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1.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807864

RESUMEN

INTRODUCTION: Chronic inflammation and impaired neovascularization play critical roles in delayed wound healing in diabetic patients. To overcome the limitations of current diabetic wound (DBW) management interventions, we investigated the effects of a catechol-functionalized hyaluronic acid (HA-CA) patch combined with adipose-derived mesenchymal stem cells (ADSCs) in DBW mouse models. METHODS: Diabetes in mice (C57BL/6, male) was induced by streptozotocin (50 mg/kg, >250 mg/dL). Mice were divided into four groups: control (DBW) group, ADSCs group, HA-CA group, and HA-CA + ADSCs group (n = 10 per group). Fluorescently labeled ADSCs (5 × 105 cells/100 µL) were transplanted into healthy tissues at the wound boundary or deposited at the HA-CA patch at the wound site. The wound area was visually examined. Collagen content, granulation tissue thickness and vascularity, cell apoptosis, and re-epithelialization were assessed. Angiogenesis was evaluated by immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blot. RESULTS: DBW size was significantly smaller in the HA-CA + ADSCs group (8% ± 2%) compared with the control (16% ± 5%, p < 0.01) and ADSCs (24% ± 17%, p < 0.05) groups. In mice treated with HA-CA + ADSCs, the epidermis was regenerated, and skin thickness was restored. CD31 and von Willebrand factor-positive vessels were detected in mice treated with HA-CA + ADSCs. The mRNA and protein levels of VEGF, IGF-1, FGF-2, ANG-1, PIK, and AKT in the HA-CA + ADSCs group were the highest among all groups, although the Spred1 and ERK expression levels remained unchanged. CONCLUSIONS: The combination of HA-CA and ADSCs provided synergistic wound healing effects by maximizing paracrine signaling and angiogenesis via the PI3K/AKT pathway. Therefore, ADSC-loaded HA-CA might represent a novel strategy for the treatment of DBW.


Asunto(s)
Tejido Adiposo/metabolismo , Vendajes , Diabetes Mellitus Experimental/terapia , Angiopatías Diabéticas/terapia , Ácido Hialurónico , Trasplante de Células Madre , Células Madre/metabolismo , Cicatrización de Heridas , Heridas y Traumatismos/terapia , Tejido Adiposo/patología , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Angiopatías Diabéticas/metabolismo , Angiopatías Diabéticas/patología , Femenino , Humanos , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Masculino , Ratones , Células Madre/patología , Heridas y Traumatismos/metabolismo , Heridas y Traumatismos/patología
2.
Int J Mol Sci ; 22(5)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33808946

RESUMEN

Bone tissue engineering is a rapidly developing, minimally invasive technique for regenerating lost bone with the aid of biomaterial scaffolds that mimic the structure and function of the extracellular matrix (ECM). Recently, scaffolds made of electrospun fibers have aroused interest due to their similarity to the ECM, and high porosity. Hyaluronic acid (HA) is an abundant component of the ECM and an attractive material for use in regenerative medicine; however, its processability by electrospinning is poor, and it must be used in combination with another polymer. Here, we used electrospinning to fabricate a composite scaffold with a core/shell morphology composed of polycaprolactone (PCL) polymer and HA and incorporating a short self-assembling peptide. The peptide includes the arginine-glycine-aspartic acid (RGD) motif and supports cellular attachment based on molecular recognition. Electron microscopy imaging demonstrated that the fibrous network of the scaffold resembles the ECM structure. In vitro biocompatibility assays revealed that MC3T3-E1 preosteoblasts adhered well to the scaffold and proliferated, with significant osteogenic differentiation and calcium mineralization. Our work emphasizes the potential of this multi-component approach by which electrospinning, molecular self-assembly, and molecular recognition motifs are combined, to generate a leading candidate to serve as a scaffold for bone tissue engineering.


Asunto(s)
Diferenciación Celular , Ácido Hialurónico/química , Osteoblastos/citología , Osteogénesis , Fragmentos de Péptidos/química , Poliésteres/química , Andamios del Tejido/química , Animales , Materiales Biocompatibles/química , Proliferación Celular , Ratones
3.
Int J Nanomedicine ; 16: 2373-2388, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33790555

RESUMEN

Aim: The metastasis of breast cancer is an important cause of tumor recurrence. This study highlights that tyrosine kinase inhibitors dasatinib (DAS) and rosiglitazone (ROZ) inhibit tumor growth and reduce the occurrence of tumor cell metastasis. Due to the poor water solubility, short half-time in the body of DAS and ROZ, which increases the difficulty of tumor treatment, as well as the demand for nano-drug delivery systems for organ-specific therapies. Methods: Hyaluronic acid (HA) and DAS are bonded by a pH-sensitive ester bond to form an HA-DAS polymer. Then, ROZ was added as the core, D-A-tocopherol polydiethylene glycol isosuccinate (TPGS) and HA-DAS were used as carriers to form HA-DAS and TPGS mixed micelle system loaded with ROZ (THDR-NPs). The size and structure of THDR-NPs were characterized, the drug release, stability and biosafety of THDR-NPs were studied. In vitro, the cytotoxicity, targeting effect and tumor metastasis inhibition of THDR-NPs were evaluated in human breast cancer cell lines. In addition, the selective potency of designed THDR-NPs in depleting was further verified in vivo in the tumor-bearing nude mice model. Results: The designed THDR-NPs have a particle size of less than 100 nm, good stability, biological safety and sustained release, and showed strong therapeutic effects on breast cancer models in vitro and in vivo. Moreover, it has been proved that THDR-NPs have the ability to inhibit tumor metastasis. Conclusion: DAS and ROZ were designed into micelles, the efficacy of THDR-NPs was higher than that of free drugs. These results indicate that nanoparticles have a good application prospect in the treatment of tumor metastasis.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Animales , Peso Corporal/efectos de los fármacos , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Dasatinib/administración & dosificación , Dasatinib/farmacocinética , Dasatinib/farmacología , Dasatinib/uso terapéutico , Portadores de Fármacos/química , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Femenino , Hemólisis/efectos de los fármacos , Humanos , Ácido Hialurónico/química , Ratones Endogámicos BALB C , Ratones Desnudos , Micelas , Nanopartículas/química , Nanopartículas/ultraestructura , Tamaño de la Partícula , Espectroscopía de Protones por Resonancia Magnética , Ratas Sprague-Dawley , Rosiglitazona/farmacocinética , Rosiglitazona/farmacología , Rosiglitazona/uso terapéutico , Electricidad Estática , Distribución Tisular/efectos de los fármacos , Carga Tumoral/efectos de los fármacos
4.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803116

RESUMEN

Recent clinical findings suggest that mucomimetic polymers (MMP) can alter not only the texture of the aqueous tear but also the spreading and structure of the tear film (TF) lipid layer, thereby allowing for their synchronized performance in vivo. Thus, we aimed to evaluate in vitro (i) the capability of pharmaceutically applicable MMP to ensure the formation of post-evaporative ferning patterns (a characteristic feature of the "healthy" tear colloid) and (ii) the MMP interactions with human meibum films accessed in the course of blink-like deformations via Langmuir surface balance and Brewster angle microscopy (BAM). Four MMP were used- hyaluronic acid (HA), cross-linked hyaluronic acid (CHA), carboxymethyl cellulose (CMC) and gellan gum (GG)- at the concentrations of 0.0001%, 0.001%, 0.01%, 0.05% and 0.1%. Significant differences were observed in the MMP fern formation capability: CHA (≥0.001%) > HA (≥0.01%) = CMC (≥0.01%) > GG (≥0.05%). All MMP affected the spreading of meibum, with BAM micrographs revealing thickening of the films. CHA was particularly efficient, showing concentration-dependent enhancement of tear ferning and of meibomian layer structure, surfactant properties and viscoelasticity. Thus, endogenous and exogenous MMP may play key roles for the concerted action of the TF layers at the ocular surface, revealing novel routes for TF-oriented therapeutic applications.


Asunto(s)
Materiales Biomiméticos/química , Glándulas Tarsales/química , Lágrimas/química , Adulto , Carboximetilcelulosa de Sodio/química , Femenino , Humanos , Ácido Hialurónico/química , Glándulas Tarsales/metabolismo , Lágrimas/metabolismo , Viscosidad
5.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33803999

RESUMEN

The purpose of the present pilot study was to evaluate the effect of a hydrogel composed of hyaluronic acid (HA) and platelet-rich plasma (PRP) as a carrier for human mesenchymal stem cells (hMSCs) for intervertebral disc (IVD) regeneration using a disc organ culture model. HA was mixed with batroxobin (BTX) and PRP to form a hydrogel encapsulating 1 × 106 or 2 × 106 hMSCs. Bovine IVDs were nucleotomized and filled with hMSCs suspended in ~200 µL of the PRP/HA/BTX hydrogel. IVDs collected at day 0 and nucleotomized IVDs with no hMSCs and/or hydrogel alone were used as controls. hMSCs encapsulated in the hydrogel were also cultured in well plates to evaluate the effect of the IVD environment on hMSCs. After 1 week, tissue structure, scaffold integration, hMSC viability and gene expression of matrix and nucleus pulposus (NP) cell markers were assessed. Histological analysis showed a better preservation of the viability of the IVD tissue adjacent to the gel in the presence of hMSCs (~70%) compared to the hydrogel without hMSCs. Furthermore, disc morphology was maintained, and the hydrogel showed signs of integration with the surrounding tissues. At the gene expression level, the hydrogel loaded with hMSCs preserved the normal metabolism of the tissue. The IVD environment promoted hMSC differentiation towards a NP cell phenotype by increasing cytokeratin-19 (KRT19) gene expression. This study demonstrated that the hydrogel composed of HA/PRP/BTX represents a valid carrier for hMSCs being able to maintain a good cell viability while stimulating cell activity and NP marker expression.


Asunto(s)
Ácido Hialurónico/farmacología , Degeneración del Disco Intervertebral/terapia , Disco Intervertebral/trasplante , Queratina-19/genética , Trasplante de Células Madre Mesenquimatosas , Animales , Batroxobina/farmacología , Bovinos , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ácido Hialurónico/química , Hidrogeles/química , Hidrogeles/farmacología , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/patología , Células Madre Mesenquimatosas/citología , Núcleo Pulposo/crecimiento & desarrollo , Núcleo Pulposo/trasplante , Técnicas de Cultivo de Órganos , Plasma Rico en Plaquetas/química
6.
Int J Nanomedicine ; 16: 1377-1390, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33658778

RESUMEN

Background: Vascular drug delivery becomes a promising direction in the development of novel therapeutic strategies in the treatment of cardiovascular pathologies, such as hypertension. However, targeted delivery of hydrophobic substances, with poor bioavailability, remains a challenge. Here, we described the hypotensive effects of a low dose of curcumin delivered to the vascular wall using hyaluronic acid-based nanocapsules. Methods: The group of hypertensive TGR(m-Ren2)27 rats, was administrated respectively with the vehicle, curcumin solution or curcumin delivered using hyaluronic acid-based nanocapsules (HyC12-Cur), for 7 days each, maintaining the wash-out period between treatments. Arterial blood pressure (systolic - SBP, diastolic - DBP) and heart rate (HR) were monitored continuously using a telemetry system (Data Science International), and Mean Arterial Pressure (MAP) was calculated from SBP and DBP. Results: In hypertensive rats, a low dose of curcumin (4.5 mg/kg) administrated in HyC12-Cur for 7 days resulted in a gradual inhibition of SBP, DBP and MAP increase without an effect on HR. At the end of HyC12-Cur - based treatment changes in SBP, DBP and MAP amounted to -2.0±0.8 mmHg, -3.9±0.7 mmHg and -3.3±0.7 mmHg, respectively. In contrast, the administration of a curcumin solution (4.5 mg/kg) did not result in a significant hypotensive effect and the animals constantly developed hypertension. Vascular delivery of capsules with curcumin was confirmed using newly developed fluorine-rich nanocapsules (HyFC10-PFOB) with a shell based on a HA derivative and similar size as HyC12-Cur. HyFC10-PFOB gave fluorine signals in rat aortas analyzed ex vivo with a 19F NMR technique after a single intragastric administration. Conclusion: These results suggest that nanocapsules based on hyaluronic acid, the ubiquitous glycosaminoglycan of the extracellular matrix and an integral part of endothelial glycocalyx, may represent a suitable approach to deliver hydrophobic, poorly bioavailable compounds, to the vascular wall.


Asunto(s)
Curcumina/administración & dosificación , Curcumina/uso terapéutico , Ácido Hialurónico/química , Hipertensión/tratamiento farmacológico , Nanocápsulas/química , Administración Oral , Animales , Aorta/efectos de los fármacos , Aorta/patología , Presión Sanguínea/efectos de los fármacos , Curcumina/farmacología , Diástole/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Flúor/química , Frecuencia Cardíaca/efectos de los fármacos , Hidrodinámica , Interacciones Hidrofóbicas e Hidrofílicas , Hipertensión/fisiopatología , Espectroscopía de Resonancia Magnética , Masculino , Tamaño de la Partícula , Ratas , Electricidad Estática , Sístole/efectos de los fármacos
7.
Int J Nanomedicine ; 16: 1743-1755, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33688189

RESUMEN

Background: As a therapeutic target for cancer treatment, HSP90 has been explored extensively. However, the significant side effects of the HSP90 inhibitor 17AAG have limited its clinical use. Methods: In this study, we used hyaluronic acid (HA)-decorated DOTAP-PLGA hybrid nanoparticles (HA-DOTAP-PLGA NPs) as 17AAG-delivery carriers for targeted colon cancer therapy. Results: Different methods were used to characterize the successful fabrication of these hybrid PLGA NPs. Our results demonstrated that internalization of HA-NPs in colon cancer cells was governed by CD44receptor-mediated endocytosis. Annexin V-propidium iodide staining experiments revealed that cell apoptosis induced by HA-NPs-17AAG in colon cancer cells was more efficient than free 17AAG. In two animal models used to screen anticancer efficacy (Luc-HT29 subcutaneous xenograft and AOM/DSS-induced orthotopic tumor model), HA-NPs-17AAG significantly inhibited xenograft and orthotopic tumor growth, demonstrating HA-NPs-17AAG had much better therapeutic efficiency than free 17AAG. It is worth noting that great biocompatibility of HA-DOTAP-PLGA NPs was observed both in vitro and in vivo. Conclusion: Our research offers a preclinical proof of concept for colon cancer therapy with DOTAP-PLGA NPs as a creative drug-delivery system.


Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Ácido Hialurónico/química , Nanopartículas/química , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzoquinonas/farmacología , Materiales Biocompatibles/química , Línea Celular Tumoral , Neoplasias del Colon/patología , Endocitosis/efectos de los fármacos , Ácidos Grasos Monoinsaturados/química , Fluorescencia , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Receptores de Hialuranos/metabolismo , Lactamas Macrocíclicas/farmacología , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/ultraestructura , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Compuestos de Amonio Cuaternario/química , Tejido Subcutáneo/efectos de los fármacos , Tejido Subcutáneo/patología
8.
Carbohydr Polym ; 260: 117777, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33712133

RESUMEN

The combination of alginate, hyaluronic acid and multivalent ions have been reported to form alginate-hyaluronic acid ionic-crosslinking hydrogels for biomedical applications. However, injectable alginate-hyaluronic acid ionic-crosslinking hydrogels with satisfactory shear-thinning property have rarely been reported. In this study, we successfully developed an ionic-crosslinked alginate-hyaluronic acid hydrogel by simple assembly of alginate-hyaluronic acid mixture and Fe3+ complex. This hydrogel could fully recover within seconds after damaged, while displayed shear thinning behavior and good injectability which were contributed by the reversible and dynamic metal-ligand interactions formed via ferric ions and carboxyl groups of the polymers. Moreover, the local degradation of this hydrogel giving the hydrogel sustained ferric ions release property, of which led to potential long-term antibacterial activities against multiple types of bacteria including gram-negative Escherichia coli and gram-positive Staphylococcus aureus, as well as representative oral pathogenic bacteria Streptococcus mutans and Porphyromonas gingivalis.


Asunto(s)
Alginatos/química , Antiinfecciosos/química , Compuestos Férricos/química , Ácido Hialurónico/química , Hidrogeles/química , Animales , Antiinfecciosos/farmacología , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Femenino , Compuestos Férricos/metabolismo , Humanos , Hidrogeles/farmacología , Ratones , Ratones Endogámicos BALB C , Porphyromonas/efectos de los fármacos , Reología , Piel/efectos de los fármacos , Piel/patología , Staphylococcus aureus/efectos de los fármacos , Streptococcus mutans/efectos de los fármacos
9.
Carbohydr Polym ; 260: 117780, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33712136

RESUMEN

In this study, we prepared a biomimetic hyaluronic acid oligosaccharides (oHAs)-based composite scaffold to develop a bone tissue-engineered scaffold for stimulating osteogenesis and endothelialization. The functional oHAs products were firstly synthesized, namely collagen/hyaluronic acid oligosaccharides/hydroxyapatite (Col/oHAs/HAP), chitosan/hyaluronic acid oligosaccharides (CTS/oHAs), and then uniformly distributed in poly (lactic-co-glycolic acid) (PLGA) solution followed by freeze-drying to obtain three-dimensional interconnected scaffolds as temporary templates for bone regeneration. The morphology, physicochemical properties, compressive strength, and degradation behavior of the fabricated scaffolds, as well as in vitro cell responses seeded on these scaffolds and in vivo biocompatibility, were investigated to evaluate the potential for bone tissue engineering. The results indicated that the oHAs-based scaffolds can promote the attachment of endothelial cells, facilitate the osteogenic differentiation of MC3T3-E1 and BMSCs, and have ideal biocompatibility and tissue regenerative capacity, suggesting their potential to serve as alternative candidates for bone tissue engineering applications.


Asunto(s)
Materiales Biocompatibles/química , Quitosano/química , Colágeno/química , Ingeniería de Tejidos , Animales , Materiales Biocompatibles/farmacología , Diferenciación Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Durapatita/química , Ácido Hialurónico/química , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Oligosacáridos/química , Osteoblastos/citología , Osteoblastos/metabolismo , Osteogénesis/efectos de los fármacos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Andamios del Tejido/química
10.
Molecules ; 26(4)2021 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-33672365

RESUMEN

Chitosan is industrially acquired by the alkaline N-deacetylation of chitin. Chitin belongs to the ß-N-acetyl-glucosamine polymers, providing structure, contrary to α-polymers, which provide food and energy. Another ß-polymer providing structure is hyaluronan. A lot of studies have been performed on chitosan to explore its industrial use. Since chitosan is biodegradable, non-toxic, bacteriostatic, and fungistatic, it has numerous applications in medicine. Hyaluronan, one of the major structural components of the extracellular matrix in vertebrate tissues, is broadly exploited in medicine as well. This review summarizes the main areas where these two biopolymers have an impact. The reviewed areas mostly cover most medical applications, along with non-medical applications, such as cosmetics.


Asunto(s)
Quitosano/química , Ácido Hialurónico/química , Humanos , Medicina
11.
Carbohydr Polym ; 260: 117803, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33712151

RESUMEN

Biofilm-related infections and contamination of biomaterials are major problems in the clinic. These contaminations are frequently caused by Staphylococcus aureus and are a pressing issue for implantable devices, catheters, contact lenses, prostheses, and wound dressings. Strategies to decrease contamination and biofilm related infections are vital for the success of implantable biomaterials. In this context, hyaluronic acid (HA), a naturally derived carbohydrate polymer, known to be biocompatible, degradable, and immunomodulatory, has shown some antimicrobial activity effects. Due to its poor structural stability, crosslinking strategies, and the incorporation of reinforcing fibres in HA gels is required to produce tailored gels for varying applications. Whilst carbon-based reinforcing materials, such as carbon nanofibers (CNF), present some intrinsic antimicrobial activity related to their high surface area, herein, a crosslinking strategy to enhance the mechanical properties and regulate the rate of degradation of HA is presented. We utilise bis-(ß-isocyanatoethyl) disulphide (BIED) as the crosslinker with the gel reinforced using 0.25 wt% CNF. The effects of CNF and BIED on the structural, mechanical, thermal, and swelling behaviour are examined. These new HA derivatives exhibit excellent mechanical properties and are capable of withstanding physiological stresses in vivo. Antimicrobial activity of the HA derivatives were tested against Staphylococcus aureus and the results reveal antibacterial effect. These carbohydrate based materials have potential application on surfaces within clinical settings where staphylococcal contamination is currently an issue.


Asunto(s)
Antibacterianos/química , Ácido Hialurónico/química , Animales , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/química , Geles/química , Ácido Hialurónico/farmacología , Ratones , Células 3T3 NIH , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , Temperatura , Resistencia a la Tracción
12.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-33669232

RESUMEN

Tracer diffusion coefficients obtained from the Taylor dispersion technique at 25.0 °C were measured to study the influence of sodium, ammonium and magnesium salts at 0.01 and 0.1 mol dm-3 on the transport behavior of sodium hyaluronate (NaHy, 0.1%). The selection of these salts was based on their position in Hofmeister series, which describe the specific influence of different ions (cations and anions) on some physicochemical properties of a system that can be interpreted as a salting-in or salting-out effect. In our case, in general, an increase in the ionic strength (i.e., concentrations at 0.01 mol dm-3) led to a significant decrease in the limiting diffusion coefficient of the NaHy 0.1%, indicating, in those circumstances, the presence of salting-in effects. However, the opposite effect (salting-out) was verified with the increase in concentration of some salts, mainly for NH4SCN at 0.1 mol dm-3. In this particular salt, the cation is weakly hydrated and, consequently, its presence does not favor interactions between NaHy and water molecules, promoting, in those circumstances, less resistance to the movement of NaHy and thus to the increase of its diffusion (19%). These data, complemented by viscosity measurements, permit us to have a better understanding about the effect of these salts on the transport behaviour of NaHy.


Asunto(s)
Aniones/química , Cationes/química , Ácido Hialurónico/química , Agua/química , Sulfato de Amonio/química , Transporte Biológico , Difusión , Cloruro de Litio/química , Sulfato de Magnesio/química , Concentración Osmolar , Sales (Química)/química , Cloruro de Sodio/química , Soluciones , Sulfatos/química , Temperatura , Tiocianatos/química , Viscosidad
13.
Carbohydr Polym ; 261: 117846, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33766342

RESUMEN

In the clinical treatment of cancer, improving the effectiveness and targeting of drugs has always been a bottleneck problem that needs to be solved. In this contribution, inspired by the targeted inhibition on cancer from combination application of disulfiram and divalent copper ion (Cu2+), we optimized the concentration of disulfiram and Cu2+ ion for inhibiting esophageal cancer cells, and loaded them in hyaluronic acid (HA)/polyethyleneimine (PEI) nanoparticles with specific scales, in order to improve the effectiveness and targeting of drugs. The in vitro cell experiments demonstrated that more drug loaded HA/PEI nanoparticles accumulated to the esophageal squamous cell carcinoma (Eca109) and promoted higher apoptosis ratio of Eca109. Both in vitro and in vivo biological assessment verified that the disulfiram/Cu2+ loaded HA/PEI nanoparticles promoted the apoptosis of cancer cells and inhibited the tumor proliferation, but had no toxicity on other normal organs.


Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Cobre/administración & dosificación , Disulfiram/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Ácido Hialurónico/química , Nanopartículas/química , Polietileneimina/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Células Cultivadas , Cobre/farmacocinética , Disulfiram/farmacocinética , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Portadores de Fármacos/uso terapéutico , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Iones Pesados , Humanos , Ácido Hialurónico/síntesis química , Ácido Hialurónico/uso terapéutico , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/uso terapéutico , Polietileneimina/síntesis química , Polietileneimina/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Carbohydr Polym ; 261: 117873, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33766360

RESUMEN

The natural mucus cover has been a major obstacle to prevent enterocyte targeting particles from contact with the receptors. Thus, mucus penetration and intestinal targeting should be designed into one system. Based on the concept that biotin specifically recognizes epithelium receptors, enterocyte targeting muco-inert nanocomplexes were designed. Firstly, biotinylated chitosan (CS-Biotin) copolymers with different degree of substitution were synthesized and characterized. The nanocomplexes between CS-Biotin and insulin were prepared via self-assembly method. Thereafter, the nanocomplexes were fabricated by coating with various molecular weight hyaluronic acid (HA), which improved penetration efficiency in the mucus layer and small intestine in a HA molecular weight dependent manner. In vivo study indicated that hypoglycemic effect of the nanocomplexes was biotin modification degree and HA molecular weight dependent, with HA (200)-coated CS-Biotin21.8%/Insulin polyelectrolyte complex presenting the best performance. In conclusion, biotin decorated muco-inert nanocomplexes with HA coating are a promising platform for oral insulin delivery.


Asunto(s)
Biotina/metabolismo , Portadores de Fármacos/síntesis química , Sistemas de Liberación de Medicamentos/métodos , Enterocitos/metabolismo , Insulina/administración & dosificación , Moco/metabolismo , Administración Oral , Animales , Biotina/química , Permeabilidad de la Membrana Celular/efectos de los fármacos , Células Cultivadas , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapéutico , Enterocitos/efectos de los fármacos , Ácido Hialurónico/química , Ácido Hialurónico/metabolismo , Hipoglucemiantes/administración & dosificación , Insulina/farmacocinética , Absorción Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Moco/efectos de los fármacos , Nanopartículas/química , Nanopartículas/metabolismo , Nanopartículas/uso terapéutico , Polímeros/química , Polímeros/farmacocinética , Polímeros/uso terapéutico , Ratas , Ratas Sprague-Dawley , Porcinos
15.
Int J Nanomedicine ; 16: 1005-1019, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33603365

RESUMEN

Purpose: Development of hyaluronic acid conjugated metformin-phospholipid sonocomplexes (HA-MPS), a biphasic complexation product compiled for enhancing both the lipophilicity and targeting potential of Metformin (MET) to CD44 receptors on pancreatic cancer. Methods: MET was chemically conjugated to hyaluronic acid (HA) via amide coupling reaction. Then, the HA conjugated MET was physically conjugated to Lipoid™S100 via ultrasound irradiation. A combined D-optimal design was implemented to statistically optimize formulation variables. The HA-MPS were characterized through solubility studies, partition coefficient, drug content uniformity, particle size and zeta potential. The optimized HA-MPS was tested via proton nuclear magnetic resonance, infrared spectroscopy to elucidate the nature of physicochemical interactions in the complex which was further scrutinized on molecular level via molecular docking and dynamic simulation. Results: The solubility and partition studies showed a lipophilicity enhancement up to 67 folds as they adopted inverted micelles configuration based on the packing parameter hypothesis. The optimized HA-MPS showed 11.5 folds lower IC50, extra 25% reduction in oxygen consumption rate, better reduction in hypoxia-inducible factor and reactive oxygen species in MiaPaCa-2 cells. Conclusion: These results proved better internalization of MET which was reflected by abolishing hypoxic tumour microenvironment, a mainstay toward a normoxic and less resistant pancreatic cancer.


Asunto(s)
Ácido Hialurónico/química , Metformina/farmacología , Fosfolípidos/química , Sonicación , Hipoxia Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , 1-Octanol/química , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Glucosa/farmacología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Concentración 50 Inhibidora , Micelas , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Consumo de Oxígeno/efectos de los fármacos , Neoplasias Pancreáticas/patología , Tamaño de la Partícula , Espectroscopía de Protones por Resonancia Magnética , Especies Reactivas de Oxígeno/metabolismo , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Agua/química
16.
Molecules ; 26(1)2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33401465

RESUMEN

Two approaches for the synthesis of the thiodisaccharide ß-S-GlcA(1→3)ß-S-AllNAc are described here. The target disaccharide was a C-3 epimer and thio-analogue of the hyaluronic acid repetitive unit, tuned with a thiopropargyl anomeric group for further click conjugation. Thus, we analysed and tested two convenient sequences, combining the two key steps required to introduce the thioglycosidic bonds and consequently reach the target molecule: the SN2 substitution of a good leaving group (triflate) present at C-3 of a GlcNAc derivative and the introduction of the anomeric thiopropargyl substituent. The use of a 2-azido precursor showed to be a convenient substrate for the SN2 step. Nevertheless, further protecting group manipulation and the introduction of the thiopropargyl anomeric residue were then required. This approach showed to provide access to a variety of thiodisaccharide derivatives as interesting building blocks for the construction of neoglycoconjugates.


Asunto(s)
Disacáridos/química , Ácido Hialurónico/química , Disacáridos/síntesis química , Ácido Hialurónico/síntesis química
17.
Int J Mol Sci ; 22(2)2021 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-33440880

RESUMEN

Osteoarthritis (OA) remains one of the common degenerative joint diseases and a major cause of pain and disability in older adult individuals. Oral administration of non-steroidal anti-inflammatory drugs (NSAIDs) (such as diclofenac, DIC) or intra-articular injected gluco-corticosteroids (such as dexamethasone, DEX) were the conventional treatment strategies for OA to reduce joint pain. Current limitations for both drugs including severe adverse effects with risks of toxicity were noted. The aim of the present study was to generate a novel OA treatment formulation hyaluronic acid (HA)-Liposomal (Lipo)-DIC/DEX to combat joint pain. The formulation was prepared by constructing DIC with DEX-loaded nanostructured lipid carriers Lipo-DIC/DEX mixed with hyaluronic acid (HA) for prolonged OA application. The prepared Lipo-DIC/DEX nanoparticles revealed the size as 103.6 ± 0.3 nm on average, zeta potential as -22.3 ± 4.6 mV, the entrapment efficiency of 90.5 ± 5.6%, and the DIC and DEX content was 22.5 ± 4.1 and 2.5 ± 0.6%, respectively. Evidence indicated that HA-Lipo-DIC/DEX could reach the effective working concentration in 4 h and sustained the drug-releasing time for at least 168 h. No significant toxicities but increased cell numbers were observed when HA-Lipo-DIC/DEX co-cultured with articular chondrocytes cells. Using live-animal In vivo imaging system (IVIS), intra-articular injection of each HA-Lipo-DIC/DEX sufficed to reduce knee joint inflammation in OA mice over a time span of four weeks. Single-dose injection could reduce the inflammation volume down to 77.5 ± 5.1% from initial over that time span. Our results provided the novel drug-releasing formulation with safety and efficiency which could be a promising system for osteoarthritis pain control.


Asunto(s)
Dexametasona/administración & dosificación , Diclofenaco/química , Ácido Hialurónico/química , Liposomas , Nanopartículas/química , Animales , Portadores de Fármacos/química , Liberación de Fármacos , Humanos , Cinética , Elastasa de Leucocito/metabolismo , Ratones , Estructura Molecular , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo
18.
Carbohydr Polym ; 256: 117519, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33483040

RESUMEN

Vitreous, an essential dioptric medium for the human eyes, must be filled with artificial materials once damaged. Carboxymethyl chitosan (CMCTS) is one of the most important water-soluble chitosan derivatives with improved biocompatibility and biodegradability. In this study, oxidized hyaluronic acid (OHA) was prepared as crosslinking reagent. CMCTS and OHA were used to develop a biocompatible, self-repairing and in-situ injectable hydrogel for vitreous substitutes. Results showed the hydrogel with controllable swelling properties, high transparency, acceptable cytocompatibility on mouse fibroblast L929 and histocompatibility in vivo. Furthermore, hydrogel was injected in-situ into the vitreous cavity after vitrectomy on New Zealand Rabbits, no significant and persistent adverse effects were observed during the 90-day follow-up period. In addition, the hydrogel maintained intraocular pressure of the operated eyes and the inherent position of the retina. Collectively, this injectable, biodegradable, nontoxic hydrogel possessed enormous potential to become a vitreous substitute material.


Asunto(s)
Materiales Biocompatibles/química , Quitosano/análogos & derivados , Ácido Hialurónico/química , Hidrogeles/química , Cuerpo Vítreo/cirugía , Animales , Materiales Biocompatibles/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Quitosano/química , Quitosano/farmacología , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Ácido Hialurónico/farmacología , Hidrogeles/farmacología , Inyecciones Intraoculares , Presión Intraocular/efectos de los fármacos , Presión Intraocular/fisiología , Masculino , Ratones , Conejos , Ratas , Ratas Sprague-Dawley , Solubilidad , Resultado del Tratamiento , Vitrectomía/métodos , Agua/química
19.
Int J Biol Macromol ; 172: 154-161, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33428951

RESUMEN

We report on layer-by-layer (LbL) films of chitosans (CHI) and hyaluronic acid (HA) whose properties could be controlled by employing chitosans with different degrees of deacetylation (DD¯ ≈ 85%; 65%; 40%) and high average molecular weight (ca. 106 g/mol). In spite of their high molecular weight, these chitosans are soluble within a wide pH range, including physiological pH. HA/CHI LbL films produced from polymer solutions at pH 4.5 were thinner, smoother, more hydrophilic than those prepared at pH 7.2. This is attributed to the more extended conformation adopted by chitosan due to its very high charge density at low pH, favoring a compact chain packing during the film formation and resulting in lower film thickness and roughness. The smoother HA/CHI LbL films obtained at pH 4.5 were effective against Escherichia coli, while the thicker, rougher LbL films fabricated at pH 7.2 could be used in the controlled released of Rose Bengal dye. In summary, the tuning of only two parameters, i.e. solution pH and DD¯ of chitosans, provides access to a library of HA/CHI LbL films for tailored, diversified applications.


Asunto(s)
Antiinfecciosos/química , Quitosano/química , Antiinfecciosos/farmacología , Escherichia coli/efectos de los fármacos , Ácido Hialurónico/química , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Polímeros/química
20.
Int J Biol Macromol ; 171: 502-513, 2021 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-33422513

RESUMEN

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder is currently incurable. Methotrexate and Teriflunomide are routinely prescribed drugs but their uses are limited due to severe hepatotoxicity. Hyaluronic acid (HYA) is a targeting ligand for CD44 receptors overexpressed on inflamed macrophages. The present investigation aimed at design and fabrication of HYA coated hydroxyapatite nanoparticles (HA-NPs) loaded with Methotrexate (MTX) and Teriflunomide (TEF) (HAMT-NPs) to form HYA-HAMT-NPs for the treatment of RA. HYA-HAMT-NPs showed the nanoscale size of 274.9 ± 64 nm along with a zeta potential value of -26.80 ± 6.08 mV. FTIR spectra of HYA and HYA-HAMT-NPs proved the coating of HYA on HYA-HAMT-NPs. HYA-HAMT-NPs showed less cell viability compared to drugs on RAW 264.7 macrophage cells. A biodistribution study by gamma scintigraphy imaging further strengthened the results by revealing significantly higher (p<0.05) percentage radioactivity (76.76%) of HYA-HAMT-NPs in the synovial region. The results obtained by pharmacodynamic studies ensured the better efficacy of HYA-HAMT-NPs in preventing disease progression and promoting articular regeneration. Under hepatotoxicity evaluation, liver histopathology and liver enzyme assay revealed ~29% hepatotoxicity was reduced by HYA-HAMT-NPs when compared to conventional FOLITRAX-10 and AUBAGIO oral treatments. Overall, the results suggest that HYA-HAMT-NP is a promising delivery system to avoid drug-induced hepatotoxicity in RA.


Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Crotonatos/administración & dosificación , Portadores de Fármacos/administración & dosificación , Durapatita/química , Ácido Hialurónico/química , Metotrexato/administración & dosificación , Nanopartículas/administración & dosificación , Toluidinas/administración & dosificación , Animales , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapéutico , Antirreumáticos/toxicidad , Artritis Experimental/patología , Crotonatos/farmacocinética , Crotonatos/uso terapéutico , Crotonatos/toxicidad , Citocinas/sangre , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidad , Evaluación Preclínica de Medicamentos , Liberación de Fármacos , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Metotrexato/farmacocinética , Metotrexato/uso terapéutico , Metotrexato/toxicidad , Ratones , Nanopartículas/toxicidad , Células RAW 264.7 , Ratas , Ratas Wistar , Espectroscopía Infrarroja por Transformada de Fourier , Distribución Tisular , Toluidinas/farmacocinética , Toluidinas/uso terapéutico , Toluidinas/toxicidad
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