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1.
Int J Nanomedicine ; 14: 6117-6131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534337

RESUMO

Background: NT4 has been regarded as a promising therapeutic protein for treatment of damaged retinal pigment epithelium cells. Purpose: Here, we studied physicochemical parameters of an NT4-polyamidoamine (PAMAM) electrostatic complex, which can provide a sustained concentration of protein in intraocular space over an extended period after delivery. Adsorption/desorption of NT4 molecules to/from positively charged PAMAM dendrimers were precisely determined to control the concentration of bounded/unbounded protein molecules, diffusion coefficient, and size of a protein-laden dendrimer structure. We determined kinetics of NT4 desorption in PBS, vitreous, and damaged retina. Methods: Initially, adsorption of NT4 molecules on PAMAM dendrimers was studied in PBS using dynamic light scattering, electrophoresis, solution depletion, ELISA, and atomic force microscopy. This allowed us precisely to determine desorption of NT4 from nanoparticles under in situ conditions. The maximum coverage of irreversibly adsorbed NT4 determined by ELISA allowed us to devise a robust procedure for preparing stable and well-controlled coverage of NT4 on PAMAM nanoparticles. Thereafter, we studied diffusion of nanospheres containing NT4 molecules by injecting them into vitreous cavities of mice exposed to intravenous injections of sodium iodate and evaluated their intraocular desorption kinetics from drug carriers in vivo. Results: Our measurements revealed NT4-dendrimer nanoparticles can be used for continuous neurotrophic factor delivery, enhancing its distribution into mouse vitreous, as well as damaged retina over 28 days of postinjury observation. Conclusion: Understanding of polyvalent neurotrophin interactions with dendrimer nanoparticles might be useful to obtain well-ordered protein layers, targeting future development of drug-delivery systems, especially for neuroprotection of damaged retinal neurons.


Assuntos
Dendrímeros/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Fatores de Crescimento Neural/farmacologia , Eletricidade Estática , Adsorção , Animais , Preparações de Ação Retardada/farmacologia , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos BALB C , Retina/efeitos dos fármacos , Retina/lesões , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/lesões
2.
Int J Nanomedicine ; 14: 6357-6369, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496691

RESUMO

Background: Diabetic retinopathy (DR) is a complication of diabetes that affects the eyes and vision. It is a leading cause of visual impairment and blindness in working-age people. Vascular endothelial growth factor-A (VEGF-A) is a primary initiator and potential mediator of DR. Matrix metalloproteinase-9 (MMP-9) plays a progressive role in the onset and severity of DR. Interleukin-12 (IL-12) is a cytokine of the chemokine family that could reduce the levels of MMP-9 and VEGF-A and suppress tumor angiogenesis. We hypothesize that IL-12 may also have superior therapeutic efficacy against DR. However, protein drugs are prone to degradation by various proteases after drug injection. Therefore, they have short half-lives and low blood concentrations. The objective of this study was to develop IL-12-loaded nanoparticles for long-term and sustained DR treatment. Methods: IL-12-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (IL-12-PNP) were developed by double emulsion. The characteristics, anti-DR activity, and mechanisms of IL-12-PNP were examined in vitro and in vivo. Results: The nanoparticles had suitable particle size (~132.8 nm), drug encapsulation efficiency (~34.7%), and sustained drug release profile. Compared with IL-12 and blank nanoparticles, IL-12-PNP showed better inhibitory efficacy against VEGF-A and MMP-9 expression in rat endothelial cells and DR mouse retina. Intraocular IL-12-PNP administration significantly reduced retinal damage in DR mice as they presented with increased thickness and decreased neovascularization after treatment. Conclusion: These data indicate that IL-12-PNP is an effective drug delivery platform for DR therapy. It restores the thickness and reduces neovascularization of the retinas of DR mice.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Interleucina-12/administração & dosagem , Interleucina-12/uso terapêutico , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Preparações de Ação Retardada/farmacologia , Retinopatia Diabética/patologia , Células Endoteliais/metabolismo , Injeções Intravítreas , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Nanopartículas/ultraestrutura , Neovascularização Patológica/tratamento farmacológico , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
J Agric Food Chem ; 67(36): 9989-9999, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31430135

RESUMO

Zein's prevalent hydrophobic character is one of the major challenges associated with ineffective utilization as an aqueous nanocarrier for pesticides. Herein, we report an effective approach to hydrophilic modification of zein by phosphorylation using nontoxic sodium tripolyphosphate (STP), thereby improving the water-solubility, foliage wettability, and adhesion ability of zein as a nanocarrier for sustained release of pesticides. The procedure relied on zein grafted with STP via N- and O- phosphate bonds and encapsulation of avermectin (AVM) as a hydrophobic model drug using phosphorylated zein (P-Zein), which achieved pH sensitivity to controlled release of AVM in various applicable environments. The chemical interaction between zein and STP was confirmed by Fourier transform infrared, thermogravimetric analysis, and differential scanning calorimetric. Scanning electron microscopy, dynamic light scattering, and zeta potential technique were applied to investigate their structural characteristics and stability, from which it was found that AVM encapsulated in P-Zein (AVM@P-Zein) formed uniform nanoparticles with average sizes in the range of 174-278 nm under different conditions, and had an excellent stability in aqueous solution. Besides, AVM@P-Zein facilitated the wettability on the foliage surface evidenced from contact angle values owing to the amphiphilic character after phosphorylation as well as enhanced the adhesion ability between liquid and leaf, restricting the pesticide runoff. Ultraviolet-visible spectroscopy was employed to explore the anti-UV property and encapsulation as well as release behavior, which revealed that the presence of P-Zein like a shell protects AVM from UV photolysis with encapsulation efficiency of approximately 81.52%, and the release of AVM from P-Zein showed pH-responsive behavior ascribed to protonation and deprotonation of phosphate under various pH conditions fitting to Elovich kinetic model, achieving the relatively more rapid release under acidic conditions. More importantly, AVM@P-Zein retained the toxicity for insecticidal effect.


Assuntos
Preparações de Ação Retardada/química , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Inseticidas/química , Ivermectina/análogos & derivados , Nanopartículas/química , Zeína/química , Animais , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/efeitos da radiação , Composição de Medicamentos/instrumentação , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Inseticidas/farmacologia , Ivermectina/química , Ivermectina/farmacologia , Cinética , Mariposas/efeitos dos fármacos , Mariposas/crescimento & desenvolvimento , Nanopartículas/efeitos da radiação , Fosforilação , Polifosfatos/química , Raios Ultravioleta , Zeína/efeitos da radiação
4.
J Agric Food Chem ; 67(36): 10000-10009, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31442045

RESUMO

Improving plant resistance against systemic diseases remains a challenging research topic. In this study, we developed a dual-action pesticide-loaded hydrogel with the capacity to significantly induce plant resistance against tobacco mosaic virus (TMV) infection and promote plant growth. We produced an alginate-lentinan-amino-oligosaccharide hydrogel (ALA-hydrogel) by coating the surface of an alginate-lentinan drug-loaded hydrogel (AL-hydrogel) with amino-oligosaccharide using electrostatic action. We determined the formation of the amino-oligosaccharide film using various approaches, including Fourier transform infrared spectrometry, the ζ potential test, scanning electron microscopy, and elemental analysis. It was found that the ALA-hydrogel exhibited stable sustained-release activity, and the release time was significantly longer than that of the AL-hydrogel. In addition, we demonstrated that the ALA-hydrogel was able to continuously and strongly induce plant resistance against TMV and increase the release of calcium ions to promote Nicotiana benthamiana growth. Meanwhile, the ALA-hydrogel maintained an extremely high safety to organisms. Our findings provide an alternative to the traditional approach of applying pesticide for controlling plant viral diseases. In the future, this hydrogel with the simple synthesis method, green synthetic materials, and its efficiency in the induction of plant resistance will attract increasing attention and have good potential to be employed in plant protection and agricultural production.


Assuntos
Antivirais/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Lentinano/química , Lentinano/farmacologia , Doenças das Plantas/virologia , Vírus do Mosaico do Tabaco/fisiologia , Tabaco/virologia , Alginatos/química , Antivirais/farmacologia , Preparações de Ação Retardada/química , Resistência à Doença , Hidrogéis/química , Doenças das Plantas/imunologia , Tabaco/imunologia
5.
Int J Nanomedicine ; 14: 6001-6018, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447554

RESUMO

Background: The gastroretentive drug delivery system is an effective administration route, which can improve the bioavailability of the drug and the therapeutic effect by prolonging the release time of the drug and controlling the release rate in the stomach. Methods: Inspired by the excellent adhesion properties of mussel protein, we prepared novel catechol-grafted chitosan alginate/barium sulfate microcapsules (Cat-CA/BS MCs) with mucoadhesive properties and computed tomography (CT) imaging function for gastric drug delivery. First, barium sulfate nanoclusters used as CT contrast agent were synthesized in situ in the Cat-CA/BS MCs through a one-step electronic spinning method. Next, catechol-grafted chitosan as the mucoadhesive moiety was coated on the surface of Cat-CA/BS MCs by polyelectrolyte molecule self-assembly. Results: The prepared Cat-CA/BS MCs could effectively retained in the stomach for 48 hours and successively released ranitidine hydrochloride, which could be used for the treatment of gastric ulcer. Cat-CA/BS MCs exhibited superior CT contrast imaging properties for real-time tracking in vivo after oral administration. Conclusion: These findings demonstrate that Cat-CA/BS MCs serving as multifunctional oral drug carriers possess huge potential in gastroretentive drug delivery and non-invasive visualization.


Assuntos
Sulfato de Bário/química , Cápsulas/química , Catecóis/farmacologia , Quitosana/química , Sistemas de Liberação de Medicamentos , Estômago/efeitos dos fármacos , Estômago/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adesividade , Administração Oral , Animais , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos , Feminino , Camundongos Endogâmicos C57BL , Muco/química , Nanopartículas/química , Nanopartículas/ultraestrutura , Ranitidina/farmacologia , Espectroscopia de Luz Próxima ao Infravermelho , Estômago/patologia
6.
Food Chem ; 299: 125109, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31295635

RESUMO

The aim of this research is to develop, characterize and utilize a multi-layer antibacterial film using chitosan (CS) and sodium alginate (SA) as biopolymers and cinnamon essential oil (CEO) as main antibacterial ingredients. The dense cross-section of SA layer in the scanning electron microscopy (SEM) analysis verified that layer-by-layer method improved physical and mechanical properties of CS-CEO single layer film. The thermogravimetric (TGA) and fourier transform infrared (FT-IR) analysis indicated that the layer-by-layer method changed the intermolecular interaction and the thermal stability. Importantly, the multi-layer film exhibited more sustained release and higher retention rate of CEO compared CS-CEO single layer film. The multi-layer coating showed a more significant and lasting inhibition of penicillium expansion which further demonstrated that the layer-by-layer method improved the release and retention of CEO in the multiphased system. To summarize, the multilayer film system is a promising controllable release system for loading essential oils.


Assuntos
Antifúngicos/farmacologia , Cinnamomum zeylanicum/química , Malus/microbiologia , Óleos Voláteis/farmacologia , Penicillium/efeitos dos fármacos , Alginatos/química , Antifúngicos/química , Quitosana/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Frutas/efeitos dos fármacos , Frutas/microbiologia , Malus/efeitos dos fármacos , Microscopia Eletrônica de Varredura , Óleos Voláteis/farmacocinética , Penicillium/patogenicidade , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Termogravimetria
7.
J Agric Food Chem ; 67(33): 9220-9231, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31347838

RESUMO

Slow-release fungicide formulations (azoxystrobin, epoxiconazole, and tebuconazole) shaped as pellets and granules in a matrix of biodegradable poly(3-hydroxybutyrate) and natural fillers (clay, wood flour, and peat) were constructed. Infrared spectroscopy showed no formation of chemical bonds between components in the experimental formulations. The formulations of pesticides had antifungal activity against Fusarium verticillioides in vitro. A study of biodegradation of the experimental fungicide formulations in the soil showed that the degradation process was mainly influenced by the type of formulation without significant influence of the type of filler. More active destruction of the granules led to a more rapid accumulation of fungicides in the soil. The content of fungicides present in the soil as a result of degradation of the formulations and fungicide release was determined by their solubility. Thus, all formulations are able to function in the soil for a long time, ensuring gradual and sustained delivery of fungicides.


Assuntos
Argila/química , Preparações de Ação Retardada/química , Composição de Medicamentos/métodos , Fungicidas Industriais/química , Hidroxibutiratos/química , Poliésteres/química , Solo/química , Madeira/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Composição de Medicamentos/instrumentação , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Fungicidas Industriais/farmacologia , Fusarium/efeitos dos fármacos , Cinética , Pirimidinas/química , Pirimidinas/farmacologia , Estrobilurinas/química , Estrobilurinas/farmacologia , Triazóis/química , Triazóis/farmacologia
8.
Eur J Pharm Biopharm ; 142: 322-333, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31295503

RESUMO

The purpose of this work was the development of antibacterial delivery systems for vancomycin, with potential application in the prevention or treatment of orthopedic implant infections. Previous studies have shown tandem thermal gelling and Michael addition cross-linking of hydrogels based on methacrylate, acrylate or vinylsulfone triblock copolymers of PEG-p(HPMAm-lac1-2) and thiolated hyaluronic acid. In this work we exploited these α-ß unsaturated derivatives of PEG-p(HPMAm-lac1-2) triblock copolymers and used them in combination with thiolated hyaluronic acid as controlled delivery systems for vancomycin. It was found that the antibiotic was sustainably released from the hydrogel networks for at least 5 days with release kinetics depending on diffusion and dissociation of the positively charged vancomycin from the negatively charged hyaluronic acid. The release of vancomycin could be tailored mainly by HA-SH solid content and degree of thiolation. The developed hydrogels were demonstrate efficacious in preserving the structural and functional integrity of the encapsulated drug by physical immobilization within the gel network and ionic interaction with hyaluronic acid, thereby preventing vancomycin deamidation processes. Furthermore, the antimicrobial activity of vancomycin loaded hydrogels was assessed, demonstrating retention of inhibitory activity towards Staphylococcus aureus during formulation and release, with slightly increased activity of vancomycin encapsulated in hydrogels of higher HA-SH content as compared to controls.


Assuntos
Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Hidrogéis/química , Infecções Relacionadas à Prótese/tratamento farmacológico , Vancomicina/química , Vancomicina/farmacologia , Acrilatos/química , Antibacterianos/química , Antibacterianos/farmacologia , Ácido Hialurônico/química , Metacrilatos/química , Ortopedia/métodos , Polietilenoglicóis/química , Polímeros/química , Próteses e Implantes/microbiologia , Infecções Relacionadas à Prótese/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos
9.
Mater Sci Eng C Mater Biol Appl ; 102: 134-141, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31146984

RESUMO

Microencapsulation of pesticide is a promising technology to reduce the negative environmental impact and benefit the sustainable development. Trifluralin, commonly used as a selective pre-emergence herbicide, is vulnerably subject to loss by volatilization and decomposition by sunlight when applied to the surface of soils. In the present study, trifluralin has been encapsulated using biodegradable poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (PHB) polymers as carriers to develop controlled release formulations. PHB trifluralin microcapsules were obtained using a convenient solvent evaporation method. The influences of preparation parameters on the size and its distribution of the microcapsules were discussed. The particle size decreased from 4.44 µm to 2.50 µm as the shearing speeds increased from 4000 r/min to 12,000 r/min, and the value decreased from 3.64 µm to 3.23 µm as the mass fraction of emulsifier polyvinyl alcohol increased from 0.5% to 2.0%. The loading content (LC) as well as the encapsulation efficiency (EE) of trifluralin microcapsules are multiple factors dependent. Orthogonal table L9(34) was designed and range analysis was used to suggest the optimal preparation parameters. When performed under the optimized conditions, the corresponding LC and EE were 16.50% and 90.65%, respectively. The release of trifluralin from PHB microcapsules showed slow and sustained patterns, which could be easily achieved by modifying the preparation parameters including shearing speed and concentration of emulsifier. Compared to conventional trifluralin formulation of emulsifiable concentrate, trifluralin microcapsules exhibited significantly improved photostability and herbicidal activity against target weed barnyardgrass. These results demonstrated that microencapsulation with PHB could dramaticlly improve the effective utilization rate and decrease the dosage of such agricultural chemicals.


Assuntos
Herbicidas/farmacologia , Hidroxibutiratos/química , Luz , Poliésteres/química , Trifluralina/farmacologia , Cápsulas , Preparações de Ação Retardada/farmacologia , Liberação Controlada de Fármacos , Echinochloa/efeitos dos fármacos , Cinética , Fotólise , Raios Ultravioleta
10.
Mater Sci Eng C Mater Biol Appl ; 102: 578-588, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147030

RESUMO

An adsorbent-heater-thermometer nanomaterial, (ZIF-8,EuxTby)@AuNP, based on ZIF-8 (adsorbent), containing Eu3+ and/or Tb3+ ions (thermometer) and gold nanoparticles (AuNPs, heater) was designed, synthetized, characterized, and applied to controlled drug release. These composite materials were characterized as core-shell nanocrystals with the AuNPs being the core, around which the crystalline ZIF-8 has grown (shell) and onto which the lanthanide ions have been incorporated or chemosorbed. This shell of ZIF-8 acts as adsorbent of the drugs, the AuNPs act as heaters, while the luminescence intensities of the ligand and the lanthanide ions are used for temperature monitoring. This thermo-responsive material can be activated by visible irradiation to release small molecules in a controlled manner as established for the model pharmaceutical compounds 5-fluorouracil and caffeine. Computer simulations and transition state theory calculations shown that the diffusion of small molecules between neighboring pores in ZIF-8 is severely restricted and involves high-energy barriers. These findings imply that these molecules are uploaded onto and released from the ZIF-8 surface instead of being inside the cavities. This is the first report of ZIF-8 nanocrystals (adsorbents) containing simultaneously lanthanide ions as sensitive nanothermometers and AuNPs as heaters for controlled drug release in a physiological temperature range. These results provide a proof-of-concept that can be applied to other classes of materials, and offer a novel perspective on the design of self-assembly multifunctional thermo-responsive adsorbing materials that are easily prepared and promptly controllable.


Assuntos
Preparações de Ação Retardada/farmacologia , Liberação Controlada de Fármacos , Ouro/química , Nanopartículas Metálicas/química , Nanoestruturas/química , Termômetros , Zeolitas/química , Adsorção , Cafeína/farmacologia , Morte Celular/efeitos dos fármacos , Difusão , Érbio/química , Fluoruracila/farmacologia , Luminescência , Temperatura Ambiente , Térbio/química , Fatores de Tempo
11.
Int J Nanomedicine ; 14: 2903-2914, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114199

RESUMO

Background: Titanium (Ti) implant-associated infection, which is mostly caused by bacterial adhesion and biofilm formation, may result in implant failure and secondary surgery. Thus it is an urgent issue to prevent bacterial infections at the earliest step. Purpose: To develop a novel surface strategy of polydopamine (PDA) and silver (Ag) nanoparticle-loaded TiO2 nanorods (NRDs) coatings on Ti alloy. Materials and methods: Ag-TiO2@PDA NRDs was fabricated on Ti alloy by hydrothermal synthesis. The antibacterial activity of Ag-TiO2@PDA NRDs against Escherichia coli and methicillin-resistant Staphylococcus aureus were tested by FE-SEM, Live/Dead staining, zone of inhibition, bacteria counting method and protein leakage analysis in vitro. In addition, an implant infection model was conducted and the samples were tested by X-ray, Micro-CT and histological analysis in vivo. Besides, cell morphology and cytotoxicity of Mouse calvarial cells (MC3T3-E1) were characterized by FE-SEM, immunofluorescence and CCK-8 test in vitro. Results: Our study successfully developed a new surface coating of Ag-TiO2@PDA NRDs. The selective physical puncture of bacteria and controlled release of Ag+ ions of Ag-TiO2@PDA NRDs achieved a long-lasting bactericidal ability and anti-biofilm activity with satisfied biocompatibility. Conclusion: This strategy may be promising for clinical applications to reduce the occurrence of infection in the implant surgeries.


Assuntos
Antibacterianos/farmacologia , Indóis/química , Nanopartículas Metálicas/química , Nanotubos/química , Polímeros/química , Prata/farmacologia , Titânio/química , Animais , Aderência Bacteriana/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Forma Celular/efeitos dos fármacos , Preparações de Ação Retardada/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/ultraestrutura , Íons , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Camundongos , Testes de Sensibilidade Microbiana , Nanotubos/ultraestrutura , Infecções Relacionadas à Prótese/microbiologia , Infecções Relacionadas à Prótese/patologia , Propriedades de Superfície
12.
Int J Nanomedicine ; 14: 2433-2447, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040666

RESUMO

Purpose: The antitumoral effect of ATP requires its accumulation in the extracellular space to interact with membrane receptors in target cells. We propose the use of albumin nanoparticles (ANPs) coated with erythrocyte membranes (EMs) to load, deliver, release, and enhance the extracellular anticancer activity of ATP. Materials and methods: ANPs were synthesized by desolvation method and optimal values of pH, albumin concentration, and ethanol volume were determined. EMs were derived from erythrocyte lysates and were coated on to ANPs using an extruder. Size was determined by transmission electron microscopy (TEM) and hydrodynamic size and zeta potential were determined by dynamic light scattering. Coating of the ANPs with the EMs was verified by TEM and confocal microscopy. Nanoparticle cell uptake was analyzed by confocal microscopy using HeLa and HEK-293 cell cultures treated with nanoparticles stained with 1,1'-diocta-decyl-3,3,3',3'-tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt (DiD) for EM-ANPs and Alexa 488 for ANPs. Cell viability was analyzed by [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) and Annexin V/propidium iodide assays. Results: Optimal values of ANP preparation were as follows: pH=9, 10 mg/mL albumin concentration, and 2.33±0.04 mL ethanol volume. Size distributions as analyzed by TEM were as follows: ANPs =91.9±4.3 nm and EM-ANPs =98.3±5.1 nm; hydrodynamic sizes: ANPs =180.5±6.8 nm and EM-ANPs =197.8±3.2 nm; and zeta potentials: ANPs =17.8±3.5 mV, ANPs+ATP =-13.60±0.48 and EM-ANPs =-13.7±2.9 mV. The EMs coating the ANPs were observed by TEM and confocal microscopy. A fewer number of internalized EM-ANPs+ATP compared to non-coated ANPs+ATP was observed in HeLa and HEK-293 cells. Cell viability decreased up to 48.6%±2.0% with a concentration of 400 µM ATP after 72 hours of treatment and cell death is caused mainly via apoptosis. Conclusion: Our current results show that it is possible to obtain nanoparticles from highly biocompatible, biodegradable materials and that their coating with EMs allows the regulation of the internalization process in order to promote extracellular activity of ATP.


Assuntos
Trifosfato de Adenosina/farmacologia , Antineoplásicos/uso terapêutico , Materiais Biomiméticos/química , Espaço Extracelular/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Albuminas/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/farmacologia , Liberação Controlada de Fármacos , Difusão Dinâmica da Luz , Endocitose/efeitos dos fármacos , Membrana Eritrocítica/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Tamanho da Partícula , Eletricidade Estática
13.
Biomed Res Int ; 2019: 2928507, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119162

RESUMO

Hyaluronic acid functionalized mesoporous hollow alumina nanoparticles (HMHA) were used as a tumor-targeted delivery carrier for liver cancer therapy. Paclitaxel (PAC) incorporated in the carrier by the adsorption method was analyzed by X-ray diffraction and differential scanning calorimetry. PAC was found to be in an amorphous state. The hyaluronic acid coated on the surface of mesoporous hollow alumina nanoparticles (MHA) regulated the drug release rate and the loaded samples obtained a sustained drug release. In vitro experiments demonstrated that paclitaxel-hyaluronic acid functionalized mesoporous hollow alumina nanoparticles (PAC-HMHA) had a high cellular uptake, which increased the drug level in tumor tissues and was beneficial to promote apoptosis. An in vivo tumor inhibition rate study demonstrated that PAC-HMHA (64.633 ± 4.389%) had a better antitumor effect than that of paclitaxel-mesoporous alumina nanoparticles (PAC-MHA, 56.019 ± 6.207%) and pure PAC (25.593 ± 4.115%). Therefore it can be concluded that PAC-HMHA are a prospective tumor-targeted delivery medium and can be useful for future cancer therapy.


Assuntos
Albuminas/farmacologia , Sistemas de Liberação de Medicamentos , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas Metálicas/química , Paclitaxel/farmacologia , Albuminas/química , Óxido de Alumínio/química , Apoptose/efeitos dos fármacos , Calorimetria , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Neoplasias Hepáticas/patologia , Nanopartículas Metálicas/ultraestrutura , Paclitaxel/química , Dióxido de Silício/química , Difração de Raios X
14.
ACS Appl Mater Interfaces ; 11(20): 18691-18700, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31038909

RESUMO

Polyprodrug nanoparticles have been employed recently for safer and more effective cancer treatment. However, it remains a challenge to elucidate how and when the polyprodrug nanoparticles are dissociated and activated to release active drugs in cancer cells. Herein, a visible light-activatable Pt(IV) prodrug and an aggregation-induced emission luminogen (AIEgen) were copolymerized and embedded in the main chain of PtAIECP, and the chemotherapeutic doxorubicin (DOX) was subsequently encapsulated in the nanoparticles self-assembled by PtAIECP (PtAIECP@DOX NP). PtAIECP@DOX NP enabled the monitoring of both the light-activation of Pt(IV) prodrug to active Pt(II) and release of encapsulated DOX intracellularly through the fluorescence "turn-on" in the course of visible-light-induced polymer-main-chain cleavage and self-assembled structure dissociation in vitro and ex vivo. The synergistic anticancer efficacy of the activated Pt(II) drug and DOX in PtAIECP@DOX NP was also investigated in vitro and in vivo. The implementation of polyprodrug and AIE combination strategy empowered dual drug release and monitoring, which could be further used to guide the temporal and spatial control of light irradiation to maximize therapeutic efficiency, and will inspire other combinational bioimaging and therapy strategies.


Assuntos
Portadores de Fármacos , Luz , Nanopartículas , Neoplasias Ovarianas/tratamento farmacológico , Pró-Fármacos , Animais , Linhagem Celular Tumoral , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia
15.
J Nanobiotechnology ; 17(1): 60, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31084622

RESUMO

BACKGROUND: Nanoscale drug-delivery systems (DDSs) have great promise in tumor diagnosis and treatment. Platelet membrane (PLTM) biomimetic DDSs are expected to enhance retention in vivo and escape uptake by macrophages, as well as minimizing immunogenicity, attributing to the CD47 protein in PLTM sends "don't eat me" signals to macrophages. In addition, P-selectin is overexpressed on the PLTM, which would allow a PLTM-biomimetic DDS to specifically bind to the CD44 receptors upregulated on the surface of cancer cells. RESULTS: In this study, porous nanoparticles loaded with the anti-cancer drug bufalin (Bu) were prepared from a chitosan oligosaccharide (CS)-poly(lactic-co-glycolic acid) (PLGA) copolymer. These were subsequently coated with platelet membrane (PLTM) to form PLTM-CS-pPLGA/Bu NPs. The PLTM-CS-pPLGA/Bu NPs bear a particle size of ~ 192 nm, and present the same surface proteins as the PLTM. Confocal microscopy and flow cytometry results revealed a greater uptake of PLTM-CS-pPLGA/Bu NPs than uncoated CS-pPLGA/Bu NPs, as a result of the targeted binding of P-selectin on the surface of the PLTM to the CD44 receptors of H22 hepatoma cells. In vivo biodistribution studies in H22-tumor carrying mice revealed that the PLTM-CS-pPLGA NPs accumulated in the tumor, because of a combination of active targeting effect and the EPR effect. The PLTM-CS-pPLGA/Bu NPs led to more effective tumor growth inhibition over other bufalin formulations. CONCLUSIONS: Platelet membrane biomimetic nanoparticles played a promising targeted treatment of cancer with low side effect.


Assuntos
Antineoplásicos/química , Materiais Biomiméticos/química , Bufanolídeos/química , Portadores de Fármacos/química , Nanopartículas/química , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Transporte Biológico , Plaquetas/metabolismo , Bufanolídeos/efeitos adversos , Bufanolídeos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Oligossacarídeos/química , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Distribuição Tecidual
16.
AAPS PharmSciTech ; 20(4): 158, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30963353

RESUMO

The present study deals with the formulation of topical insulin for wound healing with extended stability and sustained release, by applying quality by design concepts. Insulin has been promoted as a promising therapeutic wound healing agent. Topical formulation of insulin faced major problems, as it cannot be delivered safely to the wound with a controlled rate. Formulation of insulin-loaded vesicles in optimized bio-adhesive hydrogels has been explored to ensure a safe delivery of insulin to wounds in a controlled manner. Quality by design (QbD) was applied to study the effect of several critical process parameters on the critical quality attributes. Ishikawa diagram was used to identify the highest risk factors, which were screened by a fractional factorial design and augmented by Box-Behnken design. The optimized formula was incorporated into a mucoadhesive gel, which was further subjected to stability and clinical studies. An optimized formula was obtained with a particle size of 257.751 nm, zeta potential - 20.548 mv, 87.379% entrapment efficiency, and a release rate of 91.521 µg/cm2/h. The results showed that liposomal insulin remained stable for 6 months in aqueous dispersion state at 4°C. Moreover, the release was sustained up to 24 h. The clinical study showed an improvement in the wound healing rate, 16 times, as the control group, with magnificent reduction in the erythema of the ulcer and no signs of hypoglycemia. Insulin-loaded liposomal chitosan gel showed a promising drug delivery system with high stability and sustained release.


Assuntos
Preparações de Ação Retardada/farmacologia , Insulina/farmacologia , Cicatrização/efeitos dos fármacos , Quitosana/farmacologia , Sistemas de Liberação de Medicamentos , Hidrogéis/farmacologia , Lipossomos/farmacologia , Tamanho da Partícula
17.
Biomed Res Int ; 2019: 8043415, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949510

RESUMO

The aim of the present study was to investigate the suitability of insoluble Eudragit® water dispersions (NE, NM, RL, and RS) for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matrices. The process characteristics, ss-NMR analysis, in vitro dissolution behavior, drug release mechanism and kinetics, texture profile analysis of the gel layer, and PCA analysis were explored. An application of water dispersions directly on levetiracetam was feasible only in a multistep process. All prepared formulations exhibited a 12-hour sustained release profile characterized by a reduced burst effect in a concentration-dependent manner. No effect on swelling extent of HPMC K100M was observed in the presence of Eudragit®. Contrary, higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit®. Not only the type and concentration of Eudragit®, but also the presence of the surfactant in water dispersions played a key role in the dissolution characteristics. The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directly granulated by the water dispersion of Eudragit® NE (5% of solid polymer per tablet) with a relatively high amount of surfactant nonoxynol 100 (1.5%). The initial burst release of drug was reduced to 8.04% in 30 min (a 64.2% decrease) while the total amount of the released drug was retained (97.02%).


Assuntos
Derivados da Hipromelose , Lactose/análogos & derivados , Metilcelulose/análogos & derivados , Nonoxinol , Ácidos Polimetacrílicos , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Liberação Controlada de Fármacos , Derivados da Hipromelose/química , Derivados da Hipromelose/farmacocinética , Derivados da Hipromelose/farmacologia , Lactose/química , Lactose/farmacocinética , Lactose/farmacologia , Metilcelulose/química , Metilcelulose/farmacocinética , Metilcelulose/farmacologia , Nonoxinol/química , Nonoxinol/farmacocinética , Nonoxinol/farmacologia , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacocinética , Ácidos Polimetacrílicos/farmacologia
18.
ACS Appl Mater Interfaces ; 11(16): 14647-14659, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30933478

RESUMO

Ineffective drug delivery and poor prognosis are two major challenges in the treatment of pancreatic ductal adenocarcinoma (PDAC). While there is significant downregulation of tumor suppressor microRNA-34a (miR-34a), which targets many oncogenes related to proliferation, apoptosis, and invasion, high expression level of Polo-like kinase 1 (PLK1) is closely associated with short survival rates of pancreatic cancer patients. Therefore, the objective is to codeliver miR-34a mimic and small molecule PLK1 inhibitor volasertib (BI6727) using poly(ethylene glycol)-poly[aspartamidoethyl( p-boronobenzyl)diethylammonium bromide] (PEG-B-PAEBEA). This polymer could self-assemble into micelles of ∼100 nm with 10% drug loading of volasertib and form a complex with miR-34a at the N/P ratio of 18 and higher. Combination treatment of volasertib and miR-34a displayed the synergistic effect and superior antiproliferative activity along with an enhanced G2/M phase arrest and suppression of colony formation, leading to cell death due to potential c-myc targeting therapeutics. Orthotopic pancreatic tumor bearing NSG mice were scanned for fluorescence by IVIS after systemic administration of micelles encapsulating volasertib and miR-34a at doses of 5 and 1 mg/kg, respectively. Cy5.5 concentration in plasma and major organs was determined by measuring fluorescence intensity. There was significant reduction in tumor volume, and histological examination of major organs suggested negligible systemic toxicity. In conclusion, PEG-B-PAEBEA micelles carrying volasertib and miR-34a mimic have the potential to treat pancreatic cancer.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Micelas , MicroRNAs/farmacologia , Neoplasias Pancreáticas , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pteridinas , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas/química , Pteridinas/farmacologia
19.
Biomed Pharmacother ; 114: 108823, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30965238

RESUMO

We previously developed propranolol-encapsulated liposomes-in-microspheres (PLIM) to realize the sustained propranolol release for the treatment of hemangiomas. However, the liposomes released from the microspheres still lacked specificity for CD133-positive hemangioma-derived stem cells (HemSCs) which are considered to be the seeds of hemangiomas. Therefore, we hereby encapsulated propranolol-loaded CD133 aptamers conjugated liposomes in poly(lactic-co-glycolic acid (PLGA) microspheres to develop propranolol-loaded CD133 aptamers conjugated liposomes-in-microspheres (PCLIM), to realize the aim of the sustained and targeted therapy of hemangiomas. The evaluation of the release of propranolol from PCLIM was carried out, and the cytotoxic effect and angiogenic growth factor expression inhibitory ability of PCLIM were performed in HemSCs. The in vivo hemangioma inhibitory ability of PCLIM was also investigated in nude mice with subcutaneous human hemangiomas. PCLIM possessed a desired size of 29.2 µm, drug encapsulation efficiency (25.3%), and a prolonged drug release for 40 days. Importantly, PCLIM could inhibit HemSCs proliferation and the protein expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF) in HemSCs to a greater extent compared with PLIM. In nude mice bearing hemangioma xenograft, PCLIM showed the best therapeutic efficacy towards hemangiomas, as reflected by remarkably decreased hemangioma volume, weight and microvessel density (MVD). Thus, our results demonstrated that PCLIM realized the sustained and targeted treatment of hemangiomas, resulting in remarkable inhibition of hemangiomas.


Assuntos
Antígeno AC133/química , Aptâmeros de Nucleotídeos/química , Preparações de Ação Retardada/farmacologia , Hemangioma/tratamento farmacológico , Lipossomos/química , Propranolol/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Preparações de Ação Retardada/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/fisiologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Hemangioma/metabolismo , Humanos , Camundongos Nus , Microesferas , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Propranolol/química , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Mater Sci Eng C Mater Biol Appl ; 100: 466-474, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948082

RESUMO

The aim of this study is to develop an electrospun calixarene nanofiber based calixarene for controlled release of hydrophobic drugs. To accomplish this, we have synthesized 5,17-bis-[Methyl-N-Methyltranylate]-25,26,27,28-tetrahydroxycalix[4]arene (Compound 3) of which nanofiber (F-14) was produced by electrospinning. The fabricated multilayered electrospun nanofiber was first characterized in terms of morphology and then drug loading and release kinetics were studied in different physiological pH. For this purpose, we have selected two fluorescent drugs which are thiabendazole (Tbz) and donepezil (Dnp) as model drugs to show the usage of the synthesized nanofiber in drug delivery system. Drug loading and release kinetics were monitored by using fluorescence spectroscopy. According to the results, maximum amount of loaded Dnp onto nanofiber was found to be as 30.529 µg in 20 mM Tris buffer, pH 7.4 end of 120 min. Data showed that loading amount of Tbz onto the nanofiber was measured to be as 1.688 µg to the 2.25 cm2 of surface in 20 mM of Tris buffer, pH 7.4 at the end of 120 min. While max release of Dnp from nanofiber was also 9.720 µg at pH 2.2, that of Tbz from nanofiber was 0.243 µg at pH 7.4 at the end of 90 min. Drug loading to nanofibers was clarified by SEM, TEM, EDX and FT-IR analysis.


Assuntos
Calixarenos/química , Preparações de Ação Retardada/farmacologia , Nanofibras/química , Calixarenos/síntese química , Liberação Controlada de Fármacos , Nanofibras/ultraestrutura , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier
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