental scanning electron microscopy (ESEM) images demonstrated that lyophilization induced microporous voids in the PEGDMA hydrogels while swelling studies show the hydrogels retain their innate swelling properties. Change in pore size was observed between drying methods, polymer blend, and thickness when imaged in the hydrated state. Human adipose-derived stem cells (hASCs) were seeded on lyophilized and non-lyophilized hydrogels to determine if the scaffolds would support cell attachment and proliferation of a clinically relevant cell type. Cell attachment and morphology of the hASCs were evaluated using fluorescence imaging. Qualitative observations in cell attachment and morphology of hASCs on the surface of the different hydrogel spatial configurations indicate these multiscale porosity hydrogels create a suitable scaffold for hASC culture. These findings offer another factor of tunability in creating biomimetic hydrogels for various tissue engineering applications including tissue repair, regeneration, wound healing, and controlled release of growth factors.


Assuntos
Materiais Biocompatíveis/química , Hidrogéis/química , Metacrilatos/química , Polietilenoglicóis/química , Tecidos Suporte/química , Adipócitos/metabolismo , Materiais Biocompatíveis/metabolismo , Adesão Celular , Diferenciação Celular , Sobrevivência Celular , Reagentes para Ligações Cruzadas/química , Humanos , Hidrogéis/metabolismo , Células-Tronco Mesenquimais/metabolismo , Metacrilatos/metabolismo , Conformação Molecular , Polietilenoglicóis/metabolismo , Porosidade , Reologia , Propriedades de Superfície , Engenharia Tecidual
7.
Mycotoxin Res ; 35(3): 293-307, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30949955

RESUMO

This study attempts to evaluate the potential aflatoxin binder activity of a molecularly imprinted polymer (TMU95) synthesized to target the aflatoxin B1 (AFB1) analog molecule in comparison to a commercial toxin binder (CTB). Adsorption experiments were carried out to assess the ability to bind to AFB1 at various pH values. The strength of binding was investigated by the chemisorption index. The isothermal analysis was used to determine the maximum adsorption capacity values. The ability of TMU95 and CTB to adsorb essential minerals was evaluated and the obtained data suggested that CTB would significantly reduce availability of them compared to TMU95. The in vivo efficacy of TMU95 as an aflatoxin (AF) binder in duckling exposed to aflatoxin-contaminated feed from 4 to 18 days of age in comparison to the CTB was also assessed. TMU95 and CTB were effective in reducing the adverse effects caused by AFs on feed conversion ratio of duckling (p ≤ 0.01), and also showed a minor reduction of injuries caused by AFs on visceral organs enlargement (p ≤ 0.01). It was concluded that TMU95 could absorb AFB1 in vitro efficiently and had beneficial health effects that could alleviate some of the toxic effects of AFs on growing duckling performance similar to CTB.


Assuntos
Aflatoxina B1/metabolismo , Ração Animal/análise , Metacrilatos/metabolismo , Polímeros/química , Adsorção , Aflatoxina B1/toxicidade , Ração Animal/toxicidade , Animais , Patos , Contaminação de Alimentos , Concentração de Íons de Hidrogênio , Cinética , Trato Gastrointestinal Inferior/efeitos dos fármacos , Trato Gastrointestinal Inferior/patologia , Baço/efeitos dos fármacos , Baço/patologia
8.
Toxicology ; 420: 1-10, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30930120

RESUMO

Dental resin systems have been in use for several decades. (Meth)acrylic monomers are an important part of the matrix system and are either based on BPA while others lack the BPA core. The degree of conversion during restoration is in general between 50-70 % allowing leaching from unreacted monomers to the oral cavity where they can be taken up through the pulp or gastrointestinal tract after ingestion with subsequent hepatic metabolism. This study identified the in vitro Phase I and Phase II metabolism of the dental resin monomers BisGMA, UDMA, BisPMA and TCD-DI-HEA, using human liver microsomes (HLM) and human liver cytosols. During Phase I incubation with HLM, the (meth)acrylic acid in the monomers was rapidly removed followed by oxidative and hydroxylation pathways. For BisPMA an O-dealkylation pathway occurred resulting in the formation of BPA. The carbamates present in TCD-DI-HEA and UDMA were resistant to biotransformation reactions. Phase II biotransformation products were only observed for BisPMA and included conjugation reactions with sulphate and glucuronic acid. In total 4, 3, 12 and 3 biotransformation products were identified in this study for BisGMA, UDMA, BisPMA and TCD-DI-HEA respectively. Possible human health effects of these biotransformation products remain unclear due to limited data availability.


Assuntos
Bis-Fenol A-Glicidil Metacrilato/metabolismo , Cromatografia Líquida , Metacrilatos/metabolismo , Microssomos Hepáticos/metabolismo , Poliuretanos/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Remoção de Radical Alquila , Feminino , Glucuronatos/metabolismo , Humanos , Hidroxilação , Masculino , Desentoxicação Metabólica Fase I , Desintoxicação Metabólica Fase II , Oxirredução , Sulfatos/metabolismo
10.
Acta Biomater ; 88: 325-331, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30807874

RESUMO

Cholesterol esterase-like (CE) activity from saliva and esterase from cariogenic bacteria hydrolyze ester linkages of dental methacrylate resins. Collagenolytic, matrix metalloproteinase-like (MMP) activities from dentin and bacteria degrade collagen in demineralized tooth dentin. Human neutrophils in the oral cavity contain factors that are hypothesized to have CE and MMP activities that could contribute to the degradation of methacrylate resins and dentinal collagen. OBJECTIVES: To measure the CE and MMP activities from human neutrophils and their ability to degrade dental methacrylate resin composite and dentinal collagen. Neutrophils' CE and MMP activities were measured using nitrophenyl-esters or fluorimetric MMP substrates, respectively. Neutrophils' degradation of resin composite and dentinal collagen was quantified by measuring release of a universal 2,2-Bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]propane (bisGMA)-derived resin composite degradation byproduct, bishydroxy-propoxy-phenyl-propane (bisHPPP), or a collagen degradation by-product, hydroxyproline, respectively using ultra performance liquid chromatography/mass spectrometry. Neutrophils' CE activity increased the release of bisHPPP from bisGMA monomer compared to control after 24 and 48 h (p < 0.05). Neutrophils degraded polymerized resin composite and produced higher amounts of bisHPPP than buffer after 48 h of incubation (p < 0.05). Neutrophils show generic MMP, gelatinase, MMP-2 and MMP-9, and collagenase, MMP-1 and MMP-8 activities that were stable or increased over the first 24 h (p < 0.05). Neutrophils degraded demineralized dentin more than buffer-only groups, indicated by higher amounts of hydroxyproline (p < 0.05). The ability of neutrophils to degrade both dental resin composite and tooth dentin, suggest neutrophil's potential role in root caries, and in recurrent carries by accelerating the degradation of resin-dentin interfaces, and compromising the longevity of the restoration. STATEMENT OF SIGNIFICANCE: Neutrophils are part of the innate immune system and are constantly entering the oral cavity through the gingival sulcus, in direct contact with the tooth, restoration, restoration-tooth margins and pathogenic bacteria. The current study is the first to characterize and quantify degradative activities from neutrophils toward methacrylate resin and demineralized dentin, the two main components of the restoration-tooth interface, suggesting that this interface could be negatively influenced by neutrophils, potentially contributing to increase in caries formation and progression, and premature restoration failure. This study provides a significant finding to the biomaterials and oral health fields by identifying a potential weakness in current restorative procedures and materials used to manage gingival proximal and cervical gingival or sub-gingival carious lesions.


Assuntos
Resinas Acrílicas/metabolismo , Resinas Compostas/metabolismo , Dentina/metabolismo , Metacrilatos/metabolismo , Neutrófilos/metabolismo , Poliuretanos/metabolismo , Dente/química , Sobrevivência Celular , Colágeno/metabolismo , Colágeno/ultraestrutura , Humanos , Hidroxiprolina/metabolismo , Elastase de Leucócito/metabolismo , Metaloproteinases da Matriz/metabolismo , Neutrófilos/enzimologia , Propano/metabolismo , Proteólise , Esterol Esterase/metabolismo
11.
Acta Pharmacol Sin ; 40(8): 1106-1118, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30792487

RESUMO

Cinnamic acid and its analogues (pyragrel and ozagrel) undergo chain-shortened (ß-oxidative) and reductive metabolism on acyl side chain. In this study, we characterized the ß-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues using primary rat hepatocytes, hepatic mitochondrial, and microsomal systems. A compartmental model including parent compounds and metabolites was developed to characterize in vivo ß-oxidative and reductive metabolism following an intravenous dose of parent compounds to rats. The fitted total in vivo clearance values were further compared with the in vitro values predicted by the well-stirred model. We showed that hepatic microsomal CYP450s did not catalyze ß-oxidative or reductive metabolism of the three compounds. Similar to ß-oxidation of fatty acids, ß-oxidative metabolism on their acyl side chain occurred mainly in mitochondria, which was highly dependent on ATP, CoA and NAD+. Fatty acids and NADH inhibited the ß-oxidative metabolism. Reductive metabolism occurred in both mitochondria and microsomes. Reduction in mitochondria was ATP-, CoA-, and NAD(P)H-dependent and reversible, which was suppressed by enoyl reductase inhibitor triclosan. Reduction in microsomes was ATP-, CoA-, and NADPH-dependent but little affected by triclosan. Both plasma concentrations of ß-oxidative metabolites and reductive metabolites were successfully fitted using the compartmental model. The estimated total in vivo clearance values were consistent with those predicted from hepatocytes and organelles, implicating significance of in vitro kinetics. These findings demonstrate the roles of hepatic mitochondria and microsomes in ß-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues along with their metabolic characteristics.


Assuntos
Cinamatos/metabolismo , Metacrilatos/metabolismo , Pirazinas/metabolismo , Animais , Cinamatos/química , Cinamatos/farmacocinética , Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Masculino , Metacrilatos/química , Metacrilatos/farmacocinética , Microssomos Hepáticos/metabolismo , Mitocôndrias Hepáticas/metabolismo , Estrutura Molecular , NAD/metabolismo , Oxirredução/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacocinética , Ratos Sprague-Dawley , Triclosan/farmacologia
12.
ACS Nano ; 13(3): 3353-3362, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30742410

RESUMO

Untethered mobile microrobots have the potential to leverage minimally invasive theranostic functions precisely and efficiently in hard-to-reach, confined, and delicate inner body sites. However, such a complex task requires an integrated design and engineering, where powering, control, environmental sensing, medical functionality, and biodegradability need to be considered altogether. The present study reports a hydrogel-based, magnetically powered and controlled, enzymatically degradable microswimmer, which is responsive to the pathological markers in its microenvironment for theranostic cargo delivery and release tasks. We design a double-helical architecture enabling volumetric cargo loading and swimming capabilities under rotational magnetic fields and a 3D-printed optimized 3D microswimmer (length = 20 µm and diameter = 6 µm) using two-photon polymerization from a magnetic precursor suspension composed from gelatin methacryloyl and biofunctionalized superparamagnetic iron oxide nanoparticles. At normal physiological concentrations, we show that matrix metalloproteinase-2 (MMP-2) enzyme could entirely degrade the microswimmer in 118 h to solubilized nontoxic products. The microswimmer rapidly responds to the pathological concentrations of MMP-2 by swelling and thereby boosting the release of the embedded cargo molecules. In addition to delivery of the drug type of therapeutic cargo molecules completely to the given microenvironment after full degradation, microswimmers can also release other functional cargos. As an example demonstration, anti-ErbB 2 antibody-tagged magnetic nanoparticles are released from the fully degraded microswimmers for targeted labeling of SKBR3 breast cancer cells in vitro toward a potential future scenario of medical imaging of remaining cancer tissue sites after a microswimmer-based therapeutic delivery operation.


Assuntos
Anticoagulantes/química , Dextranos/química , Sistemas de Liberação de Medicamentos , Gelatina/química , Impressão Tridimensional , Nanomedicina Teranóstica , Anticoagulantes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dextranos/farmacologia , Liberação Controlada de Fármacos , Compostos Férricos/química , Compostos Férricos/metabolismo , Gelatina/metabolismo , Humanos , Campos Magnéticos , Nanopartículas de Magnetita/química , Metaloproteinase 2 da Matriz/metabolismo , Metacrilatos/química , Metacrilatos/metabolismo , Tamanho da Partícula , Fótons , Polimerização , Propriedades de Superfície
13.
Langmuir ; 35(9): 3479-3489, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30742441

RESUMO

Catalysis by enzymes on surfaces has many applications. However, strategies for efficient enzyme immobilization with preserved activity are still in need of further development. In this work, we investigate polyelectrolyte brushes prepared by both grafting-to and grafting-from with the aim to achieve high catalytic activity. For comparison, self-assembled monolayers that bind enzymes with the same chemical interactions are included. We use the model enzyme glucose oxidase and two kinds of polymers: anionic poly(acrylic acid) and cationic poly(diethylamino)methyl methacrylate. Surface plasmon resonance and spectroscopic ellipsometry are used for accurate quantification of surface coverage. Besides binding more enzymes, the "3D-like" brush environment enhances the specific activity compared to immobilization on self-assembled monolayers. For grafting-from brushes, multilayers of enzymes were spontaneously and irreversibly immobilized without conjugation chemistry. When the pH was between the pI of the enzyme and the p Ka of the polymer, binding was considerable (thousands of ng/cm2 or up to 50% of the polymer mass), even at physiological ionic strength. However, binding was observed also when the brushes were neutrally charged. For acidic brushes (both grafting-to and grafting-from), the activity was higher for covalent immobilization compared to noncovalent. For grafting-from brushes, a fully preserved specific activity compared to enzymes in the liquid bulk was achieved, both with covalent (acidic brush) and noncovalent (basic brush) immobilization. Catalytic activity of hundreds of pmol cm-2 s-1 was easily obtained for polybasic brushes only tens of nanometers in dry thickness. This study provides new insights for designing functional interfaces based on enzymatic catalysis.


Assuntos
Enzimas Imobilizadas/metabolismo , Glucose Oxidase/metabolismo , Polieletrólitos/metabolismo , Resinas Acrílicas/química , Resinas Acrílicas/metabolismo , Adsorção , Enzimas Imobilizadas/química , Glucose Oxidase/química , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Metacrilatos/química , Metacrilatos/metabolismo , Nylons/química , Nylons/metabolismo , Polieletrólitos/química , Ligação Proteica , Ressonância de Plasmônio de Superfície
14.
Biomacromolecules ; 20(2): 959-968, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30605608

RESUMO

Currently, one of the most promising treatments of lipopolysaccharides (LPS)-induced sepsis is based on hemofiltration. Nevertheless, proteins rapidly adsorbed on the artificial surface of membranes which leads to activation of coagulation impairing effective scavenging of the endotoxins. To overcome this challenge, we designed polymer-brush-coated microparticles displaying antifouling properties and functionalized them with polymyxin B (PMB) to specifically scavenge LPS the most common endotoxin. Poly[( N-(2-hydroxypropyl) methacrylamide)- co-(carboxybetaine methacrylamide)] brushes were grafted from poly(glycidyl methacrylate) microparticles using photoinduced single-electron transfer living radical polymerization (SET-LRP). Notably, only parts-per-million of copper catalyst were necessary to achieve brushes able to repel adsorption of proteins from blood plasma. The open porosity of the particles, accessible to polymerization, enabled us to immobilize sufficient PMB to selectively scavenge LPS from blood plasma.


Assuntos
Incrustação Biológica/prevenção & controle , Materiais Revestidos Biocompatíveis/farmacologia , Lipopolissacarídeos/metabolismo , Plasma/metabolismo , Acrilamidas/metabolismo , Adsorção , Compostos de Epóxi/metabolismo , Humanos , Metacrilatos/metabolismo , Polimerização/efeitos dos fármacos , Polímeros/química , Polimixina B/farmacologia , Proteínas/metabolismo , Propriedades de Superfície/efeitos dos fármacos
15.
J Mater Chem B ; 7(5): 786-795, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32254853

RESUMO

Zwitterionic polymers are a class of polymers that acts as both Lewis base and Lewis acid in solution. These polymers not only have excellent properties of hydration, anti-bacterial adhesion, charge reversal and easy chemical modification, but also have characteristics of long-term circulation and suppress nonspecific protein adsorption in vivo. Here, we describe a novel folate-targeted and acid-labile polymeric prodrug under the microenvironment of tumor cells, abbreviated as FA-P(MPC-co-PEGMA-BZ)-g-DOX, which was synthesized via a combination of reversible addition-fragmentation chain transfer (RAFT) copolymerization, Schiff-base reaction, Click chemistry, and a reaction between the amine group of doxorubicin (DOX) and aldehyde functionalities of P(MPC-co-PEGMA-BZ) pendants, wherein MPC and PEGMA-BZ represent 2-(methacryloyloxy)ethyl phosphorylcholine and polyethylene glycol methacrylate ester benzaldehyde, respectively. The polymeric prodrug could self-assemble into nanoparticles in an aqueous solution. The average particle size and morphologies of the prodrug nanoparticles were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. We also investigated the in vitro drug release behavior and observed rapid prodrug nanoparticle dissociation and drug release under a mildly acidic microenvironment. The methyl thiazolyl tetrazolium (MTT) assay verified that the P(MPC-co-PEGMA-BZ) copolymer possessed good biocompatibility and the FA-P(MPC-co-PEGMA-BZ)-g-DOX prodrug nanoparticles showed higher cellular uptake than those prodrug nanoparticles without the FA moiety. The results of cytotoxicity and the intracellular uptake of non-folate/folate targeted prodrug nanoparticles further confirmed that FA-P(MPC-co-PEGMA-BZ)-g-DOX could be efficiently accumulated and rapidly internalized by HeLa cells due to the strong interaction between multivalent phosphorylcholine (PC) groups and cell membranes. This kind of multifunctional FA-P(MPC-co-PEGMA-BZ)-g-DOX prodrug nanoparticle with combined target-ability and pH responsiveness demonstrates promising potential for cancer chemotherapy.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Ácido Fólico/metabolismo , Pró-Fármacos/química , Doxorrubicina/administração & dosagem , Ácido Fólico/farmacocinética , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Teste de Materiais , Metacrilatos/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Fosforilcolina/metabolismo , Polietilenoglicóis/metabolismo , Polímeros/química , Polímeros/metabolismo , Polímeros/farmacocinética , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacocinética
16.
J Drug Target ; 27(5-6): 582-589, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30457357

RESUMO

Whereas significant advancements have been made in our fundamental understanding of cancer, they have not yet translated into effective clinical cancer treatments. One of the areas that has the potential to improve the efficacy of cancer therapies is the development of novel drug delivery technologies. In particular, the design of pH-sensitive polymeric complexation hydrogels may allow for targeted oral delivery of a wide variety of chemotherapeutic drugs and proteins. In this work, poly(methacrylic acid-grafted-ethylene glycol) hydrogel nanoparticles were synthesised, characterised, and studied as matrix-type, diffusion-controlled, pH-responsive carriers to enable the oral delivery of the chemotherapeutic agent interferon alpha (IFN-α). The biophysical mechanisms controlling the transport of IFN-α were investigated using a Caco-2/HT29-MTX co-culture as a gastrointestinal (GI) tract model. The synthesised nanoparticles exhibited pH-responsive swelling behaviour and allowed the permeation of IFN-α through the tight junctions of the developed cellular GI epithelium model. These studies demonstrate the capabilities of these particles to contribute to the improved oral delivery of protein chemotherapeutics.


Assuntos
Etilenoglicol/química , Interferon-alfa/metabolismo , Mucosa Intestinal/metabolismo , Metacrilatos/química , Nanopartículas/metabolismo , Junções Íntimas/metabolismo , Células CACO-2 , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Etilenoglicol/metabolismo , Células HT29 , Humanos , Hidrogéis/química , Hidrogéis/metabolismo , Concentração de Íons de Hidrogênio , Metacrilatos/metabolismo , Nanopartículas/química , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo
17.
Physiol Res ; 67(Suppl 2): S293-S303, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30379551

RESUMO

In this review we summarize several synthetic approaches to the advanced synthesis of star-like polymer-based drug carriers. Moreover, their application as nanomedicines for therapy or the diagnosis of neoplastic diseases and their biodistribution are reviewed in detail. From a broad spectrum of star-like systems, we focus only on fully water-soluble systems, mainly based on poly(ethylene glycol) or N-(2-hydroxypropyl)methacrylamide polymer and copolymer arms and polyamidoamine dendrimers serving as the core of the star-like systems.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Polímeros/química , Polímeros/metabolismo , Animais , Portadores de Fármacos/administração & dosagem , Humanos , Metacrilatos/administração & dosagem , Metacrilatos/química , Metacrilatos/metabolismo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Polímeros/administração & dosagem , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia
18.
Physiol Res ; 67(Suppl 2): S357-S365, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30379556

RESUMO

Novel star polymers based on the water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer and cyclodextrin were synthesized and the physico-chemical behavior of these precursors was studied. Semitelechelic HPMA copolymers were grafted onto the cyclodextrin core, thus forming star-like structure. Both prepared systems were designed as possible polymer carriers for the controlled release of cytostatic drugs, which after the drug release and degradation will be eliminated from the organism. Two synthesis approaches were used to obtain similar polymer carriers with different degradation rates. All the polymers were prepared by reversible addition-fragmentation chain-transfer polymerization, which guarantees low dispersity of the prepared systems.


Assuntos
Química Farmacêutica/métodos , Ciclodextrinas/síntese química , Polímeros/síntese química , Água/química , Ciclodextrinas/metabolismo , Metacrilatos/síntese química , Metacrilatos/metabolismo , Polímeros/metabolismo , Solubilidade , Água/metabolismo
19.
Bioconjug Chem ; 29(7): 2181-2194, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29712427

RESUMO

Methacrylate-based polymers represent promising nonviral gene delivery vectors, since they offer a large variety of polymer architectures and functionalities, which are beneficial for specific demands in gene delivery. In combination with controlled radical polymerization techniques, such as the reversible addition-fragmentation chain transfer polymerization, the synthesis of well-defined polymers is possible. In this study we prepared a library of defined linear polymers based on (2-aminoethyl)-methacrylate (AEMA), N-methyl-(2-aminoethyl)-methacrylate (MAEMA), and N,N-dimethyl-(2-aminoethyl)-methacrylate (DMAEMA) monomers, bearing pendant primary, secondary, and tertiary amino groups, and investigated the influence of the substitution pattern on their gene delivery capability. The polymers and the corresponding plasmid DNA complexes were investigated regarding their physicochemical characteristics, cytocompatibility, and transfection performance. The nonviral transfection by methacrylate-based polyplexes differs significantly from poly(ethylene imine)-based polyplexes, as a successful transfection is not affected by the buffer capacity. We observed that polyplexes containing a high content of primary amino groups (AEMA) offered the highest transfection efficiency, whereas polyplexes bearing tertiary amino groups (DMAEMA) exhibited the lowest transfection efficiency. Further insights into the uptake and release mechanisms could be identified by fluorescence and transmission electron microscopy, emphasizing the theory of membrane-pore formation for the time-efficient endosomal release of methacrylate-based vectors.


Assuntos
Técnicas de Transferência de Genes , Metacrilatos/metabolismo , Polímeros/metabolismo , Aminas/química , Membrana Celular/metabolismo , Endossomos/metabolismo , Humanos , Polimerização , Porosidade , Relação Estrutura-Atividade
20.
Chem Commun (Camb) ; 54(49): 6252-6255, 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29736504

RESUMO

Fluorescent unimolecular micelles (FUMs) with multicolor emission acting as fluorescent nanoagents for optical fluorescence imaging have, for the first time, been reported. The FUMs show good water-solubility, ultra-small size, and enhanced biocompatibility, which endow the FUMs with versatile applications including organelle labeling, multicolor markers and high tumor accumulation, revealing that our design can serve as a rational strategy for the development of UM-based fluorescent nanoagents for bioprocess monitoring.


Assuntos
Corantes Fluorescentes/metabolismo , Metacrilatos/metabolismo , Micelas , Neoplasias/diagnóstico por imagem , Polietilenoglicóis/metabolismo , beta-Ciclodextrinas/metabolismo , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Carbocianinas/síntese química , Carbocianinas/química , Carbocianinas/metabolismo , Linhagem Celular Tumoral , Citoesqueleto/metabolismo , Feminino , Fluoresceínas/síntese química , Fluoresceínas/química , Fluoresceínas/metabolismo , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Lisossomos/metabolismo , Metacrilatos/síntese química , Metacrilatos/química , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Tamanho da Partícula , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Rodaminas/síntese química , Rodaminas/química , Rodaminas/metabolismo , Solubilidade , beta-Ciclodextrinas/síntese química , beta-Ciclodextrinas/química
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