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1.
Chem Commun (Camb) ; 55(61): 9015-9018, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31290867
2.
J Nanobiotechnology ; 17(1): 78, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269964

RESUMO

BACKGROUND: The construction of a multifunctional drug delivery system with a variety of advantageous features, including targeted delivery, controlled release and combined therapy, is highly attractive but remains a challenge. RESULTS: In this study, we developed a MoS2-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving targeted delivery of camptothecin (CPT) and dual-stimuli-responsive drug release. HA was connected to MoS2 via a disulfide linkage, forming a sheddable HA shell on the surface of MoS2. This unique design not only effectively prevented the encapsulated CPT from randomly leaking during blood circulation but also significantly accelerated the drug release in response to tumor-associated glutathione (GSH). Moreover, the MoS2-based generated heat upon near-infrared (NIR) irradiation could further increase the drug release rate as well as induce photothermal ablation of cancer cells. The results of in vitro and in vivo experiments revealed that MoS2-SS-HA-CPT effectively suppressed cell proliferation and inhibited tumor growth in lung cancer cell-bearing mice under NIR irradiation via synergetic chemo-photothermal therapy. CONCLUSIONS: The as-prepared MoS2-SS-HA-CPT with high targeting ability, dual-stimuli-responsive drug release, and synergistic chemo-photothermal therapy may provide a new strategy for cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Dissulfetos/química , Portadores de Fármacos/química , Molibdênio/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Liberação Controlada de Fármacos , Feminino , Corantes Fluorescentes/química , Humanos , Ácido Hialurônico/química , Hipertermia Induzida , Raios Infravermelhos , Camundongos Nus , Transplante de Neoplasias , Oxirredução , Fotoquimioterapia/métodos
3.
Chemphyschem ; 20(17): 2204-2209, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31298452

RESUMO

The efficiency of MRI contrast agents depends on the relaxation rate enhancement that they can induce at imaging fields. It is well known that, at these fields, large relaxation rates are obtained by binding of gadolinium(III) ions to large molecules. By the same token, the interaction of the gadolinium(III) complexes with macromolecules that are found in biological tissues can be responsible for an increase of the relaxation rate with respect to the value observed in liquids. We investigate here the relaxation enhancement of gadoteridol (Gd-HP-DO3A) in crosslinked hyaluronic acid, taken as model tissue, using fast field-cycling relaxometry. The analysis of the relaxation profiles as a function of the magnetic fields indicates that a sizable increase in the relaxation rates is due to a modest interaction of the contrast agent with the hydrogel and to the slower mobility of the water molecules outside the first-coordination sphere of the gadolinium(III) ion.


Assuntos
Meios de Contraste/química , Compostos Heterocíclicos/química , Ácido Hialurônico/química , Imagem por Ressonância Magnética/métodos , Modelos Biológicos , Compostos Organometálicos/química , Gadolínio/química , Água/química
4.
Int J Nanomedicine ; 14: 4649-4666, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31303753

RESUMO

Introduction: Herein, a hyaluronic acid (HA)-coated redox-sensitive chitosan-based nanoparticle, HA(HECS-ss-OA)/GA, was successfully developed for tumor-specific intracellular rapid delivery of gambogic acid (GA). Materials and methods: The redox-sensitive polymer, HECS-ss-OA, was prepared through a well-controlled synthesis procedure with a satisfactory reproducibility and stable resulted surface properties of the assembled cationic micelles. GA was solubilized into the inner core of HECS-ss-OA micelles, while HA was employed to coat outside HECS-ss-OA/GA for CD44-mediated active targeting along with protection from cation-associated in vivo defects. The desirable redox-sensitivity of HA(HECS-ss-OA)/GA was demonstrated by morphology and particle size changes alongside in vitro drug release of nanoparticles in different simulated reducing environments. Results: The results of flow cytometry and confocal microscopy confirmed the HA-receptor mediated cellular uptake and burst drug release in highly reducing cytosol of HA(HECS-ss-OA)/GA. Consequently, HA(HECS-ss-OA)/GA showed the highest apoptosis induction and cytotoxicity over the non-sensitive (HA(HECS-cc-OA)/GA) and HA un-coated (HECS-ss-OA/GA) controls against A549 NSCLC model both in vitro and in vivo. Furthermore, a diminished systemic cytotoxicity was observed in HA(HECS-ss-OA)/GA treated mice compared with those treated by HA un-coated cationic ones and GA solution.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Ácido Hialurônico/química , Micelas , Neoplasias/tratamento farmacológico , Xantonas/administração & dosagem , Xantonas/uso terapêutico , Células A549 , Animais , Antineoplásicos/farmacologia , Apoptose , Varredura Diferencial de Calorimetria , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quitosana/síntese química , Humanos , Ácido Hialurônico/síntese química , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Neoplasias/patologia , Oxirredução , Propionatos/síntese química , Propionatos/química , Espectroscopia de Prótons por Ressonância Magnética , Reprodutibilidade dos Testes , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Xantonas/farmacologia
5.
Life Sci ; 232: 116669, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31326566

RESUMO

AIMS: This study investigated the effects of hyaluronic acid (HA), a commonly used osteogenic medium referred to as DAG, and the combined administration of HA and DAG (CG) on the osteogenic differentiation of human amniotic mesenchymal stem cells (hAMSCs), and the underlying mechanism. MAIN METHODS: The phenotype of hAMSCs was detected by flow cytometry and immunocytochemical staining. Alkaline phosphatase (ALP) and calcium deposition assays were employed for evaluating the osteogenic differentiation of hAMSCs. The expression of osteogenesis-related genes and proteins was determined by quantitative reverse transcription PCR (qRT-PCR) and Western blotting, respectively. Meanwhile, the molecular mechanism of osteogenic differentiation of hAMSCs was detected by PCR array and qRT-PCR. KEY FINDINGS: The results showed that treatment with CG could significantly stimulate hAMSC ALP activity and calcium deposition compared to treatment with DAG, while HA had little effect. The expression of osteogenesis-related molecules and stemness-related molecules was up-regulated at the mRNA and protein levels in all three groups, and this up-regulation was most significant in the CG group. In addition, treatment with CG significantly increased the gene expressions involved in regulation of the TGF-ß/Smad signalling pathway compared to treatment with DAG. Furthermore, the pro-osteogenic differentiation effects as well as the up-regulated expression of genes observed in the CG treatment group were significantly inhibited when the cells were pre-treated with SB431542, an inhibitor of the TGF-ß/Smad pathway. SIGNIFICANCE: These results suggest that HA in combination with DAG could significantly enhance the osteogenic differentiation of hAMSCs, potentially via the TGF-ß/Smad signalling pathway.


Assuntos
Âmnio/citologia , Diferenciação Celular/efeitos dos fármacos , Ácido Hialurônico/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células Cultivadas , Humanos , Ácido Hialurônico/química , Células-Tronco Mesenquimais/citologia , Peso Molecular
6.
Carbohydr Polym ; 219: 423-430, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151543

RESUMO

Colloidal polyaniline dispersions stabilized with biocompatible polysaccharides, sodium hyaluronate and chitosan (both with two different molecular weights), were successfully formulated. The colloids were characterized by UV-vis spectra, particle-size distributions and morphology, as well as by their biological properties in terms of cytotoxicity and antibacterial activity. Colloids containing both chitosan and hyaluronate showed only mild cytotoxicities, which were mainly governed by the concentration of conducting polyaniline in the colloid. Antibacterial activity of the samples, however, depended both on the type of polysaccharide and the ratio between the stabilizer and polyaniline mass. The colloid synthetized using 0.2 M aniline hydrochloride, 0.1 M ammonium persulfate, and 1 wt.% sodium hyaluronate of molecular weight of 1.8-2.1 × 106 exhibited the highest antibacterial activity against both gram positive and gram negative bacteria. This formulation, therefore, allowed for the formation of potentially stimuli-responsive antibacterial colloidal particles with low cytotoxicity.


Assuntos
Compostos de Anilina , Antibacterianos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Coloides , Ácido Hialurônico/química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Coloides/química , Coloides/farmacologia , Escherichia coli/efeitos dos fármacos , Camundongos , Células NIH 3T3 , Nanocompostos/química , Staphylococcus aureus/efeitos dos fármacos
7.
J Nanobiotechnology ; 17(1): 76, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217009

RESUMO

BACKGROUND: Molybdenum disulfide (MoS2) has been widely explored for biomedical applications due to its brilliant photothermal conversion ability. In this paper, we report a novel multifunctional MoS2-based drug delivery system (MoS2-SS-HA). By decorating MoS2 nanosheets with hyaluronic acid (HA), these functionalized MoS2 nanosheets have been developed as a tumor-targeting chemotherapeutic nanocarrier for near-infrared (NIR) photothermal-triggered drug delivery, facilitating the combination of chemotherapy and photothermal therapy into one system for cancer therapy. RESULTS: The nanocomposites (MoS2-SS-HA) generated a uniform diameter (ca. 125 nm), exhibited great biocompatibility as well as high stability in physiological solutions, and could be loaded with the insoluble anti-cancer drug erlotinib (Er). The release of Er was greatly accelerated under near infrared laser (NIR) irradiation, showing that the composites can be used as responsive systems, with Er release controllable through NIR irradiation. MTT assays and confocal imaging results showed that the MoS2-based nanoplatform could selectively target and kill CD44-positive lung cancer cells, especially drug resistant cells (A549 and H1975). In vivo tumor ablation studies prove a better synergistic therapeutic effect of the joint treatment, compared with either chemotherapy or photothermal therapy alone. CONCLUSION: The functionalized MoS2 nanoplatform developed in this work could be a potent system for targeted drug delivery and synergistic chemo-photothermal cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Dissulfetos/química , Portadores de Fármacos/química , Cloridrato de Erlotinib/farmacologia , Hipertermia Induzida , Molibdênio/química , Nanocompostos/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Cloridrato de Erlotinib/química , Feminino , Humanos , Ácido Hialurônico/química , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fototerapia
8.
Int J Nanomedicine ; 14: 2533-2542, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114189

RESUMO

Background: Drug delivery systems (DDS) capable of targeting both cell and organelle levels are highly desirable for effective cancer therapy. In this study, we developed a novel enzyme-responsive, multistage-targeted anticancer DDS based on mesoporous silica nanoparticles (MSNs), which possessed both CD44-targeting and mitochondrial-targeting properties. Materials and methods: Triphenylphosphine (TPP), a mitochondria-targeting compound, was grafted onto the surface of MSNs firstly. Then, Doxorubicin (Dox) was encapsulated into the pore of MSNs, followed by capping with tumor-targeting molecules hyaluronic acid (HA) through electrostatic interactions to form the final product consist of Dox loaded, TPP attached, HA capped mesoporous silica nanoparticles (MSN-DPH). Results: Our results suggested that MSN-DPH was preferentially taken up by cancer cells via CD44 receptor-mediated endocytosis. Moreover, MSN-DPH mainly accumulated in mitochondria owing to the mitochondrial-targeting ability of TPP. Degradation of HA by overexpressed HAase facilitated the release of Dox in cancer cells. Thus, MSN-DPH efficiently killed the cancer cells while exhibited much lower cytotoxicity to normal cells. Conclusion: This study demonstrates a promising multistage-targeted DDS for cancer chemotherapy.


Assuntos
Sistemas de Liberação de Medicamentos , Mitocôndrias/metabolismo , Nanopartículas/química , Neoplasias/patologia , Dióxido de Silício/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Ácido Hialurônico/química , Nanopartículas/ultraestrutura , Neoplasias/tratamento farmacológico , Porosidade
9.
Carbohydr Res ; 478: 25-32, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042589

RESUMO

Polysaccharide peptides (or protein-bound polysaccharides, PSPs) are commonly found in mushrooms and plants and possess important nutritional properties and health benefits. The pathogenic bacterium Streptococcus zooepidemicus does not inherently produce PSPs but secretes the capsular polysaccharide hyaluronan. However, in a previous investigation of the catalytic mechanism of UDP-glucose dehydrogenase (UGDH), a PSP of peptide-bound hyaluronan was found to be produced by S. zooepidemicus through the in vivo expression of a mutant of the gene encoding UGDH. In the present study, this hyaluronan-derived PSP was structurally characterized by FT-IR, NMR, and high-performance liquid chromatography-mass spectrometry (HPLC-MS), and the data confirmed that the polysaccharide backbone, hyaluronan, is covalently bound to the side-chain peptides via an amide linkage. More importantly, the bacterial production of a PSP via this genetic modification method should inspire further research on the in vitro enzymatic synthesis of PSPs or even naturally occurring polysaccharide derivatives and may provide a theoretical foundation for investigating the in vivo synthetic mechanism of PSPs.


Assuntos
Ácido Hialurônico/biossíntese , Proteoglicanas/biossíntese , Streptococcus equi/metabolismo , Configuração de Carboidratos , Ácido Hialurônico/química , Ácido Hialurônico/isolamento & purificação , Proteoglicanas/química , Proteoglicanas/isolamento & purificação , Streptococcus equi/genética
10.
Carbohydr Polym ; 216: 25-35, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047065

RESUMO

The unique physicochemical and functional characteristics of starch-based biomaterials and wound dressings have been proposed for several biomedical applications. Film dressings of cornstarch/hyaluronic acid/ ethanolic extract of propolis (CS/HA/EEP) were prepared by solvent-casting and characterized by attenuated total reflectance/Fourier transform infrared spectroscopy, scanning electron microscopy, gas chromatography/mass spectrometry, light transmission, opacity measurements, EEP release, equilibrium swelling, and in vitro and in vivo evaluations. The CS/HA/0.5%EEP film dressing exhibited higher antibacterial activity against Staphylococcus aureus (2.08 ± 0.14 mm), Escherichia coli (2.64 ± 0.18 mm), and Staphylococcus epidermidis (1.02 ± 0.15 mm) in comparison with the CS, CS/HA, and CS/HA/0.25%EEP films. Also, it showed no cytotoxicity for the L929 fibroblast cells. This wound dressing could effectively accelerate the wound healing process at Wistar rats' skin excisions. These results indicate that enrichment of cornstarch wound dressings with HA and EEP can significantly enhance their potential efficacy as wound dressing material.


Assuntos
Antibacterianos/farmacologia , Ácido Hialurônico/química , Curativos Oclusivos , Própole/farmacologia , Amido/química , Animais , Antibacterianos/química , Antibacterianos/toxicidade , Galinhas , Escherichia coli/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Ácido Hialurônico/toxicidade , Hidrólise , Muramidase/química , Própole/química , Própole/toxicidade , Ratos Wistar , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Amido/toxicidade , Cicatrização/efeitos dos fármacos
11.
Artif Cells Nanomed Biotechnol ; 47(1): 1710-1721, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31062604

RESUMO

A dual-layer biomimetic cartilage scaffold was prepared by mimicking the structural design, chemical cues and mechanical characteristics of mature articular cartilage. The surface layer was made from collagen (COL), chitosan (CS) and hyaluronic acid sodium (HAS). The transitional layer with microtubule array structure was prepared with COL, CS and silk fibroin (SF). The PLAG microspheres containing kartogenin (KGN) and the polylysine-heparin sodium nanoparticles containing TGF-ß1 (TPHNs) were constructed for the surface, transitional layer, respectively. The SEM result showed that the dual-layer composite scaffold had a double structure similar to natural cartilage. The vitro biocompatibility experiment showed that the biomimetic cartilage scaffold with orientated porous structure was more conducive to the proliferation and adhesion of BMSCs. A rabbit KOA cartilage defect model was established and biomimetic cartilage scaffolds were implanted in the defect area. Compared with the surface layer and transitional layer scaffolds group, the results of dual-layer biomimetic cartilage scaffold group showed that the defects had been completely filled, the boundary between new cartilage and surrounding tissue was difficult to identify, and the morphology of cells in repair tissue was almost in accordance with the normal cartilage after 16 weeks. All those results indicated that the biomimetic cartilage scaffold could effectively repair the defect of KOA, which is related to the fact that the scaffold could guide the morphology, orientation, and proliferation and differentiation of BMSCs. This work could potentially lead to the development of multilayer scaffolds mimicking the zonal organization of articular cartilage.


Assuntos
Materiais Biomiméticos/farmacologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Osteoartrite do Joelho/patologia , Tecidos Suporte/química , Animais , Materiais Biomiméticos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Colágeno/química , Fibroínas/química , Ácido Hialurônico/química , Masculino , Fenômenos Mecânicos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Porosidade , Coelhos , Propriedades de Superfície
12.
BMC Musculoskelet Disord ; 20(1): 196, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064359

RESUMO

BACKGROUND: High molecular weight (HMW) hyaluronic acid (HA) is a treatment option for knee osteoarthritis (OA). The efficacy of HMW-HA in knee OA is investigated extensively, but the effectiveness in patients in the working age is unknown. Nevertheless, the number knee OA patients in the working age is increasing. Surgical treatment options are less eligible in these patients and productivity losses are high. In this study the effectiveness of intra-articular HMW-HA added to regular non-surgical usual care in everyday clinical practice (UC) compared to UC over 52 weeks in symptomatic knee OA patients in the working age was investigated. METHODS: In this open labelled randomized controlled trial, subjects aged between 18 and 65 years with symptomatic knee OA (Kellgren and Lawrence I-III) were enrolled and randomized to UC + 3 weekly injections with HMW-HA (intervention) or UC only (control). The primary outcome was the between group difference in responders to therapy according to OMERACT-OARSI criteria after 52 weeks. These criteria include the domains pain, knee related function and patient's global assessment (PGA). Function was evaluated with the KOOS questionnaire. Pain was assessed with the Numeric Rating Scale. Secondary outcome comprised the between group difference on the individual responder domains, as analysed with a random effects model. Odds Ratios (OR) were calculated by logistic regression analysis. Sensitivity analyses were performed. RESULTS: In total, 156 subjects were included (intervention group 77, control group 79). Subjects in the intervention group (HMW-HA + UC) were more often responder compared to the controls (UC). Depending on whether pain during rest or pain during activity was included in the responder domains, 57.1% versus 34.2% (p = 0.006) and 54.5% versus 34.2% (p = 0.015) was responder to therapy respectively. The results of the secondary outcome analyses show that scores on individual responder domains over all follow-up moments were statistically significant in favour of the intervention group in the domains pain during rest (δ 0.8, 95%CI 0.2; 1.4, p = 0.010), knee related function (δ - 6.8, 95%CI -11.9; - 1.7, p = 0.010) and PGA (δ - 0.7, 95%CI -0.9; - 0.4, p < 0.0001). CONCLUSIONS: Intra-articular HMW-HA added to usual care is effective for knee OA in patients in the working age. TRIAL REGISTRATION: www.trialregister.nl , NTR1651, registered 2009-3-3.


Assuntos
Artralgia/terapia , Ácido Hialurônico/administração & dosagem , Osteoartrite do Joelho/terapia , Viscossuplementos/administração & dosagem , Adulto , Artralgia/diagnóstico , Artralgia/etiologia , Feminino , Seguimentos , Humanos , Ácido Hialurônico/química , Injeções Intra-Articulares , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peso Molecular , Países Baixos , Osteoartrite do Joelho/complicações , Medição da Dor , Qualidade de Vida , Resultado do Tratamento , Viscossuplementos/química , Adulto Jovem
13.
Phys Chem Chem Phys ; 21(19): 9845-9857, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31032510

RESUMO

All-atom molecular dynamics simulations have been used to investigate the adsorption of low molecular weight hyaluronic acid to lipid membranes. We have determined the interactions that govern the adsorption of three different molecular weight hyaluronic acid molecules (0.4, 3.8 & 15.2 kDa) to lipid bilayers that are representative of the surface-active phospholipid bilayers found in synovial joints. We have found that both direct hydrogen bonds and water-mediated interactions with the lipid headgroups play a key role in the binding of hyaluronic acid to the lipid bilayer. The water-mediated interactions become increasingly important in stabilising the adsorbed hyaluronic acid molecules as the molecular weight of hyaluronic acid increases. We also observe a redistribution of ions around bound hyaluronic acid molecules and the associated lipid headgroups, and that the degree of redistribution increases with the molecular weight of hyaluronic acid. By comparing this behaviour to that observed in simulations of the charge-neutral polysaccharide dextran (MW ∼ 15 kDa), we show that this charge redistribution leads to an increased alignment of the lipid headgroups with the membrane normal, and therefore to more direct and water-mediated interactions between hyaluronic acid and the lipid membrane. These findings provide a detailed understanding of the general structure of hyaluronic acid-lipid complexes that have recently been presented experimentally, as well as a potential mechanism for their enhanced tribological properties.


Assuntos
Ácido Hialurônico/química , Bicamadas Lipídicas/química , Líquido Sinovial/química , Simulação de Dinâmica Molecular , Estrutura Molecular
14.
Vasc Endovascular Surg ; 53(5): 379-386, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982448

RESUMO

INTRODUCTION: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid-polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. METHODS: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy-intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the -intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. RESULTS: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. CONCLUSIONS: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Artéria Carótida Primitiva/efeitos dos fármacos , Portadores de Fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Neointima , Polímeros/química , Sinvastatina/administração & dosagem , Túnica Íntima/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Administração Oral , Animais , Caproatos/química , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Artéria Carótida Primitiva/metabolismo , Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/fisiopatologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Composição de Medicamentos , Humanos , Ácido Hialurônico/química , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Lactonas/química , Micelas , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ratos Sprague-Dawley , Ácidos Siálicos/química , Sinvastatina/química , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Túnica Íntima/fisiopatologia
15.
Anal Bioanal Chem ; 411(15): 3321-3330, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30989271

RESUMO

Hyaluronic acid and its acrylate derivatives are important intermediates for various pharmaceutical, biomedical, and cosmetic applications due to their biocompatibility and viscoelasticity properties. However, these polymers are inherently difficult to characterize due to their significant heterogeneity regarding molar mass and chemical composition (degree of substitution, DS). The present study describes the development of a comprehensive online two-dimensional liquid chromatography (2D-LC) approach to characterize hyaluronic acid and its acrylate derivatives (DS ranging from 0.4 to 3.1) in terms of molar mass and degree of substitution. In the first dimension of the 2D-LC method, separation according to chemical composition/DS was achieved by using a stepwise solvent gradient and a reversed phase C8 column. Fractions from the first dimension were automatically transferred to the second dimension comprising size exclusion chromatographic separation of the fractions according to molar mass. It was found that the hyaluronic acid derivatives were broadly distributed with regard to both chemical composition and molar mass. Fractions with different degrees of substitution were identified, and their molar mass distributions were determined. The study proved that comprehensive 2D-LC is a powerful approach to reveal the complex nature of hyaluronic acid and its derivatives. Graphical abstract.


Assuntos
Acrilatos/química , Cromatografia Líquida/instrumentação , Ácido Hialurônico/análogos & derivados , Cromatografia em Gel/instrumentação , Cromatografia em Gel/métodos , Cromatografia Líquida/métodos , Cromatografia de Fase Reversa/instrumentação , Cromatografia de Fase Reversa/métodos , Desenho de Equipamento , Ácido Hialurônico/química , Peso Molecular , Solventes
16.
Int J Pharm ; 563: 445-456, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30965121

RESUMO

The aim of this study was to develop an innovative in situ gelling suspension for effective nasal delivery of fluticasone. Pectin, gellan gum and sodium hyaluronate were used as gelling/thickening agents, and Tween 80 as a suspending agent. The influence of the formulation and/or administration parameters on formulation sprayability and nasal deposition was explored with an appropriate experimental design with the range for parameters in the design obtained from previous research and domain knowledge. All formulations exhibited appropriate sprayability and instant gelation upon mixing with simulated nasal fluid exhibiting weak gel properties convenient for nasal delivery. Targeted turbinate deposition depended on administration and formulation parameters, including their interactions. Decrease in the administration angle from horizontal plane, increase in inspiratory flow and presence of sodium hyaluronate significantly increased deposition in turbinate region. Parameters in interactions included concentration of polymers, surfactant and fluticasone, as well as administration angle. Selected formulations with high turbinate deposition exhibited significant increase in viscosity upon gelation, showing potential to prolong the drug retention at the nasal mucosa. The highest effect on the gel viscosity, strength and fluticasone release profile was observed for gellan gum, thus recognised as crucial parameter for the optimisation of overall therapeutic effect.


Assuntos
Corticosteroides/administração & dosagem , Corticosteroides/química , Fluticasona/administração & dosagem , Fluticasona/química , Mucosa Nasal/metabolismo , Administração Intranasal , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Géis , Humanos , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Masculino , Pessoa de Meia-Idade , Modelos Anatômicos , Pectinas/administração & dosagem , Pectinas/química , Polissacarídeos Bacterianos/administração & dosagem , Polissacarídeos Bacterianos/química , Polissorbatos/administração & dosagem , Polissorbatos/química , Suspensões , Viscosidade
17.
ACS Appl Mater Interfaces ; 11(18): 16922-16933, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-30985111

RESUMO

The utilization of layer-by-layer composite nanoparticles fabricated from zein and hyaluronic acid (HA) for the codelivery of curcumin and quercetagetin was investigated. A combination of hydrophobic effects and hydrogen bonding was responsible for the interaction of zein with both curcumin and quercetagetin inside the nanoparticles. Electrostatic attraction and hydrogen bonding were mainly responsible for the layer-by-layer deposition of hyaluronic acid on the surfaces of the nanoparticles. The secondary structure of zein was altered by the presence of the two nutraceuticals and HA. The optimized nanoparticle formulation contained relatively small particles ( d = 231.2 nm) that were anionic (ζ = -30.5 mV). The entrapment efficiency and loading capacity were 69.8 and 2.5% for curcumin and 90.3 and 3.5% for quercetagetin, respectively. Interestingly, the morphology of the nanoparticles depended on their composition. In particular, they changed from coated nanoparticles to nanoparticle-filled microgels as the level of HA increased. The nanoparticles were effective at reducing light and thermal degradation of the two encapsulated nutraceuticals and remained physically stable throughout 6 months of long-term storage. In addition, the nanoparticles were shown to slowly release the nutraceuticals under simulated gastrointestinal tract conditions, which may help improve their oral bioavailability. In summary, we have shown that layer-by-layer composite nanoparticles based on zein and HA are an effective codelivery system for two bioactive compounds.


Assuntos
Disponibilidade Biológica , Curcumina/química , Flavonas/química , Nanopartículas/química , Ânions/química , Dicroísmo Circular , Curcumina/farmacologia , Flavonas/farmacologia , Humanos , Ácido Hialurônico/química , Ligações de Hidrogênio , Cinética , Estrutura Molecular , Nanopartículas/administração & dosagem , Imagem Óptica , Espectroscopia de Infravermelho com Transformada de Fourier , Zeína/química
18.
Appl Microbiol Biotechnol ; 103(11): 4363-4375, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968163

RESUMO

Hyaluronic acid (HA) is a biopolymer with wide biomedical and cosmetic applications, wherein the molecular weight of HA (MWHA) is an important quality parameter that determines its suitability for the targeted application. To produce HA with desired molecular weight, it is important to identify parameters that offer tunability and control of MWHA at a desired value during fermentation. In this work, two tunable parameters, viz. glucose concentration and combination of HA biosynthetic genes expressed, were used to produce HA of different molecular weights. Three recombinant strains of Lactococcus lactis were constructed, using a combination of the has-operon genes from Streptococcus zooepidemicus (hasA, hasB, hasE) and the α-phosphoglucomutase gene (pgmA) from L. lactis. Batch fermentations of these recombinant strains at different initial glucose concentrations enabled production of HA with different molecular weights. Co-expression of hasABE was observed to be particularly effective in improving the MWHA. It was observed during batch fermentations of all these recombinant L. lactis cultures that the MWHA decreases steadily during the later part of the fermentation and the final value is 19-43% lower than the peak MWHA produced. Analysis of the fermentation data showed that the decrease in MWHA correlated strongly with the decrease in specific productivity of the culture. To overcome this decrease in MWHA, a glucostat strategy was successfully devised which could maintain a high value of specific productivity throughout the glucostat phase and result in constant-MW HA production. Glucostat processes were designed with the three recombinant L. lactis strains at two different glucose concentrations to produce constant molecular weight HA ranging from 0.4 to 1.4 MDa. This is the first report of its kind in literature that demonstrates production of controlled MW HA over a wide range by using a combination of tunable parameters and suitable process control strategies.


Assuntos
Adjuvantes Imunológicos/biossíntese , Adjuvantes Imunológicos/química , Ácido Hialurônico/biossíntese , Ácido Hialurônico/química , Lactococcus lactis/genética , Lactococcus lactis/metabolismo , Peso Molecular , Fermentação , Expressão Gênica , Engenharia Metabólica/métodos , Técnicas Microbiológicas/métodos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Streptococcus equi/enzimologia , Streptococcus equi/genética
19.
Mater Sci Eng C Mater Biol Appl ; 101: 487-498, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029343

RESUMO

Wound dressing is distinctly important to wound healing, because it can not only protect wound from external disturbance, but also provide an ideal environment for wound closure. However, most of wound dressings need additional active ingredients to assist the repair process. In order to develop new dressings that can present spontaneous healing activity, herein, an injectable hydrogel consisted of collagen I and hyaluronic acid has been designed to mimic extracellular matrix for vascular cells growing and wound closure. The preparation of hydrogel (COL-HA) was realized through in situ coupling of phenol moieties of collagen I-hydroxybenzoic acid (COL-P) and hyaluronic-acid-tyramine (HA-Tyr) through horseradish peroxidase (HRP). The physical structure and properties were characterized, and the biological performances were analyzed. COL-HA hydrogel presented porous structure that contributed to the exchange of gas, medium and nutrition. Human microvascular endothelial cells (HMEC) and fibroblasts (COS-7) cultured within this hydrogel showed significant proliferation behaviors. More importantly, a certain level of vascular endothelial growth factor (VEGF) was observed in HMEC cultured hydrogel, which led to the possibility of vascular regeneration. For the full-thickness wound, the healing ratio and validity of wound treated with COL-HA hydrogel were higher than commercial drug and individual COL-P hydrogel, HA-Tyr hydrogel groups, since collagen and hyaluronic acid made joint efforts to improve wound repair.


Assuntos
Biomimética/métodos , Colágeno/química , Colágeno/farmacologia , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Hidrogéis/química , Cicatrização/efeitos dos fármacos , Animais , Células COS , Linhagem Celular , Cercopithecus aethiops , Humanos
20.
Eur J Pharm Sci ; 133: 251-263, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30959103

RESUMO

Most of nanomaterials composed of hyaluronic acid (HA) used for drug targeting are spherical. In this investigation, we suggest that the morphology of HA nanomaterials could be considered as a new parameter to control their interactions with cells. However, designing nanomaterials with elongated morphology and controlled size is still challenging. The aim of this study was to design and to characterize non-spherical HA nanomaterials with flat surfaces and to highlight main parameters controlling the size. Nanoparticles were formed by mixing HA hydrophobically-modified with palmitoyl groups (PA-HA) and α-cyclodextrin in water. These particles, called nano-platelets, had symmetrical hexagonal shape, flattened surfaces and were 9-fold larger than thick. Small nano-platelets with well-defined shape were obtained with low PA-HA degree of substitution, by adding 5 wt% of α-cyclodextrin solution for a fixed concentration of PA-HA (1 wt%) (569 nm) and for long stirring periods (735-538 nm for 72-168 h). PA-HA was successfully conjugated to a near-infrared fluorescent probe suitable for in vitro and in vivo experiments without nano-platelet size and surface charge modification. This is the first report showing the design of non-spherical and flattened HA nano-platelets that could be used to study the impact of nanomaterial shape on molecular interactions with cells.


Assuntos
Ácido Hialurônico/química , Nanopartículas/química , Corantes Fluorescentes/química , Ácido Palmítico/química , Tamanho da Partícula , alfa-Ciclodextrinas/química
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