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1.
Carbohydr Polym ; 229: 115394, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826406

RESUMO

In this study, an injectable and near-infrared (NIR) light-triggered ROS-degradable hyaluronic acid hydrogel platform was developed as localized delivery vehicle for photosensitizer protophorphyrin IX (PpIX) and anticancer drug doxorubicin (DOX), to achieve superior combined chemo-photodynamic therapy with light-tunable on-demand drug release. The in situ-forming hydrogel fabricated readily via the formation of dynamic covalent acylhydrazone bonds could efficiently prevent severe self-quenching effect of water-insoluble PpIX due to the covalent binding, leading to localized enhanced photodynamic therapy (PDT). Moreover, the extensive ROS generated by the hydrogel under NIR light irradiation could not only realize efficient PDT effect, but also cleave the ROS-cleavable small molecule crosslinker, inducing the desirable degradation of hydrogel and subsequent on-demand DOX release for cascaded chemotherapy. The developed versatile hyaluronic acid hydrogels have tunable properties, excellent biocompatibility, biodegradability and exhibit outstanding therapeutic effects in both in vitro cellular experiments and in vivo antitumor studies.


Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Ácido Hialurônico/administração & dosagem , Hidrogéis/administração & dosagem , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/administração & dosagem , Protoporfirinas/administração & dosagem , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Ácido Hialurônico/efeitos da radiação , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Fotoquimioterapia , Fármacos Fotossensibilizantes/efeitos da radiação , Protoporfirinas/efeitos da radiação
2.
Carbohydr Polym ; 227: 115349, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31590840

RESUMO

Release of Zn2+ ions from zinc oxide nanoparticles (ZnO NPs) is a major mechanism for oligodynamic activities of these metal oxide NPs against eukaryotic and prokaryotic microorganisms. In addition to this mechanism, ZnO NPs can form reactive oxygen species (ROSs) resulted from electron-hole formation under certain light wavelength. These properties with suitable biocompatibility and biodegradability of ZnO NPs compared to other metal NPs have caused higher applications of these nanomaterials in therapeutic and cosmetic fields. Recently, natural polymers including cellulose, chitosan, and alginate polymers have gained more attention as safe and cost-effective scaffold for wound healing. Both ZnO NPs and these polymers have not been able to satisfy related patients. In this way, the coupling of these materials and nanomaterials as nanocomposites (NCs) is an alternative way to increase the mechanical and antibacterial properties of wound-healing tissue scaffolds. Controllable release of Zn2+ ions in physiological medium should be considered as an indispensable factor to obtain appropriate industrial formulation. Therefore, in this review, attempts were made to highlight particularly important antibacterial results of these NCs in recent investigations.


Assuntos
Alginatos , Antibacterianos , Celulose , Quitosana , Hidrogéis , Nanocompostos , Nanopartículas , Óxido de Zinco , Alginatos/administração & dosagem , Alginatos/química , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Celulose/administração & dosagem , Celulose/química , Quitosana/administração & dosagem , Quitosana/química , Humanos , Hidrogéis/administração & dosagem , Hidrogéis/química , Nanocompostos/administração & dosagem , Nanocompostos/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Cicatrização , Óxido de Zinco/administração & dosagem , Óxido de Zinco/química
3.
BMC Complement Altern Med ; 19(1): 254, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31511001

RESUMO

BACKGROUND: Fumaria species (Fumariacea) has traditionally been used in wound healing in Iranian folk medicine. However, with the discovery of newer agents, its use has faded off into total obscurity. This study explored the wound healing potential of a gel containing 10% Fumaria vaillantii Loisel through topical application of total extract in a model of excisional as well as incisional wound healing in albino Wistar rats. METHODS: Rats were anesthetized, and excisional skin wound was established using a sterilized surgical scissors. The animals were then treated with 10% F.vaillantii topical gel formulation along with the gel base. The treatments were administered once a day after the injury for 21 days. For topical treatment, the hydrogel was formulated and evaluated for chemical and physical characteristics. Histopathological analysis with hematoxylin and eosin (H&E) was used for microscopic examination of the skin tissues on 21-day-old sections of excision wound. To verify collagen formation, hydroxyproline determination was performed 21 days post wound healing. Breaking strength was determined in a 10-day-old incision wound by the uniaxial tensile test. RESULTS: Topical administration of F.vaillantii gel formulation significantly enhanced skin wound closure on the 6th post-wounding day compared to both gel base and the negative control, indicating an accelerated wound healing process, while a significant difference was observed on 10th and 14th post -wound days in F.vaillantii treatment compared to the negative control groups. Gel formulation prepared with a 10% F. vaillantii extract exhibited a response in terms of wound epithelialization, angiogenesis and number of hair follicles at wound area better than the gel base on the 21st post-wound day. Application of gel base produced further advantages by increasing hydroxyproline content and collagen fiber thickness. Our results on incision wound model were supported by histopathological data indicating the role of gel base in the enhancement of breaking strength. CONCLUSION: Traditional use of Fumaria species in the skin diseases was justified in this study by revealing the increase in wound healing activity after hydrogel containing F. vaillantii total extract administration.


Assuntos
Fumaria/química , Extratos Vegetais/administração & dosagem , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Administração Tópica , Animais , Humanos , Hidrogéis/administração & dosagem , Hidrogéis/química , Masculino , Extratos Vegetais/química , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/lesões , Pele/fisiopatologia , Ferimentos e Lesões/fisiopatologia
4.
J Orthop Surg Res ; 14(1): 297, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488155

RESUMO

BACKGROUND: Due to our aging population, an increase in proximal femur fractures can be expected, which is associated with impaired activities of daily living and a high risk of mortality. These patients are also at a high risk to suffer a secondary osteoporosis-related fracture on the contralateral hip. In this context, growth factors could open the field for regenerative approaches, as it is known that, i.e., the growth factor BMP-7 (bone morphogenetic protein 7) is a potent stimulator of osteogenesis. Local prophylactic augmentation of the proximal femur with a BMP-7 loaded thermoresponsive hydrogel during index surgery of an osteoporotic fracture could be suitable to reduce the risk of further osteoporosis-associated secondary fractures. The present study therefore aims to test the hypothesis if a BMP-7 augmented hydrogel is an applicable carrier for the augmentation of non-fractured proximal femurs. Furthermore, it needs to be shown that the minimally invasive injection of a hydrogel into the mouse femur is technically feasible. METHODS: In this study, male C57BL/6 mice (n = 36) received a unilateral femoral intramedullary injection of either 100 µl saline, 100 µl 1,4 Butan-Diisocyanat (BDI)-hydrogel, or 100 µl hydrogel loaded with 1 µg of bone morphogenetic protein 7. Mice were sacrificed 4 and 12 weeks later. The femora were submitted to high-resolution X-ray tomography and subsequent histological examination. RESULTS: Analysis of normalized CtBMD (Cortical bone mineral density) as obtained by X-ray micro-computed tomography analysis revealed significant differences depending on the duration of treatment (4 vs 12 weeks; p < 0.05). Furthermore, within different anatomically defined regions of interest, significant associations between normalized TbN (trabecular number) and BV/TV (percent bone volume) were noted. Histology indicated no signs of inflammation and no signs of necrosis and there were no cartilage damages, no new bone formations, or new cartilage tissues, while BMP-7 was readily detectable in all of the samples. CONCLUSIONS: In conclusion, the murine femoral intramedullary injection model appears to be feasible and worth to be used in subsequent studies that are directed to examine the therapeutic potential of BMP-7 loaded BDI-hydrogel. Although we were unable to detect any significant osseous effects arising from the mode or duration of treatment in the present trial, the effect of different concentrations and duration of treatment in an osteoporotic model appears of interest for further experiments to reach translation into clinic and open new strategies of growth factor-mediated augmentation.


Assuntos
Proteína Morfogenética Óssea 7/administração & dosagem , Fraturas do Fêmur/prevenção & controle , Fêmur/efeitos dos fármacos , Hidrogéis/administração & dosagem , Animais , Proteína Morfogenética Óssea 7/análise , Avaliação Pré-Clínica de Medicamentos/métodos , Fraturas do Fêmur/patologia , Fêmur/química , Fêmur/patologia , Fixação Intramedular de Fraturas/métodos , Hidrogéis/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL
5.
Biomed Mater Eng ; 30(4): 403-417, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31498118

RESUMO

BACKGROUND: Various biomaterials/technologies have been tested for treatment of intervertebral disc (IVD) degeneration (IDD). Only few non-surgical options exist. OBJECTIVE: Assessment of efficacy and safety of the hyaluronic acid derivative hydrogel HYADD®4-G in IDD using a well-established rabbit annular puncture model. METHODS: Rabbits were punctured at two IVDs to induce IDD. Thirty days after, IVDs were injected with HYADD®4-G or saline. IVD hydration, height, appearance and tissue organization were assessed by radiographs, MRI and histopathology. Safety of HYADD®4-G injection was evaluated in non-punctured IVDs. RESULTS: HYADD®4-G injection restored disc height to over 75% of the pre-punctured disc, saline injections led to 50% of initial disc height. Compared to saline, HYADD®4-G treatment resulted in improved water retention as revealed by MRI quantification. 83.3% of HYADD®4-G injected discs had normal appearance and reached grade I of the Pfirrmann scale. Regarding tissue organization and cellularity, HYADD®4-G treatment resulted in significantly lower IDD scores than saline (p < 0.01). HYADD®4-G injected into healthy IVDs did not induce inflammation or foreign body reactions. CONCLUSIONS: Intra-discal HYADD®4-G injection is safe and has therapeutic benefits: IDD could be limited through restoration of disc height and hydration and maintenance of normal IVD tissue organization.


Assuntos
Ácido Hialurônico/uso terapêutico , Hidrogéis/uso terapêutico , Degeneração do Disco Intervertebral/terapia , Disco Intervertebral/patologia , Viscossuplementos/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Ácido Hialurônico/administração & dosagem , Hidrogéis/administração & dosagem , Injeções Espinhais , Disco Intervertebral/efeitos dos fármacos , Degeneração do Disco Intervertebral/patologia , Coelhos , Viscossuplementos/administração & dosagem
6.
J Nanobiotechnology ; 17(1): 99, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530285

RESUMO

BACKGROUND: Combined therapy has demonstrated to be an effective strategy for cancer therapy. Herein, an injectable hydrogel based on the genetically engineered polypeptide and hollow gold nanoshells (HAuNS) has been developed for chemo-photothermal therapy of HepG2 tumor. METHODS: PC10A/DOX/HAuNS nanogel was prepared with layer-by-layer through the adsorption of DOX and PC10A successively. DOX with positive charge and PC10A with negative charge were coated step by step onto the surface of negatively charged HAuNS. The multifunctional hydrogel PC10A/DOX/HAuNS were prepared via dissolving hybrid PC10A/DOX/HAuNS nanogel in polypeptide PC10A. Chemotherapy drug DOX in the PC10A/DOX/HAuNS hydrogel was absorbed on the HAuNS and directly embedded in the PC10A hydrogel, which contributes to sequentially release of the drug. Specifically, DOX adsorbed on the HAuNS could be released slowly for sustainable chemotherapy. RESULTS: The PC10A/DOX/HAuNS hydrogel could pass 26-gauge needle without clogging, indicating that it is injectable. In addition, the PC10A/DOX/HAuNS hydrogel possessed outstanding photothermal effect and photothermal stability. In both in vitro cell and in vivo tumor-bearing mice experiments, a remarkably enhance tumor inhibition was observed by the combined therapy of chemo-photothermal therapy compared with photothermal therapy or chemotherapy alone. CONCLUSIONS: The combined chemotherapy and photothermal therapy of PC10A/DOX/HAuNS hydrogels could significantly improve the therapeutic effect. Therefore, the multifunctional hydrogel PC10A/DOX/HAuNS is promising to provide a new strategy for sustained chemo-photothermal therapy.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Ouro/química , Hidrogéis/administração & dosagem , Hidrogéis/química , Nanoconchas/química , Animais , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Portadores de Fármacos/química , Células Hep G2 , Humanos , Masculino , Camundongos , Nanosferas/química , Fototerapia/métodos
7.
J Mater Sci Mater Med ; 30(9): 106, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31502009

RESUMO

With the advantage of handy process, random pattern skin flaps are generally applied in limb reconstruction and wound repair. Apelin-13 is a discovered endogenous peptide, that has been shown to have potent multiple biological functions. Recently, thermosensitive gel-forming systems have gained increasing attention as wound dressings due to their advantages. In the present study, an apelin-13-loaded chitosan (CH)/ß-sodium glycerophosphate (ß-GP) hydrogel was developed for promoting random skin flap survival. Random skin flaps were created in 60 rats after which the animals were categorized to a control hydrogel group and an apelin-13 hydrogel group. The water content of the flap as well as the survival area were then measured 7 days post-surgery. Hematoxylin and eosin staining was used to evaluate the flap angiogenesis. Cell differentiation 34 (CD34) and vascular endothelial growth factor (VEGF) levels were detected by immunohistochemistry and Western blotting. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were assessed by enzyme linked immunosorbent assays (ELISAs). Oxidative stress was estimated via the activity of tissue malondialdehyde (MDA) and superoxide dismutase (SOD). Our results showed that CH/ß-GP/apelin-13 hydrogel could not only reduce the tissue edema, but also improve the survival area of flap. CH/ß-GP/apelin-13 hydrogel also upregulated levels of VEGF protein and increased mean vessel densities. Furthermore, CH/ß-GP/apelin-13 hydrogel was shown to significantly inhibit the expression of TNF-α and IL-6, along with increasing the activity of SOD and suppressing the MDA content. Taken together, these results indicate that this CH/ß-GP/apelin-13 hydrogel may be a potential therapeutic way for random pattern skin flap.


Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/farmacocinética , Transplante de Pele/métodos , Pele/efeitos dos fármacos , Temperatura , Animais , Temperatura Corporal/fisiologia , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Hidrogéis/administração & dosagem , Hidrogéis/farmacocinética , Masculino , Malondialdeído/metabolismo , Necrose/patologia , Necrose/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Pele/metabolismo , Pele/patologia , Fenômenos Fisiológicos da Pele/efeitos dos fármacos , Retalhos Cirúrgicos/fisiologia , Retalhos Cirúrgicos/transplante
8.
BMC Complement Altern Med ; 19(1): 213, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412845

RESUMO

BACKGROUND: Various extracts of Centella asiatica (Apiaceae) and its active constituent, asiaticoside, have been reported to possess wound healing property when assessed using various in vivo and in vitro models. In an attempt to develop a formulation with accelerated wound healing effect, the present study was performed to examine in vivo efficacy of asiaticoside-rich hydrogel formulation in rabbits. METHODS: Asiaticoside-rich fraction was prepared from C. asiatica aerial part and then incorporated into polyvinyl alcohol/polyethylene glycol (PVA/PEG) hydrogel. The hydrogel was subjected to wound healing investigation using the in vivo incision model. RESULTS: The results obtained demonstrated that: i) the hydrogel formulation did not cause any signs of irritation on the rabbits' skin and; ii) enhanced wound healing 15% faster than the commercial cream and > 40% faster than the untreated wounds. The skin healing process was seen in all wounds marked by formation of a thick epithelial layer, keratin, and moderate formation of granulation tissues, fibroblasts and collagen with no fibrinoid necrosis detected. CONCLUSION: The asiaticoside-rich hydrogel developed using the freeze-thaw method was effective in accelerating wound healing in rabbits.


Assuntos
Centella/química , Triterpenos/administração & dosagem , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Animais , Humanos , Hidrogéis/administração & dosagem , Hidrogéis/química , Masculino , Coelhos , Triterpenos/química , Ferimentos e Lesões/fisiopatologia
9.
Int J Pharm ; 569: 118610, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31415875

RESUMO

The aim was to investigate the effect of constant current iontophoresis on the delivery and biodistribution of buflomedil hydrochloride (BUF) in the buccal mucosa. Quantification was by UHPLC-MS/MS; in addition to total delivery, the amounts present in the epithelia and the lamina propria (the target tissue) were also determined. Two-compartment vertical diffusion cells were used to investigate the effect of current density (0.5, 1 and 2 mA/cm2), application time (5, 10 and 20 min) and concentration (5, 10 and 20 mM) on iontophoretic delivery of BUF from aqueous solutions. In contrast to passive delivery, iontophoresis for 10 min at 1 mA/cm2 resulted in statistically equivalent transport from a 20 mM solution and a 2% HEC hydrogel (with equivalent BUF loading; 20 µmol). BUF delivery from the hydrogel using diffusion cells and a new coplanar "side-by-side" set-up was statistically equivalent (304.2 ±â€¯28.9 and 278.2 ±â€¯40.3 µg/cm2) - passive delivery was also similar. Iontophoresis (10 min at 1 mA/cm2) using a thin film (20 µmol BUF) was superior to the passive control (323.3 ±â€¯5.9 and 24.8 ±â€¯5.9 µg/cm2). Concentrations in the LP were ~700-fold > IC50 to block collagen production, potentially providing a new therapeutic strategy for oral submucous fibrosis.


Assuntos
Mucosa Esofágica/metabolismo , Hidrogéis/administração & dosagem , Iontoforese , Fibrose Oral Submucosa/tratamento farmacológico , Pirrolidinas/administração & dosagem , Vasodilatadores/administração & dosagem , Administração Cutânea , Animais , Disponibilidade Biológica , Suínos
10.
AAPS PharmSciTech ; 20(7): 297, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444661

RESUMO

Miconazole nitrate (MZ) is a BCS class II antifungal poorly water-soluble drug with limited dissolution properties and gastrointestinal side effects. Self-nanoemulsifying delivery system-based gel of MZ can improve both solubility and oral mucosal absorption with enhanced antifungal activity. The study aims to formulate MZ self-nanoemulsion (MZ-NE) and combine it within hyaluronic acid-based gel. MZ solubility in various oils, surfactants, and cosurfactant used in NE formulations were evaluated. Mixture design was implemented to optimize the levels of NE components as a formulation variable to study their effects on the mean globule size and antifungal inhibition zones. Further, the optimized MZ-NE was loaded into a hyaluronic acid gel base. Rheological behavior of the prepared gel was assessed. Ex vivo permeability of optimized formulation across buccal mucous of sheep and inhibition against Candida albicans were examined. Mixture design was used to optimize the composition of MZ-NE formulation as 22, 67, and 10% for clove oil, Labrasol, and propylene glycol, respectively. The optimized formulation indicated globule size of 113 nm with 29 mm inhibition zone. Pseudoplastic flow with thixotropic behavior was observed, which is desirable for oral gels. The optimized formulation exhibited higher ex vivo skin permeability and enhanced antifungal activity by 1.85 and 2.179, respectively, compared to MZ-SNEDDS, and by 1.52 and 1.72 folds, respectively, compared to marketed gel. Optimized MZ-NE hyaluronic acid-based oral gel demonstrated better antifungal activity, indicating its potential in oral thrush pharmacotherapy.


Assuntos
Antifúngicos/administração & dosagem , Candidíase Bucal/tratamento farmacológico , Química Farmacêutica/métodos , Ácido Hialurônico/administração & dosagem , Miconazol/administração & dosagem , Nanocápsulas/administração & dosagem , Administração Oral , Animais , Antifúngicos/síntese química , Antifúngicos/farmacocinética , Candidíase Bucal/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Emulsões/administração & dosagem , Emulsões/síntese química , Emulsões/farmacocinética , Ácido Hialurônico/síntese química , Ácido Hialurônico/farmacocinética , Hidrogéis/administração & dosagem , Hidrogéis/síntese química , Hidrogéis/farmacocinética , Miconazol/síntese química , Miconazol/farmacocinética , Nanocápsulas/química , Ovinos
11.
Biomater Sci ; 7(10): 4195-4207, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31386700

RESUMO

A dual pH- and temperature-responsive physically crosslinked and injectable hydrogel system was developed for efficient and long-term delivery of oncolytic adenoviruses (Ads). Three different types of physically crosslinked hydrogels with different chemical compositions and properties were prepared. These hydrogels with good biocompatibility can be injected at pH 9.0 and room temperature and rapidly form a gel under body or tumor microenvironment conditions. Ads encapsulated in hydrogels were released gradually without burst release. Moreover, these physically crosslinked hydrogels provided a protective environment for Ads and maintained their bioactivity for a long period of time. Compared to naked Ads, Ads protected by these physically crosslinked hydrogels showed strong cytotoxicity to cancer cells even after 11 days. The Ad-loaded hydrogel system also exhibited enhanced and long-term antitumor therapeutic effects in human xenograft tumor models. Due to these outstanding properties, Ad-loaded injectable hydrogels might have potential for long-term cancer treatment.


Assuntos
Adenoviridae , Hidrogéis/administração & dosagem , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Hidrogéis/química , Injeções , Masculino , Camundongos Nus , Neoplasias/patologia , Neoplasias/terapia , Poliuretanos/administração & dosagem , Poliuretanos/química , Sulfametazina/administração & dosagem , Sulfametazina/química , Carga Tumoral
12.
Int J Pharm ; 569: 118589, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31386880

RESUMO

Polymer microcapsules offer a possibility of storing increased amounts of drugs. Appropriate design and composition of the microcapsules allow tuning of the drug-release process. In this paper, we report on synthesis of hydrogel microcapsules sensitive to temperature and pH and degradable by glutathione and hydrogen peroxide. Microcapsules were based on thermo-responsive poly(N-isopropylacrylamide) and degradable cystine crosslinker, and were synthesized by applying precipitation polymerization. Such way of polymerization was appropriately modified to limit the crosslinking in the microcapsule center. This led to a possibility of washing out the pNIPA core at room temperature and the formation of a capsule. Microcapsules revealed rather high drug-loading capacity of ca. 17%. The degradation of the microcapsules by the reducing agent (GSH) and the oxidizing agent (H2O2) was confirmed by using the DLS, UV-Vis, SEM and TEM techniques. Depending on pH and concentration of the reducing/oxidizing agents a fast or slow degradation of the microcapsules and a burst or long-term release of doxorubicin (DOX) were observed. The DOX loaded microcapsules appeared to be cytotoxic against A2780 cancer cells similarly to DOX alone, while unloaded microcapsules did not inhibit proliferation of the cells.


Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Hidrogéis/administração & dosagem , Antineoplásicos/química , Cápsulas , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Doxorrubicina/química , Liberação Controlada de Fármacos , Glutationa/farmacologia , Humanos , Hidrogéis/química , Peróxido de Hidrogênio/farmacologia , Concentração de Íons de Hidrogênio , Temperatura
13.
Int J Pharm ; 569: 118584, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31376466

RESUMO

This study aimed to develop biocompatible deep eutectic solvents (DESs) as carriers for improving the nasal delivery of insulin. The DES was prepared from malic acid and choline chloride broadly used in foods, drugs, or cosmetics as biocompatible additives. The DES of choline chloride and malic acid (CM-DES) demonstrated lower melting point (-59.1 °C) and higher viscosity (120,000 cP) compared with hydrogels based on sodium carboxyl methyl cellulose (CMC-Na). The conformational structure of insulin does not change in CM-DES as characterized by circular dichroism. The in vitro results showed that CM-DES dissociated gradually but did not disintegrate immediately upon contact with water. CM-DES was able to improve the hypoglycemic effect of insulin significantly at different doses compared with hydrogels or solutions of insulin, which could be ascribed to facilitated penetration of insulin across the nasal epithelia by CM-DES. The hypoglycemic effect of CM-DES loading insulin at a dose of 25 IU/kg was similar to that of subcutaneous insulin at 1 IU/kg. In addition, no evident toxicity to nasal epithelia was observed after nasal administration to rats for seven consecutive days. In conclusion, CM-DES showed promising potential in enhancing the hypoglycemic effect of insulin via the nasal route.


Assuntos
Colina/administração & dosagem , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Malatos/administração & dosagem , Solventes/administração & dosagem , Administração Intranasal , Animais , Glicemia/efeitos dos fármacos , Colina/química , Liberação Controlada de Fármacos , Hidrogéis/administração & dosagem , Hidrogéis/química , Hipoglicemiantes/química , Insulina/química , Malatos/química , Mucosa Nasal/metabolismo , Ratos , Ratos Sprague-Dawley , Solventes/química , Água/química
14.
Int J Pharm ; 569: 118557, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31377405

RESUMO

This study describes the fabrication of chemically crosslinked pectin-based LA-co-MAA hydrogels through free radical polymerization technique for the colonic delivery of oxaliplatin. Methylene bisacrylamide was used as a crosslinking agent and ammonium persulfate as an initiator. The successful fabrication and drug loading were confirmed through Fourier transform infrared spectroscopy (FTIR). The thermal investigations through differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) suggested the higher thermal stability of the unloaded and OXP-loaded formulations as compared to the raw materials. X-ray diffraction (XRD) analysis showed a decrease in crystallinity after crosslinking. The swelling, drug loading, and drug release were increased with an increase in the concentration of pectin and lactic acid (LA) while methacrylic acid (MAA) displayed an inverse behavior. The in-vitro biodegradability was evaluated against lysozyme and collagenase. The results showed that the hydrogels were stable against blank PBS as compared to lysozyme and collagenase. MTT-assay proved that the blank hydrogels were cytocompatible while free OXP and OXP-loaded hydrogels displayed dose-dependent effect against Vero, MCF-7, and HCT-116 cell lines. The oral tolerability study in rabbits confirmed that the hydrogel dispersion was well-tolerable up to 3650 mg/kg of body weight without causing any histopathological or hematological changes when compared with the control group.


Assuntos
Sistemas de Liberação de Medicamentos , Hidrogéis/administração & dosagem , Ácido Láctico/administração & dosagem , Metacrilatos/administração & dosagem , Oxaliplatina/administração & dosagem , Pectinas/administração & dosagem , Animais , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/química , Sobrevivência Celular/efeitos dos fármacos , Colo/metabolismo , Feminino , Células HCT116 , Humanos , Hidrogéis/química , Concentração de Íons de Hidrogênio , Ácido Láctico/química , Células MCF-7 , Masculino , Metacrilatos/química , Oxaliplatina/química , Pectinas/química , Coelhos , Células Vero
15.
Nat Commun ; 10(1): 3523, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388014

RESUMO

Injectable hydrogels can fill irregular defects and promote in situ tissue regrowth and regeneration. The ability of directing stem cell differentiation in a three-dimensional microenvironment for bone regeneration remains a challenge. In this study, we successfully nanoengineer an interconnected microporous networked photocrosslinkable chitosan in situ-forming hydrogel by introducing two-dimensional nanoclay particles with intercalation chemistry. The presence of the nanosilicates increases the Young's modulus and stalls the degradation rate of the resulting hydrogels. We demonstrate that the reinforced hydrogels promote the proliferation as well as the attachment and induced the differentiation of encapsulated mesenchymal stem cells in vitro. Furthermore, we explore the effects of nanoengineered hydrogels in vivo with the critical-sized mouse calvarial defect model. Our results confirm that chitosan-montmorillonite hydrogels are able to recruit native cells and promote calvarial healing without delivery of additional therapeutic agents or stem cells, indicating their tissue engineering potential.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Hidrogéis/administração & dosagem , Nanocompostos/administração & dosagem , Engenharia Tecidual/métodos , Cicatrização/efeitos dos fármacos , Animais , Bentonita/administração & dosagem , Bentonita/química , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/química , Diferenciação Celular/efeitos dos fármacos , Quitosana/administração & dosagem , Quitosana/química , Modelos Animais de Doenças , Módulo de Elasticidade , Humanos , Hidrogéis/química , Masculino , Células-Tronco Mesenquimais , Camundongos , Nanocompostos/química , Osteogênese/efeitos dos fármacos , Crânio/diagnóstico por imagem , Crânio/efeitos dos fármacos , Crânio/lesões , Microtomografia por Raio-X
16.
Biomater Sci ; 7(10): 4230-4236, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31393463

RESUMO

Oxidative damage generated by various biochemical pathways can disrupt the oxidant/antioxidant balance in cells, causing slow wound healing and tissue regeneration; in this regard, a hydrogel dressing with antioxidant properties can promote wound healing; however, its design is still a challenge. Herein, a polydopamine/puerarin (PDA/PUE) nanoparticle-incorporated polyethylene glycol diacrylate hybrid hydrogel (PEG-DA/PDA/PUE) with antioxidant properties was prepared and used as a wound-healing material. Experimental observations indicated that the PEG-DA/PDA/PUE hydrogel possessed excellent swelling capacity and mechanical property. Moreover, the antioxidant capability was enhanced with an increase in the concentration of polydopamine/puerarin nanoparticles in the hydrogel. The hydrogel presented good cell proliferation and antioxidant activity, including a decrease in ROS and increase in the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity under oxidative stress conditions. Furthermore, the full-thickness skin-defect-regeneration process could be accelerated via the antioxidant hydrogel treatment. This study validated the potential applications of an antioxidant hydrogel for wound healing.


Assuntos
Antioxidantes/administração & dosagem , Materiais Biocompatíveis/administração & dosagem , Hidrogéis/administração & dosagem , Indóis/administração & dosagem , Isoflavonas/administração & dosagem , Nanopartículas/administração & dosagem , Polímeros/administração & dosagem , Cicatrização/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Polpa Dentária/citologia , Masculino , Ligamento Periodontal/citologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Células-Tronco/efeitos dos fármacos
17.
Carbohydr Polym ; 222: 115039, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31320053

RESUMO

The purpose of this study was to design an injectable hydrogel with temperature-sensitive property for safe and high efficient in vivo colon cancer hyperthermia and chemotherapy. Chitosan (CS) solution was injected into the tumor at room temperature and automatically gelled after warming to body temperature in the present of ß-glycerophosphate (ß-GP). Combined localized tumor photothermal and chemotherapy were achieved by dissolving photothermal material MoS2/Bi2S3-PEG (MBP) nanosheets and drug molecule doxorubicin (DOX) into the hydrogel, and the gel system could encapsulate DOX and MBP nanosheets and prevent them from entering the blood circulation and damaging normal tissues and cells. More importantly, the CS/MBP/DOX (CMD) hydrogel exhibited a photothermal efficiency of 22.18% and 31.42% in the first and second near infrared light (NIR I and NIR II) biowindows respectively at a low MBP concentration (0.5 mg/mL). Besides, the release of the DOX from CMD hydrogel was controllable since the gel temperature could be governed by NIR laser irradiation. Moreover, the chitosan-based hydrogel had antibacterial effects. The designed composite hydrogel is anticipated to act as a platform for the high efficient treatment of tumors owing to the different penetration depths of NIR I and NIR II.


Assuntos
Antineoplásicos/uso terapêutico , Quitosana/química , Neoplasias do Colo/tratamento farmacológico , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Hidrogéis/química , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/administração & dosagem , Bismuto/administração & dosagem , Linhagem Celular , Quitosana/administração & dosagem , Quitosana/farmacologia , Dissulfetos/administração & dosagem , Dissulfetos/efeitos da radiação , Doxorrubicina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacologia , Liberação Controlada de Fármacos , Escherichia coli/efeitos dos fármacos , Hidrogéis/administração & dosagem , Hidrogéis/farmacologia , Hipertermia Induzida/métodos , Raios Infravermelhos , Injeções , Camundongos Endogâmicos BALB C , Molibdênio/administração & dosagem , Molibdênio/efeitos da radiação , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Sulfetos/administração & dosagem , Sulfetos/efeitos da radiação , Temperatura , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int J Pharm ; 567: 118495, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31276761

RESUMO

We developed a new oil-based delivery system for transdermal protein delivery, a gel-in-oil (G/O) nanosuspension, where gelatin-based hydrogel was coated with hydrophobic surfactants. The high entrapment efficiency of a model protein, phycocyanin (PC), into nano-sized gelatin hydrogel particles was achieved. Spectroscopic evaluation of PC suggested that the G/O nanosuspension could retain the functional form of PC in isopropyl myristate. In vitro skin permeation studies showed that the G/O nanosuspension facilitated the delivery of PC through the stratum corneum of Yucatan micropig skin.


Assuntos
Portadores de Fármacos/administração & dosagem , Gelatina/administração & dosagem , Hidrogéis/administração & dosagem , Miristatos/administração & dosagem , Nanopartículas/administração & dosagem , Ficocianina/administração & dosagem , Administração Cutânea , Animais , Feminino , Óleos/administração & dosagem , Tamanho da Partícula , Pele/metabolismo , Absorção Cutânea , Suínos , Porco Miniatura
19.
Eur J Pharm Sci ; 137: 104993, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302214

RESUMO

Therapeutic protein medicines have transformed the treatment of blinding diseases (e.g. age-related macular degeneration, AMD) during the last 1-2 decades. Many blinding conditions such as AMD are chronic; and require multiple intravitreal injections over a long period to achieve a high and reproducible dose needed for clinical benefit. Prolonging the duration of action of ophthalmic drugs is critical to reduce the frequency of injections. Thermoresponsive hydrogels (e.g. N-isopropylacrylamide, NIPAAM) that collapse in physiological conditions can entrap and sustain the release of a therapeutic protein. However, most NIPAAM hydrogels are not biodegradable and often requires invasive surgery to remove the depot. Here, we report the preparation of a hydrogel derived from NIPAAM and acrylated hyaluronic acid (Ac-HA) as a biodegradable, macromolecular crosslinker. Ac-HA was prepared by the acrylation of hyaluronic acid (HA). Antibody (infliximab (INF), 5.0 mg/mL or bevacizumab (BEVA), 12.5 mg/mL), NIPAAM (0.35 mmol) and Ac-HA (2.0-10.0 mg/mL, 40.0-200.0 nmol) were first mixed prior to redox polymerisation to ensure maximal protein mixing and to shorten the burst release. Hydrogels with lower amounts of Ac-HA (2.0-4.0 mg/mL, 40.0-80.0 nmol) showed favourable lower critical solution temperature (LCST) values and injectability (27-29G) than higher amounts of Ac-HA (>4.0 mg/mL, >80.0 nmol). These hydrogels were further characterised (swelling ratio (SR), water retention (WR) and rheology). All hydrogels degraded in presence of bovine testes hyaluronidase (0-50 U/mL, 37 °C, 100 rpm). Release studies of BEVA-loaded hydrogels were investigated in vitro using the PK-Eye™ model, which estimates the human clearance times of proteins from the back of the eye. Phosphate buffered saline (PBS, pH 7.4, 37 °C) was used rather than simulated vitreous to more effectively map trends between the formulations. A zero-order release profile was observed between days 5 to 50 with 43.3 ±â€¯9.5% protein released at day 50. Determining protein binding and functionality from a formulation is crucial to determine the optimal formulation prior to more detailed studies that might be necessary. BEVA showed binding to human vascular growth endothelial factor (VEGF165) throughout the study (two months) while still maintaining a therapeutic dose (123.5 ±â€¯45.6 ng) in the posterior cavity of the PK-Eye™ model. These encouraging results suggest that extended release of proteins in the vitreous can be achieved using injectable hydrogels derived from NIPAAM and HA.


Assuntos
Acrilamidas/administração & dosagem , Inibidores da Angiogênese/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Bevacizumab/administração & dosagem , Ácido Hialurônico/administração & dosagem , Hidrogéis/administração & dosagem , Infliximab/administração & dosagem , Acrilamidas/química , Anti-Inflamatórios/química , Bevacizumab/química , Olho/metabolismo , Humanos , Ácido Hialurônico/química , Hialuronoglucosaminidase/química , Hidrogéis/química , Infliximab/química , Injeções Intravítreas , Modelos Biológicos
20.
Mater Sci Eng C Mater Biol Appl ; 103: 109751, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349422

RESUMO

The limited regenerative capacity of the heart after a myocardial infarct results in remodeling processes that can progress to congestive heart failure (CHF). Several strategies including mechanical stabilization of the weakened myocardium and regenerative approaches (specifically stem cell technologies) have evolved which aim to prevent CHF. However, their final performance remains limited motivating the need for an advanced strategy with enhanced efficacy and reduced deleterious effects. An epicardial carrier device enabling a targeted application of a biomaterial-based therapy to the infarcted ventricle wall could potentially overcome the therapy and application related issues. Such a device could play a synergistic role in heart regeneration, including the provision of mechanical support to the remodeling heart wall, as well as providing a suitable environment for in situ stem cell delivery potentially promoting heart regeneration. In this study, we have developed a novel, single-stage concept to support the weakened myocardial region post-MI by applying an elastic, biodegradable patch (SPREADS) via a minimal-invasive, closed chest intervention to the epicardial heart surface. We show a significant increase in %LVEF 14 days post-treatment when GS (clinical gold standard treatment) was compared to GS + SPREADS + Gel with and without cells (p ≤ 0.001). Furthermore, we did not find a significant difference in infarct quality or blood vessel density between any of the groups which suggests that neither infarct quality nor vascularization is the mechanism of action of SPREADS. The SPREADS device could potentially be used to deliver a range of new or previously developed biomaterial hydrogels, a remarkable potential to overcome the translational hurdles associated with hydrogel delivery to the heart.


Assuntos
Implantes Absorvíveis , Terapia Baseada em Transplante de Células e Tecidos/instrumentação , Hidrogéis/administração & dosagem , Células-Tronco Mesenquimais , Infarto do Miocárdio/terapia , Tecido Adiposo/citologia , Animais , Materiais Biocompatíveis , Movimento Celular/efeitos dos fármacos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Desenho de Equipamento , Feminino , Humanos , Ácido Hialurônico , Hidrogéis/química , Hidrogéis/farmacologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , Infarto do Miocárdio/fisiopatologia , Pericárdio , Suínos , Viscosidade
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