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1.
Int J Nanomedicine ; 15: 5113-5129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764940

RESUMO

Background: Low bioavailability and poor permeability of the blood-brain barrier are problematic when delivering therapeutic agents and particularly anti-human immunodeficiency virus therapy to the central nervous system. The intranasal route offers an alternative for central nervous system delivery. Cubosomes have been reported as helpful vehicles for intranasal delivery of therapeutics to enable brain targeting. Objective: In this study, we aimed to develop the intranasal cubosomal thermogelling dispersion of saquinavir mesylate for central nervous system delivery. Methods: The Box-Behnken design was applied to study the effect of monoolein, Poloxamer 407, and polyvinyl alcohol as independent factors and the particle size, entrapment efficiency, gelation temperature, and stability index as responses. The optimized cubosomes were evaluated using transmission electron microscopy, ex vivo permeation, and in vivo pharmacokinetics. Results: The optimized formula consisting of monoolein (8.96%), Poloxamer 407 (17.45%), and polyvinyl alcohol (7.5%) was prepared and evaluated. Higher values for the steady-state flux, permeability coefficient, and enhancement factor were observed for the cubosomal thermogelling dispersion of saquinavir during ex vivo permeation in comparison with an aqueous suspension of saquinavir. From the pharmacokinetic profile, the relative bioavailability for the intranasal optimized formula was approximately 12-fold higher when compared with oral aqueous suspension and 2.5-fold greater when compared to the intranasal aqueous suspension of saquinavir. Conclusion: Overall, the saquinavir-loaded cubosomal thermogelling formulation is promising for central nervous system delivery by intranasal administration.


Assuntos
Portadores de Fármacos/química , Cristais Líquidos/química , Nanoestruturas/química , Saquinavir/farmacologia , Temperatura , Administração Intranasal , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Géis , Glicerídeos/química , Masculino , Tamanho da Partícula , Permeabilidade , Poloxâmero/química , Álcool de Polivinil/química , Saquinavir/administração & dosagem , Saquinavir/metabolismo
2.
Int J Nanomedicine ; 15: 5239-5252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801689

RESUMO

Introduction: The main pathological mechanism of restenosis after percutaneous coronary intervention (PCI) is intimal hyperplasia, which is mainly caused by proliferation and migration of vascular smooth muscle cells (VSMCs). Our previous study found that honokiol (HNK), a small-molecule polyphenol, can inhibit neointimal hyperplasia after balloon injury, but its specific mechanism is still unclear. Moreover, poor water solubility as well as low bioavailability of honokiol has limited its practical use. Methods: We used mesoporous silica nanoparticles (MSNPs) as a standard substance to encapsulate HNK and then assemble into honokiol-mesoporous silica nanoparticles, and we investigated the effect of these nanoparticles on the process of restenosis after common carotid artery injury in rats. Results: We report a promising delivery system that loads HNK into MSNPs and finally assembles it into a nanocomposite particle. These HNK-MSNPs not merely inhibited proliferation and migration of VSMCs by reducing phosphorylation of Smad3, but also showed a higher suppression of intimal thickening than the free-honokiol-treated group in a rat model of balloon injury. Conclusion: To sum up, this drug delivery system supplies a potent nano-platform for improving the biological effects of HNK and provides a promising strategy for preventing vascular restenosis.


Assuntos
Compostos de Bifenilo/farmacologia , Reestenose Coronária/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Lignanas/farmacologia , Nanopartículas/química , Intervenção Coronária Percutânea/efeitos adversos , Animais , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacocinética , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Reestenose Coronária/metabolismo , Modelos Animais de Doenças , Humanos , Lignanas/administração & dosagem , Lignanas/farmacocinética , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nanopartículas/administração & dosagem , Poloxâmero/química , Ratos Sprague-Dawley , Dióxido de Silício/química
3.
AAPS PharmSciTech ; 21(5): 162, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488761

RESUMO

Hyaluronic acid (HA) is widely used to treat various ocular diseases like dry eye syndrome, keratoconus, and other corneal epithelial injuries. The currently available eye drop solutions need frequent doses affecting the routine life style of patients. In this work, the silicone contact lens was designed to entrap HA and Pluronic®F127 to improve the wettability of the contact lens to treat various ocular diseases. The soaking method (HA-SM) was compared with the direct entrapment (DL-HA-PI) technique. The HA-Pluronic®F127-laden contact lenses (DL-HA-PI) showed acceptable optical transmittance with improved swelling (water content) properties. The in vitro release data showed high burst release with HA-SM contact lenses (12-36 h), while DL-HA-PI contact lenses showed prolong release up to 96 h. The in vivo release in the rabbit tear fluid showed high HA concentration (tear fluid) with DL-HA-PI contact lenses in comparison to the HA-SM contact lenses. The DL-HA-PI-3 batch with Pluronic®F127 showed more promising results in schirmer strip study in comparison to DL-HA-3 batch (without Pluronic®F127). The presence of Pluronic®F127 with HA showed high potential to improve hydration property of the contact lens. The corneal healing model showed reduction in the ocular inflammatory symptoms with DL-HA-PI-3 batch, thus demonstrating the potential of HA and Pluronic®F127 to be used in various ocular diseases.


Assuntos
Lentes de Contato Hidrofílicas , Epitélio Anterior/patologia , Ácido Hialurônico/química , Poloxâmero/química , Animais , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Ceratite/fisiopatologia , Masculino , Coelhos , Molhabilidade , Cicatrização
4.
AAPS PharmSciTech ; 21(5): 141, 2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32419084

RESUMO

Current study is focused to enhance the solubility of poorly soluble drug olanzapine (OLZ) by nanogels drug delivery system, as improved solubility is one of the most important applications of nanosystems. Poor solubility is a major issue, and 40% of marketed and about 75% of new active pharmaceutical ingredients are poorly water soluble which significantly affect the bioavailability and therapeutic effects of these drugs. In this study, nanogels, a promising system for solubility enhancement, were developed by free-radical polymerization technique. Different formulations were synthesized in which poloxamer-407 was cross-linked with 2-acrylamido-2-methylpropane sulfonic acid (AMPS) with the help of cross-linker methylene bisacrylamide (MBA). The chemically cross-linked nanogels were characterized by Fourier transform infrared spectroscopy (FT-IR), thermos gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM), zeta size, swelling, sol-gel analysis, drug loading, solubility, and in vitro drug release studies. In order to determine the biocompatibility and cytotoxicity of nanogels to biological system, toxicity study on rabbits was also carried out. It was confirmed that the developed nanogels was thermally stable, safe, effective, and compatible to biological system, and the solubility of olanzapine (OLZ) was enhanced up to 38 folds as compared with reference product.


Assuntos
Antipsicóticos/administração & dosagem , Reagentes para Ligações Cruzadas , Nanogéis , Olanzapina/administração & dosagem , Poloxâmero/química , Acrilamidas , Animais , Antipsicóticos/química , Antipsicóticos/toxicidade , Disponibilidade Biológica , Liberação Controlada de Fármacos , Excipientes , Radicais Livres , Olanzapina/química , Olanzapina/toxicidade , Tamanho da Partícula , Coelhos , Solubilidade
5.
Nat Commun ; 11(1): 2323, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385252

RESUMO

An on-demand anesthetic that would only take effect when needed and where the intensity of anesthesia could be easily adjustable according to patients' needs would be highly desirable. Here, we design and synthesize a macromolecular prodrug (P407-CM-T) in which the local anesthetic tetracaine (T) is attached to the polymer poloxamer 407 (P407) via a photo-cleavable coumarin linkage (CM). P407-CM-T solution is an injectable liquid at room temperature and gels near body temperature. The macromolecular prodrug has no anesthetic effect itself unless irradiated with a low-power blue light emitting diode (LED), resulting in local anesthesia. By adjusting the intensity and duration of irradiation, the anesthetic effect can be modulated. Local anesthesia can be repeatedly triggered.


Assuntos
Anestésicos Locais/química , Anestesia Local/métodos , Animais , Sistemas de Liberação de Medicamentos , Humanos , Estrutura Molecular , Poloxâmero/química , Pró-Fármacos/química , Temperatura
6.
Soft Matter ; 16(21): 4990-4998, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32436559

RESUMO

We have identified the hierarchical (primary, secondary, tertiary and quaternary) structures of a polypseudorotaxane (PPR) gel composed of the Pluronic F108 and ß-cyclodextrin system to be ß-cyclodextrin crystalline, lamellar sheets, lamellar stacks and "grains", respectively. The correlation between the rheological properties and the proposed structures under shear flows was rationalized. Alignment of lamellar stacks and reorganization of grain boundaries under shear flows were investigated by rheo-SANS, small angle X-ray scattering and small-angle light scattering. The relaxation of highly aligned lamellar stacks is slow (>2 h) after flow cessation compared to that of the regrouped grains (a few minutes). The main contribution to thixotropic behavior is likely from the faster relaxation of the reorganized grains containing highly oriented lamellar stacks. The comprehensive understanding of structure-function relationship of the PPR gel will facilitate the rational design for its applications.


Assuntos
Hidrogéis/química , Poloxâmero/química , Rotaxanos/química , beta-Ciclodextrinas/química , Reologia
7.
Chemosphere ; 254: 126732, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32320831

RESUMO

Effective targeted delivery of nanoparticle agents may enhance the remediation of soils and site characterization efforts. Nanoparticles coated with Pluronic, an amphiphilic block co-polymer, demonstrated targeted binding behaviour toward light non-aqueous phase liquids such as heavy crude oil. Various factors including coating concentration, oil concentration, oil type, temperature, and pH were assessed to determine their effect on nanoparticle binding to heavy crude oil-impacted sandy aquifer material. Nanoparticle binding was increased by decreasing the coating concentration, increasing oil concentration, using heavier oil types, and increasing temperature, while pH over the range of 5-9 was found to have no effect. Nanoparticle transport and binding in columns packed with clean and oily porous media demonstrated the ability for efficient nanoparticle targeted binding. For the conditions explored, the attachment rate coefficient in columns packed with clean sand was 2.10 ± 0.66 × 10-4 s-1; however, for columns packed with oil-impacted sand a minimum attachment rate coefficient of 8.86 ± 0.43 × 10-4 s-1 was estimated. The higher attachment rate for the oil-impacted sand system indicates that nanoparticles may preferentially accumulate to oil-impacted zones present at heterogeneous impacted sites. Simulations were used to demonstrate this hypothesis using the set of parameters generated in this effort. This work contributes to our understanding of the application conditions that are required for efficient targeted binding of nanoparticles to crude-oil impacted porous media.


Assuntos
Compostos Férricos/química , Hidrocarbonetos/química , Nanopartículas/química , Petróleo , Poluentes do Solo/química , Água Subterrânea/química , Hidrocarbonetos/isolamento & purificação , Poloxâmero/química , Porosidade , Dióxido de Silício/química , Poluentes do Solo/isolamento & purificação
8.
Nanotechnology ; 31(25): 255101, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32143196

RESUMO

Drug delivery carriers hold tremendous promise for improving cancer treatment, and polyrotaxane (PR) has shown excellent drug-carrying properties. However, there have been some reports that, when used as a drug carrier, water-soluble PR is not easily labeled with organic fluorescent dyes. Herein, we synthesized a drug-loaded fluorescent porphyrin-terminated PR (PR-COOH) which can be used as a tracer material in drug and gene delivery. The structure, morphology and zeta potential of PR-COOH were characterized by nuclear magnetic resonance, high-resolution transmission electron microscopy and zeta potentiometry. In this research, cisplatin (CDDP) is used as a model drug. The zeta potential, drug encapsulation efficiency and drug release of CDDP-loaded PR (PR-COOH-Pt) were studied. Confocal laser scanning microscopy showed that PR-COOH could be internalized by HeLa and CT26 cells. The antitumor efficacy of PR-COOH-Pt was investigated in vitro by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and in vivo by a xenograft tumor model. The results showed that PR-COOH-Pt could significantly inhibit tumor growth; thus PR-COOH-Pt has a promising role in cancer therapy.


Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Ciclodextrinas/síntese química , Neoplasias Hepáticas/tratamento farmacológico , Poloxâmero/síntese química , Porfirinas/química , Rotaxanos/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Ciclodextrinas/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Células HeLa , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Nanopartículas , Poloxâmero/química , Rotaxanos/química , Ensaios Antitumorais Modelo de Xenoenxerto
9.
PLoS One ; 15(3): e0227784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160196

RESUMO

Pleural empyema is an inflammatory condition characterized by accumulation of pus inside the pleural cavity, which is usually followed by bacterial pneumonia. During the disease process, the pro-inflammatory and pro-fibrotic cytokines in the purulent pleural effusion cause proliferation of fibroblasts and deposition of extracellular matrix, which lead to fibrin deposition and fibrothorax. Urokinase instillation therapy through a chest drainage tube is frequently used for fibrinolysis in patients with empyema. However, urokinase treatment requires multiple instillation (2-3 times per day, for 4-8 days) and easily flows out from the chest drainage tube due to its high water solubility. In this in vitro study, we developed a thermo-responsive hydrogel based on poloxamer 407 (P407) combined with hyaluronic acid (HA) for optimal loading and release of urokinase. Our results show that the addition of HA to poloxamer gels provides a significantly more compact microstructure, with smaller pore sizes (**p < 0.001). The differential scanning calorimetry (DSC) profile revealed no influence on the micellization intensity of poloxamer gel by HA. The 25% poloxamer-based gel was significantly superior to the 23% poloxamer-based gel, with slower gel erosion when comparing the 16th hour residual gel weight of both gels (*p < 0.05; **p < 0.001). The 25% poloxamer-HA gel also exhibited a superior urokinase release profile and longer release time. A Fourier-transform infrared spectroscopy (FT-IR) study of the P407/HA hydrogel showed no chemical interactions between P407 and HA in the hydrogel system. The thermoresponsive P407/HA hydrogel may have a promising potential in the loading and delivery of hydrophilic drugs. On top of that, in vitro toxicity test of this combination demonstrates a lower toxicity.


Assuntos
Portadores de Fármacos/química , Empiema Pleural/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem , Linhagem Celular , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Empiema Pleural/patologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibrina/metabolismo , Fibrinolíticos/farmacocinética , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/toxicidade , Hidrogéis/química , Hidrogéis/toxicidade , Poloxâmero/química , Poloxâmero/toxicidade , Temperatura , Fatores de Tempo , Testes de Toxicidade , Ativador de Plasminogênio Tipo Uroquinase/farmacocinética
10.
Int J Nanomedicine ; 15: 779-793, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099365

RESUMO

Purpose: Cancer chemotherapy effect has been largely limited by cell autophagy and little drug accumulation at the action sites. Herein, we designed an intelligent strategy involving paclitaxel (PTX) polymer micelles in response to biological functions of ambroxol (Ax). The amphiphilic polymers polyethyleneglycol-polylactic acid (PEG-PLA) and Pluronic P105 were selected as nanocarriers to encapsulate PTX to form into lung affinity PEG-PLA/P105/PTX micelles. Ax which can up-regulate the secretion of pulmonary surfactant (PS) and inhibit autophagy was hired to change the microenvironment of the lung, thereby promoting the lung accumulation and increasing cell-killing sensitivity of the micelles. Methods: The physical and chemical properties of the micelles were characterized including size, morphology, critical micellar concentration (CMC) and in vitro drug release behavior. The therapeutic effects of the combination regimen were characterized both in vitro and in vivo including study on Ax in promoting the secretion of pulmonary surfactant, in vitro cytotoxicity, cellular uptake, Western blotting, in vivo biodistribution, in vivo pharmacokinetics and in vivo antitumor efficacy. Results: The PEG-PLA/P105/PTX micelles showed a particle size of 16.7 ± 0.5 nm, a nearly round shape, small CMC and sustained drug release property. Moreover, the in vitro results indicated that Ax could increase PS and LC3 protein secretion and enhance the cytotoxicity of PEG-PLA/P105/PTX micelles toward A549 cells. The in vivo results indicated that the combination therapeutic regimen could promote the micelles to distribute in lung and enhance the therapeutic effect on lung cancer. Conclusion: This multifunctional approach of modulating the tumor microenvironment to enhance drug transportation and cell-killing sensitivity in the action sites might offer a new avenue for effective lung cancer treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamento farmacológico , Ambroxol/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Micelas , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Tamanho da Partícula , Poloxâmero/química , Polietilenoglicóis/química , Polímeros/química , Ratos Sprague-Dawley , Distribuição Tecidual
11.
Int J Nanomedicine ; 15: 1129-1148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110012

RESUMO

Introduction: Solid lipid nanoparticles (SLNs) are considered a promising system in enhancing the oral bioavailability of poorly water-soluble drugs; owing to their intrinsic ability to increase the solubility together with protecting the incorporated drugs from extensive metabolism. Objective: Exploiting such properties, SLNs loaded with gliclazide (GLZ) were developed in an attempt to improve the oral bioavailability and the anti-diabetic action of GLZ, together with prolonging its duration of action for better glycemic control. Methods: SLNs were prepared by ultra-sonication technique using glyceryl behenate (Compritol®888 ATO) as a lipid matrix and poloxamer 188 (PLX) as a stabilizer. A 2*3 asymmetrical factorial design was adopted to study the effect of different stabilizer concentrations at different sonication times on the shape, and size of the particles, PDI and drug loading. The selected optimum formulation was then freeze dried using trehalose di-hydrate as a cryo-protectant in different ratios with respect to glyceryl behenate concentration. After freeze drying, the formulation was tested for in-vitro drug release, pharmacokinetics, and pharmacodynamics. Safety of the selected formula was established after carrying out a subacute toxicity study. Results: The factorial design experiment resulted in an optimum formulation coded 10F2 (150 mg PLX/10 min sonication). Scanning electron micrographs showed spherical particles with smooth surface, whereas a ratio of 2:1 cryo-protectant:lipid was found to be optimum with particle size of 245.9 ± 26.2 nm, polydispersity index of 0.482 ± 0.026, and biphasic in-vitro release with an initial burst effect, followed by a prolonged release phase. On the other hand, the selected SLNs exhibited prolonged drug release when compared with the GLZ commercial immediate release (IR) tablets (Diamicron®). Pharmacokinetics study showed about 5-fold increase in GLZ oral bioavailability loaded in SLNs when compared with raw GLZ powder. Pharmacodynamics study on a diabetic rat model confirmed the better anti-diabetic action of GLZ loaded SLNs when compared to raw GLZ powder. Subacute toxicity study indicated the safety of SLNs upon repetitive oral administration.


Assuntos
Gliclazida/farmacocinética , Hipoglicemiantes/farmacocinética , Nanopartículas/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Diabetes Mellitus Experimental/tratamento farmacológico , Liberação Controlada de Fármacos , Ácidos Graxos/química , Liofilização , Gliclazida/administração & dosagem , Gliclazida/toxicidade , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/toxicidade , Lipídeos/química , Masculino , Nanopartículas/química , Tamanho da Partícula , Poloxâmero/química , Ratos Wistar , Solubilidade , Comprimidos/química , Testes de Toxicidade Subaguda
12.
Int J Nanomedicine ; 15: 1173-1186, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110015

RESUMO

Background: The facile preparation of oxygen-generating microparticles (M) consisting of Polycaprolactone (PCL), Pluronic F-127, and calcium peroxide (CPO) (PCL-F-CPO-M) fabricated through an electrospraying process is disclosed. The biological study confirmed the positive impact from the oxygen-generating microparticles on the cell growth with high viability. The presented technology could work as a prominent tool for various tissue engineering and biomedical applications. Methods: The oxygen-generated microparticles fabricated through electrospraying processes were thoroughly characterization through various methods such as X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) analysis, and scanning electron microscopy (SEM)/SEM-Energy Dispersive Spectroscopy (EDS) analysis. Results: The analyses confirmed the presence of the various components and the porous structure of the microparticles. Spherical shape with spongy characteristic microparticles were obtained with negative charge surface (ζ = -16.9) and a size of 17.00 ± 0.34 µm. Furthermore, the biological study performed on rat chondrocytes demonstrated good cell viability and the positive impact of increasing the amount of CPO in the PCL-F-CPO-M. Conclusion: This technological platform could work as an important tool for tissue engineering due to the ability of the microparticles to release oxygen in a sustained manner for up to 7 days with high cell viability.


Assuntos
Oxigênio/farmacocinética , Animais , Materiais Biocompatíveis/química , Técnicas de Cultura de Células , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Técnicas Eletroquímicas , Oxigênio/química , Peróxidos/química , Poloxâmero/química , Poliésteres/química , Porosidade , Ratos Wistar , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Engenharia Tecidual/métodos , Difração de Raios X
13.
J Colloid Interface Sci ; 565: 119-130, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31945671

RESUMO

Understanding structure-property relationships is critical for the development of new drug delivery systems. This study investigates the properties of Pluronic smart hydrogel formulations for future use as injectable controlled drug carriers. The smart hydrogels promise to enhance patient compliance, decrease side effects and reduce dose and frequency. Pharmaceutically, these systems are attractive due to their unique sol-gel phase transition in the body, biocompatibility, safety and injectability as solutions before transforming into gel matrices at body temperature. We quantify the structural changes of F127 systems under controlled temperature after flow, as experienced during real bodily injection. Empirical formulae combining the coupled thermal and shear dependency are produced to aid future application of these systems. Induced structural transitions measured in-situ by small angle x-ray and neutron scattering reveal mixed oriented structures that can be exploited to tailor the drug release profile.


Assuntos
Sistemas de Liberação de Medicamentos , Hidrogéis/química , Poloxâmero/química , Portadores de Fármacos/química , Tamanho da Partícula , Propriedades de Superfície
14.
Int J Biol Macromol ; 148: 1061-1071, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31982519

RESUMO

Calcium alginate (CA) beads loaded with clotrimazole (CZ) were modified by adding poloxamer (PLX) in this study. Blends of PLX188 or PLX407 into sodium alginate (SA) dispersions caused a decrease in the SA zeta potential and led to viscosity synergism. SA with carboxyl and hydroxyl groups can interact with the hydroxyl groups of PLX via hydrogen bonding. A stronger interaction of SA with PLX407 was found when compared to the interaction between SA and PLX188. The PLX-CA beads gave a higher CZ entrapment efficiency than the CA beads. The highest PLX content used created an amorphous form of CZ in the beads because of the CZ solubilization by the PLX micelles. The addition of 0.5 or 1% w/v PLX can strengthen the CZ-loaded CA beads. Furthermore, the PLX-CA beads display a lower water uptake than the CA beads. PLX micellization can enhance CZ release and enhance the efficacy of CZ against Candida albicans. This study indicates that the molecular interaction of SA with PLX and the PLX micellization of CZ can improve the characteristics of CZ-loaded CA beads, which offer good potential for use as drug delivery systems or drug reservoirs in tablets for oral candidiasis.


Assuntos
Alginatos/química , Antifúngicos/química , Clotrimazol/química , Portadores de Fármacos/química , Poloxâmero/química , Tensoativos/química , Candida albicans/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Micelas , Microesferas , Solubilidade , Propriedades de Superfície , Viscosidade
15.
J Nanobiotechnology ; 18(1): 8, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31918714

RESUMO

Chemotherapeutic drugs frequently encounter multidrug resistance. ATP from mitochondria helps overexpression of drug efflux pumps to induce multidrug resistance, so mitochondrial delivery as a means of "repurposing'' chemotherapeutic drugs currently used in the clinic appears to be a worthwhile strategy to pursue for the development of new anti-drug-resistant cancer agents. TPP-Pluronic F127-hyaluronic acid (HA) (TPH), with a mitochondria-targeting triphenylphosphine (TPP) head group, was first synthesized through ester bond formation. Paclitaxel (PTX)-loaded TPH (TPH/PTX) nanomicelles exhibited excellent physical properties and significantly inhibited A549/ADR cells. After TPH/PTX nanomicelles entered acidic lysosomes through macropinocytosis, the positively charged TP/PTX nanomicelles that resulted from degradation of HA by hyaluronidase (HAase) in acidic lysosomes were exposed and completed lysosomal escape at 12 h, finally localizing to mitochondria over a period of 24 h in A549/ADR cells. Subsequently, TPH/PTX caused mitochondrial outer membrane permeabilization (MOMP) by inhibiting antiapoptotic Bcl-2, leading to cytochrome C release and activation of caspase-3 and caspase-9. In an A549/ADR xenograft tumor model and a drug-resistant breast cancer-bearing mouse model with lung metastasis, TPH/PTX nanomicelles exhibited obvious tumor targeting and significant antitumor efficacy. This work presents the potential of a single, nontoxic nanoparticle (NP) platform for mitochondria-targeted delivery of therapeutics for diverse drug-resistant cancers.


Assuntos
Apoptose , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Mitocôndrias/metabolismo , Nanopartículas/química , Células A549 , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Ácido Hialurônico/síntese química , Ácido Hialurônico/química , Concentração Inibidora 50 , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Micelas , Mitocôndrias/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Nanopartículas/ultraestrutura , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Poloxâmero/síntese química , Poloxâmero/química , Espectroscopia de Prótons por Ressonância Magnética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
FASEB J ; 34(1): 446-457, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914682

RESUMO

Mechanical damage or infection to the endometrium can lead to the formation of adhesions in the uterine cavity, which may result in reduced reproductive outcome and/or pregnancy complications. The prognosis of this disease is poor due to few effective treatments and the complex environment of endometrium. Heparin-Poloxamer Hydrogel (HP hydrogel) is a nontoxic and biodegradable biomaterial, which has been commonly used as a sustained-release delivery system. In this study, we applied a mini-endometrial curette to scrape the endometrium of rats to mimic the process of curettage in patients. After the establishment of IUA model in rats, we injected the thermo-sensitive hydrogel(E2-HP hydrogel) into the injured uterine cavity and evaluated the therapeutic effect of E2-HP hydrogel on the recovery of IUA. Our results showed that E2-HP hydrogel can significantly facilitate the regeneration of injured endometrium along with inhibiting the cell apoptosis in IUA model. Furthermore, we revealed that E2-HP hydrogel on the recovery of IUA was closely associated with the upregulation of kisspeptin through activating the ERK1/2 and MAPKs p38 pathways. In conclusion, E2-HP hydrogel can effectively transfer E2 into the injured endometrium and it can be considered as a promising therapeutic method for the women with intrauterine adhesions.


Assuntos
Endométrio/citologia , Estradiol/farmacologia , Heparina/química , Hidrogéis/farmacologia , Poloxâmero/química , Regeneração , Aderências Teciduais/tratamento farmacológico , Útero/citologia , Animais , Endométrio/efeitos dos fármacos , Endométrio/lesões , Estradiol/química , Feminino , Hidrogéis/química , Gravidez , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Útero/efeitos dos fármacos , Útero/lesões
17.
Mater Sci Eng C Mater Biol Appl ; 108: 110462, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923986

RESUMO

Breast cancer is a serious public health problem that causes thousands of deaths annually. Chemotherapy continues to play a central role in the management of breast cancer but is associated with extreme off-target toxicity. Therefore, treatments that directly target the tumor and display reduced susceptibility to resistance could improve the outcome and quality of life for patients suffering from this disease. Photodynamic therapy is a targeted treatment based on the use of light to activate a photosensitizer (PS) that then interacts with molecular oxygen and other biochemical substrates to generate cytotoxic levels of Reactive Oxygen Species. Currently approved PS also tends to have poor aqueous solubility that can cause problems when delivered intravenously. In order to circumvent this limitation, in this manuscript, we evaluate the potential of a phthalocyanine-loaded nanostructured lipid carrier (NLC) functionalized with folic acid (FA). To prepare the FA labelled NLC, the polymer PF127 was first esterified with FA and emulsified with an oil phase containing polyoxyethylene 40 stearate, capric/caprylic acid triglycerides, ethoxylated hydrogenated castor oil 40 and the PS zinc phthalocyanine. The resulting PS loaded FA-NLC had a hydrodynamic diameter of 180 nm and were stable in suspension for >90 days. Interestingly, the amount of singlet oxygen generated upon light activation for the PS loaded FA-NLC was substantially higher than the free PS, yet at a lower PS concentration. The PS was released from the NLC in a sustained manner with 4.13 ±â€¯0.58% and 27.7 ±â€¯3.16% after 30 min and 7 days, respectively. Finally, cytotoxicity assays showed that NLC in the concentrations of 09.1 µM of PS present non-toxic with >80 ±â€¯6.8% viable and after 90 s of the light-exposed the results show a statistically significant decrease in cell viability (57 ±â€¯4%). The results obtained allow us to conclude that the functionalized NLC incorporated with PS associated with the PDT technique have characteristics that make them potential candidates for the alternative treatment of breast cancer.


Assuntos
Portadores de Fármacos , Ácido Fólico , Indóis , Lipídeos , Nanoestruturas , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Ácido Fólico/química , Ácido Fólico/farmacocinética , Ácido Fólico/farmacologia , Humanos , Indóis/química , Indóis/farmacocinética , Indóis/farmacologia , Lipídeos/química , Lipídeos/farmacocinética , Lipídeos/farmacologia , Células MCF-7 , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia , Poloxâmero/química , Poloxâmero/farmacocinética , Poloxâmero/farmacologia
18.
Colloids Surf B Biointerfaces ; 185: 110606, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31698265

RESUMO

This study demonstrated a novel injectable-thermoreversible hydrogel scaffold composing of PLuronic F127, carboxymethyl hexanoyl chitosan (CA) and glyoxal (Gx) for encapsulating human osteosarcoma MG-63 cells. The hydrogel was prepared by simply mixing CA, F127 and Gx. In so doing, this system exhibited short gelation time and higher gelation temperature. In addition, this hydrogel exhibited thermo-reversibility, that is, the hydrogel can liquefy at room temperature and revert to gel state at body temperature. The encapsulated cells in this hydrogel proliferated more than 400% in the 5-day incubation. Based on these results, these F127/CA/Gx hydrogels can be used to encapsulate cells for tissue engineering applications.


Assuntos
Células Imobilizadas/citologia , Quitosana/análogos & derivados , Hidrogéis/química , Injeções , Poloxâmero/química , Temperatura , Linhagem Celular Tumoral , Sobrevivência Celular , Quitosana/química , Glioxal/química , Humanos
19.
Colloids Surf B Biointerfaces ; 185: 110613, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31715454

RESUMO

The present study describes the production and characterization of poloxamer gels containing the antioxidant molecule gallic acid. The gels were particularly designed in order to obtain a formulation suitable for administration on the skin to treat melanoma. The polymer concentration was selected after rheological characterization and determination of gel transition temperature. In order to study the gallic acid diffusion, in vitro experiments were performed using Franz cells associated to different membranes. As first approach the gallic acid diffusion was evaluated through synthetic membranes, such as cellulose, nylon, polycarbonate, polytetrafluoroethylene, polyvinylidene fluoride and the commercial Strat-M® membrane. The membranes were employed separately or in association and compared to stratum corneum epidermis membranes, in order to find a system able to reproduce the gallic acid diffusion through the skin. Selected membranes were used for studying gallic acid diffusion from poloxamer gel. It was found that the diffusion of gallic acid was dramatically influenced by the type of membrane, both in the case of the aqueous solution or poloxamer gel. Scratch wound healing and migration assays conducted on human keratinocytes and melanoma cells demonstrated the ability of gallic acid loaded gel to inhibit cellular migration, suggesting its potential as adjuvant strategy for melanoma.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Ácido Gálico/uso terapêutico , Géis/química , Melanoma/tratamento farmacológico , Poloxâmero/química , Adjuvantes Imunológicos/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Difusão , Elasticidade , Ácido Gálico/farmacologia , Humanos , Cinética , Transição de Fase , Reologia , Temperatura , Viscosidade , Cicatrização/efeitos dos fármacos
20.
Mater Sci Eng C Mater Biol Appl ; 106: 110252, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753360

RESUMO

Local treatment of Inflammatory Bowel Disease (IBD) has been pointed out to be a novel therapeutic approach with several advantages when compared to conventional therapies. However, the development of systems able to fulfil the requirements of this administration route is not an easy task. The present work suggests the utilization of Artificial Intelligence Tools (AIT) as an instrument to understand polymer-polymer interactions towards obtaining thermosensitive hydrogels suitable for protein rectal administration in IBD. Enemas composed by Pluronic® F127 and F68 and Methocel® K4M were developed and characterised. Two experimental designs were carried out in order to determine the effect of each polymer on their texturometric and rheological behaviour. Using the results of the first experimental design we can justify the inclusion of each raw material PF127, PF68 and MK4M in the formulation and conclude that a compromise solution is necessary to obtain thermosensitive hydrogels of the required properties. The results of the second experimental design allowed concluding that PF127 ruled mainly syringeability and bioadhesion work. On the other hand, PF68 modulated principally gelation temperature, viscosity and protein release from hydrogel matrix. Finally, MK4M influenced bioadhesiveness and mostly determined viscosity. AIT also allowed delimiting the design space to produce easy administrable and highly bioadhesive enemas that undergo fast sol-gel transitions at body temperature.


Assuntos
Hidrogéis/química , Reto/metabolismo , Animais , Inteligência Artificial , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Poloxâmero/química , Temperatura
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