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1.
Chem Commun (Camb) ; 55(61): 9039-9042, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292589
2.
Nanoscale ; 11(18): 9163-9175, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31038150

RESUMO

Diabetes is a chronic metabolic disorder disease characterized by high blood glucose levels and has become one of the most serious threats to human health. In recent decades, a number of insulin delivery systems, including bulk gels, nanogels, and polymeric micelles, have been developed for the treatment of diabetes. Herein, a kind of glucose and H2O2 dual-responsive polymeric nanogel was designed for enhanced glucose-responsive insulin delivery. The polymeric nanogels composed of poly(ethylene glycol) and poly(cyclic phenylboronic ester) (glucose and H2O2 dual-sensitive groups) were synthesized by a one-pot thiol-ene click chemistry approach. The nanogels displayed glucose-responsive release of insulin and the release rate could be promoted by the incorporation of glucose oxidase (GOx), which generated H2O2 at high glucose levels and H2O2 further oxidizes and hydrolyzes the phenylboronic ester group. The nanogels have characteristics of long blood circulation time, a fast response to glucose, and excellent biocompatibility. Moreover, subcutaneous delivery of insulin to diabetic mice with the insulin/GOx-loaded nanogels presented an effective hypoglycemic effect compared to that of injection of insulin or insulin-loaded nanogels. This kind of nanogel would be a promising candidate for the delivery of insulin in the future.


Assuntos
Glucose Oxidase/química , Glucose/metabolismo , Peróxido de Hidrogênio/metabolismo , Hipoglicemiantes/metabolismo , Insulina/metabolismo , Polietilenoglicóis/química , Polietilenoimina/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Química Click , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Portadores de Fármacos/química , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Glucose/química , Glucose Oxidase/metabolismo , Teste de Tolerância a Glucose , Peróxido de Hidrogênio/química , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Insulina/química , Insulina/uso terapêutico , Camundongos , Células NIH 3T3 , Polietilenoglicóis/toxicidade , Polietilenoimina/toxicidade
3.
Carbohydr Polym ; 216: 332-342, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047074

RESUMO

Chitosan has received a lot of attention as a carrier for small interfering RNA (siRNA), due to its capacity for complexation and intracellular release of these molecules. However, one of its limitations is its insolubility at neutral pH and the tendency towards aggregation of its nanoparticles in isotonic ionic strength. In this study, a series of amphipathic chitosans were synthesized by varying the degree of acetylation (DA) from ˜2 to ˜30 mol% and the degree of substitution (DS) from 5 to 25%. by tertiary amino groups (DEAE) The results showed that the adjustment of these parameters decreases the interparticle interactions mediated by hydrogen bonding to obtain nanoparticles with improved colloidal stability. siRNA-containing nanoparticles of 100 to 150 nm with low polydispersities (0.15-0.2) and slightly positive zeta potentials (˜+ 5 mV) were resistant to aggregation at pH 7.4 and ionic strength of 150 mM. This resistance to aggregation is provided by changes on the nanoparticle surface and highlights the importance of more organized self-assembly in providing colloidal stability at physiological conditions. Additionally, the PEGylation of the most promising vectors conferred favorable physicochemical properties to nanoparticles. The chitosans and their nanoparticles exhibited low toxicity and an efficient cell uptake, as probed by confocal microscopy of rhodamine labeled vectors. The results provide a new approach to overcome the limited stability of chitosan nanoparticles at physiological conditions and show the potential of these amphipathic chitosans as siRNA carriers.


Assuntos
Quitosana/análogos & derivados , Portadores de Fármacos/química , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Tensoativos/química , Anidridos Acéticos/química , Acetilação , Animais , Quitosana/síntese química , Quitosana/metabolismo , Quitosana/toxicidade , Dietilaminas/química , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidade , Fluorescência , Corantes Fluorescentes/química , Concentração de Íons de Hidrogênio , Camundongos , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Tamanho da Partícula , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Polietilenoglicóis/toxicidade , Células RAW 264.7 , RNA Interferente Pequeno/química , Rodaminas/química , Tensoativos/síntese química , Tensoativos/metabolismo , Tensoativos/toxicidade
4.
Nanoscale ; 11(16): 7921-7930, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30964497

RESUMO

Poly(ethylene glycol) (PEG) based hydrogels are amongst the most studied synthetic hydrogels. However, reports on PEG-based hydrogels with high mechanical strength are limited. Herein, a class of novel, well-defined PEG-based nanocomposite hydrogels with tunable mechanical strength are synthesised via ring-opening reactions of diglycidyl ethers with carboxylate ions. The pH responsive crosslinked polyacid nanogels (NG) in the dispersed phase act as high functionality crosslinkers which covalently bond to the poly(ethylene glycol) diglycidyl ethers (PEGDGE) as the continuous matrix. A series of NG-x-PEG-y-z gels are prepared where x, y and z are concentrations of NGs, PEGDGE and the PEGDGE molecular weight, respectively. The hydrogel compositions and nano-structural homogeneity of the NGs have strong impact on the enhancement of mechanical properties which enables property tuning. Based on this design, a highly compressive PEG-based nanocomposite hydrogel (NG-13-PEG-20-6000) exhibits a compressive stress of 24.2 MPa, compressive fracture strain greater than 98% and a fracture energy density as high as 1.88 MJ m-3. The tensile fracture strain is 230%. This is amongst one of the most compressive PEG-based hydrogels reported to-date. Our chemically crosslinked gels are resilient and show highly recoverable dissipative energy. The cytotoxicity test shows that human nucleus pulposus (NP) cells remained viable after 8 days of culture time. The overall results highlight their potential for applications as replacements for intervertebral discs or articular cartilages.


Assuntos
Hidrogéis/química , Polietilenoglicóis/química , Polietilenoimina/química , Sobrevivência Celular/efeitos dos fármacos , Força Compressiva , Humanos , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Varredura , Núcleo Pulposo/citologia , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/metabolismo , Polietilenoglicóis/síntese química , Polietilenoglicóis/toxicidade , Polietilenoimina/síntese química , Polietilenoimina/toxicidade , Espalhamento a Baixo Ângulo , Resistência à Tração , Difração de Raios X
5.
Eur J Pharm Biopharm ; 139: 232-239, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954658

RESUMO

Fast in situ forming, chemically crosslinked hydrogels were prepared by the amidation reaction between N-succinimidyl ester end groups of multi-armed poly(ethylene glycol) (PEG) and amino surface groups of poly(amido amine) (PAMAM) dendrimer generation 2.0. To control the properties of the PEG/PAMAM hydrogels, PEGs were used with different arm numbers (4 or 8) as well as different linkers (amide or ester) between the PEG arms and their terminal N-succinimidyl ester groups. Oscillatory rheology measurements showed that the hydrogels form within seconds after mixing the PEG and PAMAM precursor solutions. The storage moduli increased with crosslink density and reached values up to 2.3 kPa for hydrogels based on 4-armed PEG. Gravimetrical degradation experiments demonstrated that hydrogels with ester linkages between PEG and PAMAM degrade within 2 days, whereas amide-linked hydrogels were stable for several months. The release of two different model drugs (fluorescein isothiocyanate-dextran with molecular weights of 4·103 and 2·106 g/mol, FITC-DEX4K and FITC-DEX2000K, respectively) from amide-linked hydrogels was characterized by an initial burst followed by diffusion-controlled release, of which the rate depended on the size of the drug. In contrast, the release of FITC-DEX2000K from ester-containing hydrogels was governed mainly by degradation of the hydrogels and could be modulated via the ratio between ester and amide linkages. In vitro cytotoxicity experiments indicated that the PEG/PAMAM hydrogels are non-toxic to mouse fibroblasts. These in situ forming PEG/PAMAM hydrogels can be tuned with a broad range of mechanical, degradation and release properties and therefore hold promise as a platform for the delivery of therapeutic agents.


Assuntos
Dendrímeros/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Hidrogéis/química , Polietilenoglicóis/química , Animais , Linhagem Celular , Dendrímeros/toxicidade , Dextranos/administração & dosagem , Dextranos/farmacocinética , Portadores de Fármacos/toxicidade , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Fibroblastos , Fluoresceína-5-Isotiocianato/administração & dosagem , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/farmacocinética , Hidrogéis/toxicidade , Camundongos , Polietilenoglicóis/toxicidade , Reologia , Fatores de Tempo , Testes de Toxicidade
6.
Pharm Res ; 36(5): 70, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30888509

RESUMO

PURPOSE: To prepare an oligo(lactic acid)8-rapamycin prodrug (o(LA)8-RAP)-loaded poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) micelle for injection and characterize its compatibility and performance versus a RAP-loaded PEG-b-PLA micelle for injection in vitro and in vivo. METHODS: Monodisperse o(LA)8 was coupled on RAP at the C-40 via DCC/DMAP chemistry, and conversion of o(LA)8-RAP prodrug into RAP was characterized in vitro. Physicochemical properties of o(LA)8-RAP- and RAP-loaded PEG-b-PLA micelles and their antitumor efficacies in a syngeneic 4 T1 breast tumor model were compared. RESULTS: Synthesis of o(LA)8-RAP prodrug was confirmed by 1H NMR and mass spectroscopy. The o(LA)8-RAP prodrug underwent conversion in PBS and rat plasma by backbiting and esterase-mediated cleavage, respectively. O(LA)8-RAP-loaded PEG-b-PLA micelles increased water solubility of RAP equivalent to 3.3 mg/ml with no signs of precipitation. Further, o(LA)8-RAP was released more slowly than RAP from PEG-b-PLA micelles. With added physical stability, o(LA)8-RAP-loaded PEG-b-PLA micelles significantly inhibited tumor growth relative to RAP-loaded PEG-b-PLA micelles in 4 T1 breast tumor-bearing mice without signs of acute toxicity. CONCLUSIONS: An o(LA)8-RAP-loaded PEG-b-PLA micelle for injection is more stable than a RAP-loaded PEG-b-PLA micelle for injection, and o(LA)8-RAP converts into RAP rapidly in rat plasma (t1/2 = 1 h), resulting in antitumor efficacy in a syngeneic 4 T1 breast tumor model.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Lactatos/química , Polietilenoglicóis/química , Pró-Fármacos/administração & dosagem , Sirolimo/administração & dosagem , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Feminino , Lactatos/toxicidade , Ácido Láctico/química , Camundongos , Micelas , Polietilenoglicóis/toxicidade , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/toxicidade , Ratos , Transdução de Sinais , Sirolimo/química , Sirolimo/farmacologia , Sirolimo/toxicidade , Solubilidade , Serina-Treonina Quinases TOR/metabolismo
7.
Methods Mol Biol ; 1943: 333-346, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30838627

RESUMO

For the systemic application of nucleic acids [plasmid DNA (pDNA) and small interfering RNA (siRNA)], safe and efficient carriers that overcome the poor pharmacokinetic properties of nucleic acids are required. A cationic liposome that can formulate lipoplexes with nucleic acids has significant promise as an efficient delivery system in gene therapy. To achieve in vivo stability and long circulation, most lipoplexes are modified with PEG (PEGylation). However, we reported that PEGylated liposomes lose their long-circulating properties when they are injected repeatedly at certain intervals in the same animal. This unexpected and undesirable phenomenon is referred to as the accelerated blood clearance (ABC) phenomenon. Anti-PEG IgM produced in response to the first dose of PEGylated liposomes has proven to be a major cause of the ABC phenomenon. Therefore, in a repeated dosing schedule, the detection of anti-PEG IgM in an animal treated with PEGylated lipoplex could be essential to predict the occurrence of the ABC phenomenon. This chapter introduces a method for the evaluation of serum anti-PEG IgM by a simple ELISA procedure, and describes some precautions associated with this method.


Assuntos
Técnicas de Transferência de Genes , Imunoglobulina M/sangue , Polietilenoglicóis/toxicidade , Animais , Formação de Anticorpos/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática/métodos , Terapia Genética/métodos , Imunoglobulina M/imunologia , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ácidos Nucleicos/genética , Polietilenoglicóis/administração & dosagem
8.
Colloids Surf B Biointerfaces ; 177: 253-259, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30763790

RESUMO

Magnetic nanoparticles (MNPs) represent one of the greatest promises for the development of a new generation of diagnostic agents for magnetic resonance imaging, with improved specificity and safety. Indeed, during the last decade the number of studies published in this field has grown exponentially. However, the clinical translation achieved so far has been very limited. This situation is likely related to the fact that most studies are focused on the in vitro characterization of these new nanomaterials, and very few provide an exhaustive in vivo characterization, where key aspects, such as pharmacokinetics, bioavailability, and, most importantly, toxicity, are properly evaluated. In this work, we propose a protocol for the comprehensive assessment of the toxicity of MNPs, based on the use of zebrafish embryos as an intermediate screening step between cell culture assays and studies in rodents. MNPs with different cores, ferrite and manganese ferrite oxide, and sizes between 3 and 20 nm, were evaluated. Cell viability at a concentration of 50 µg/mL of PEGylated MNPs was above 90 % in all cases. However, the exposure of zebrafish embryos to manganese based MNPs at concentrations above 100 µg/mL showed a low survival rate (<50 %). In contrast, no mortality (survival rate ∼100 %) and normal hatching rate were obtained for the iron oxide MNPs. Based on these results, together with the physicochemical and magnetic properties (r2 = 153.6 mM-1·s-1), the PEGylated 20 nm cubic shape iron oxide MNPs were selected and tested in mice, showing very good MRI contrast and, as expected, absence of toxicity.


Assuntos
Meios de Contraste/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Compostos Férricos/toxicidade , Nanopartículas de Magnetita/toxicidade , Polietilenoglicóis/toxicidade , Animais , Sobrevivência Celular , Células Cultivadas , Meios de Contraste/química , Relação Dose-Resposta a Droga , Compostos Férricos/química , Imagem por Ressonância Magnética , Nanopartículas de Magnetita/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Tamanho da Partícula , Polietilenoglicóis/química , Propriedades de Superfície , Peixe-Zebra/embriologia
9.
Environ Toxicol ; 34(5): 561-572, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30786124

RESUMO

Benzalkonium chloride (BAC) is a widely used disinfectant/preservative, and respiratory exposure to this compound has been reported to be highly toxic. Spray-form household products have been known to contain BAC together with triethylene glycol (TEG) in their solutions. The purpose of this study was to estimate the toxicity of BAC and TEG mixtures to pulmonary organs using in vitro and in vivo experiments. Human alveolar epithelial (A549) cells incubated with BAC (1-10 µg/mL) for 24 hours showed significant cytotoxicity, while TEG (up to 1000 µg/mL) did not affect cell viability. However, TEG in combination with BAC aggravated cell damage and inhibited colony formation as compared to BAC alone. TEG also exacerbated BAC-promoted production of reactive oxygen species (ROS) and reduction of glutathione (GSH) level in A549 cells. However, pretreatment of the cells with N-acetylcysteine (NAC) alleviated the cytotoxicity, indicating oxidative stress could be a mechanism of the toxicity. Quantification of intracellular BAC by LC/MS/MS showed that cellular distribution/absorption of BAC was enhanced in A549 cells when it was exposed together with TEG. Intratracheal instillation of BAC (400 µg/kg) in rats was toxic to the pulmonary tissues while that of TEG (up to 1000 µg/kg) did not show any harmful effect. A combination of nontoxic doses of BAC (200 µg/kg) and TEG (1000 µg/kg) promoted significant lung injury in rats, as shown by increased protein content and lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluids (BALF). Moreover, BAC/TEG mixture recruited inflammatory cells, polymorphonuclear leukocytes (PMNs), in terminal bronchioles and elevated cytokine levels, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in BALF. These results suggest that TEG can potentiate BAC-induced pulmonary toxicity and inflammation, and thus respiratory exposure to the air mist from spray-form products containing this chemical combination is potentially harmful to humans.


Assuntos
Compostos de Benzalcônio/toxicidade , Lesão Pulmonar/induzido quimicamente , Pulmão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pneumonia/induzido quimicamente , Polietilenoglicóis/toxicidade , Células A549 , Animais , Compostos de Benzalcônio/administração & dosagem , Compostos de Benzalcônio/metabolismo , Líquido da Lavagem Broncoalveolar/química , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Citocinas/análise , Sinergismo Farmacológico , Humanos , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Masculino , Estresse Oxidativo/imunologia , Pneumonia/metabolismo , Pneumonia/patologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Ratos Sprague-Dawley
10.
Chemosphere ; 219: 981-988, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30682763

RESUMO

In the present study, sub-lethal effects of chlorpyrifos, alone (25 and 50 µg L-1) and in combination with Polyethylene glycol (5 and 10 mg L-1), on common carp were investigated. Exposure to chlorpyrifos caused significant changes in all blood biochemical parameters compared to control groups. Total protein, triglyceride, glucose levels, as well as lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT), and creatine phosphokinase (CPK) activities in plasma changed after exposure to 10 mg L-1 polyethylene glycol (PEG), while fish exposed to PEG did not show any significant difference in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and acetylcholinesterase (AChE) activities and albumin and globulins levels. Exposure to a combination of chlorpyrifos and PEG caused a significant change in AST, GGT, CPK, LDH and AChE activity, total protein and glucose level. The influence of chlorpyrifos and PEG combination on ALP, cholesterol, triglyceride, albumin, and globulin depends on the concentration of the insecticide and PEG. With a reduction in chlorpyrifos concentration, PEG can maintain ALP activity and albumin at a normal level. Although fish exposure to chlorpyrifos, alone or in combination with polyethylene glycol, significantly increased malondialdehyde (MDA) and catalase (CAT) level, it decreased total antioxidant level (TAN). Exposure to just polyethylene glycol had no impact on CAT activity, TAN and MDA level. According to the results, PEG can have an antagonistic effect on chlorpyrifos toxicity, depending on these two materials concentration. However, chlorpyrifos increased the toxicity of PEG.


Assuntos
Carpas/metabolismo , Clorpirifos/toxicidade , Inseticidas/toxicidade , Polietilenoglicóis/toxicidade , Fosfatase Alcalina/sangue , Animais , Análise Química do Sangue , Carpas/sangue , Colesterol/sangue , Sinergismo Farmacológico , Triglicerídeos/sangue
11.
Ecotoxicol Environ Saf ; 171: 240-246, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30612011

RESUMO

Previous studies demonstrated long-term stimulation of some commercial personal care products (PCPs) on freshwater luminescent bacteria Vibrio qinghaiensis sp.-Q67 (Q67). However, whether a certain component can affect mixture's hormetic effect is still unknown. In this paper, two of ingredients in PCPs, 2-phenoxyethanol (PhE) and polyethylene glycol 400 (PEG400), were selected as object compounds to explore the relationship between concentration-response (CR) of mixtures and that of a single component. It was found that PEG400 has monotonic CR (MCR) on Q67 both at the short-term (0.25 h) and long-term (12 h) exposures while PhE has MCR at 0.25 h and hormetic CR (HCR) at 12 h. Here, the concentration-response curves (CRCs) of PEG400 at 0.25 and 12 h are overlapped each other and the CRCs of PEG400 are on the right of PhE. If the pEC50 is taken as a toxic index, the toxicities of PEG400 at two times are basically the same, and those of PhE are the same, too, but PhE is twice as toxic as PEG400. For the mixtures of PEG400 and PhE, all rays except R1 have MCRs at 0.25 h while all rays have HCRs at 12 h where the higher the mixture ratio of PhE is, the more negative the maximum stimulation effect is. More importantly, the Emin values of all rays are more negative (1.79-3.17-fold) than that of PhE worked alone, which implies that the introduction of PEG400 significantly enhances stimulative effect of PhE. At 0.25 h, all binary mixture rays but R1 produce a low-concentration additive action and high-concentration synergism. At 12 h, all rays display additive action, antagonism, additive action, and synergism in turn when the concentration changes from low to high. The overall findings suggested toxicological interactions should be considered in the risk assessment of PCPs and their potential impacts on ecological balances.


Assuntos
Etilenoglicóis/toxicidade , Polietilenoglicóis/toxicidade , Vibrio/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Cosméticos/química , Interações de Medicamentos , Hormese , Luminescência , Fatores de Tempo , Testes de Toxicidade
12.
Artif Cells Nanomed Biotechnol ; 47(1): 181-191, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30686051

RESUMO

The aim of this research is to utilize a hybrid system of liposomal doxorubicin (DOX-Lip) loaded thermogel (DOX-Lip-Gel) to realize the steady sustained delivery of doxorubicin (DOX), a small hydrophilic drug, for the treatment of breast cancer locally. Herein, liposomal doxorubicin was prepared via the traditional film dispersion method with the particle size of 75 nm and drug entrapment efficiency of 86%. And, the triblock copolymer of poly (D, L-lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly (D, L-lactide -co-glycolide) (PLGA-PEG-PLGA) was synthesized via ring-opening polymerization to prepare the thermosensitive hydrogel through dissolving the polymers in DOX-Lip solution. The liposome loaded hydrogel was in a sol state at room temperature and converted into the gel state at body temperature and would degrade gradually during the time in vivo. The drug release of DOX out of DOX-Lip-Gel could be in a steady sustained manner up to 11 days without significant burst release as compared to that of DOX-loaded hydrogel (DOX-Gel). An orthotopic breast cancer model was adopted to evaluate the in vivo antitumor efficacy. And, the results revealed DOX-Lip-Gel had better antitumor efficiency as well as lower side effects.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/análogos & derivados , Portadores de Fármacos/química , Poliésteres/química , Polietilenoglicóis/química , Temperatura Ambiente , Animais , Linhagem Celular Tumoral , Preparações de Ação Retardada , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Doxorrubicina/toxicidade , Coração/efeitos dos fármacos , Hidrogéis/química , Teste de Materiais , Camundongos , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Polietilenoglicóis/toxicidade , Viscosidade
13.
Carbohydr Polym ; 205: 571-580, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30446143

RESUMO

Introduction of linolenic acid (LNA) and methoxy poly (ethylene glycol) (MPEG) to the backbone of oligochitosan (CS) afforded LNA-modified MPEG-CS conjugate (MPEG-CS-LNA). Amphotericin B-loaded MPEG-CS-LNA micelles (AmB-M) were prepared via dialysis method with 82.27 ± 1.96% of drug encapsulation efficiency and 10.52 ± 0.22% of drug loading capacity. The AmB-M enhanced AmB's water-solubility to 1.64 mg/mL, being 1640-folds higher than native AmB. The AmB-M obviously reduced hemolytic effect and renal toxicity of AmB when compared to marketed AmB injection (AmB-I). Its antifungal activity against Candida albicans was equivalent to AmB-I although AmB's release from AmB-M was significantly retarded. According to fluorescence microscopy test, the unchanged activity should be attributed to enhanced fungal cellular uptake of AmB-M caused by combined inducement of LNA and CS. The pharmacokinetic studies demonstrated that AmB-M also improved the pharmacokinetic parameters of AmB with AmB-I as control. Conclusively, developed LNA-modified MPEG-CS micellar system could be a viable alternative to the current toxic commercial AmB-I as a highly efficacious drug delivery system.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Portadores de Fármacos/química , Ácidos Linolênicos/química , Micelas , Polímeros/química , Animais , Candida albicans/efeitos dos fármacos , Quitina/análogos & derivados , Quitina/síntese química , Quitina/química , Quitina/farmacocinética , Quitina/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Eritrócitos/efeitos dos fármacos , Hemólise , Rim/efeitos dos fármacos , Ácidos Linolênicos/síntese química , Ácidos Linolênicos/farmacocinética , Ácidos Linolênicos/toxicidade , Masculino , Camundongos , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/toxicidade , Polímeros/síntese química , Polímeros/farmacocinética , Polímeros/toxicidade , Ratos Sprague-Dawley
14.
Plant Physiol Biochem ; 132: 183-188, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30212759

RESUMO

JmjC-domain-containing (JmjC) protein, an important kind of histone demethylase in plants, plays key roles in multiple growth and development processes and in adversity resistance. In this study, we found that OsJMJ703, a known histone demethylase, is expressed in various tissues. Furthermore, over-expression of OsJMJ703 influenced the type of rice panicle, and knock-down of the expression of OsJMJ703 showed an earlier flowering time in rice. In addition, OsJMJ703 is involved in abiotic stress. Transgenic rice of over-expressing OsJMJ703 is sensitive to drought stress, whereas knocking down OsJMJ703 enhances the tolerance to drought stress. This study provides a theoretical basis of the biological function of JmjC protein and further promotes the study of drought resistance.


Assuntos
Secas , Genes de Plantas , Histona Desmetilases/genética , Oryza/enzimologia , Oryza/crescimento & desenvolvimento , Desenvolvimento Vegetal/genética , Estresse Fisiológico/genética , Flores/fisiologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Histona Desmetilases/metabolismo , Especificidade de Órgãos/genética , Oryza/efeitos dos fármacos , Oryza/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Polietilenoglicóis/toxicidade , Estresse Fisiológico/efeitos dos fármacos
15.
Plant Physiol Biochem ; 132: 128-137, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30189416

RESUMO

Ammonium (NH4+) can enhance the water stress induced drought tolerance of rice seedlings in comparison to nitrate (NO3-) nutrition. To investigate the mechanism involved in nitrogen (N) uptake, N metabolism and transcript abundance of associated genes, a hydroponic experiment was conducted in which different N sources were supplied to seedlings growing under water stress. Compared to nitrate, ammonium prevented water stress-induced biomass, leaf SPAD and photosynthesis reduction to a significantly larger extent. Water stress significantly increased root nitrate reductase (NR) and nitrite reductase (NiR) activities, but decreased leaf NiR and glutamate synthetase (GS) activities under NO3- supply, causing lower nitrate content in roots and higher in leaves. In contrast, under NH4+ supply root GS and glutamine oxoglutarate aminotransferase (GOGAT) activities were significantly decreased under water stress, but remained higher in leaves, compared to NO3- treatment, which was beneficial for the transport and assimilation of ammonium in leaves. 15N tracing assays demonstrated that rice 15N uptake rate and accumulation were significant reduced under water stress, but were higher in plants supplied with NH4+ than with NO3-. Therefore, the formers showed higher leaf soluble sugar, proline and amino acids contents, and in turn, associated with a higher photosynthesis rate and biomass accumulation. Most genes related to NO3- uptake and reduction in roots and leaves were down-regulated; however, two ammonium transporter genes closely related to NH4+ uptake (AMT1;2 and AMT1;3) were up-regulated in response to water stress. Overall, our findings suggest that ammonium supply alleviated waters tress in rice seedlings, mainly by increasing root NH4+ uptake and leaf N metabolism.


Assuntos
Compostos de Amônio/metabolismo , Oryza/fisiologia , Polietilenoglicóis/toxicidade , Plântula/fisiologia , Aminoácidos/análise , Carboidratos/análise , Desidratação , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Nitratos/metabolismo , Nitrogênio/farmacologia , Oryza/efeitos dos fármacos , Oryza/genética , Oryza/crescimento & desenvolvimento , Fotossíntese/efeitos dos fármacos , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Transpiração Vegetal/efeitos dos fármacos , Plântula/efeitos dos fármacos , Plântula/genética , Plântula/crescimento & desenvolvimento , Água/metabolismo
16.
Langmuir ; 34(32): 9516-9524, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30039972

RESUMO

Although demanding, the development of multifunctional theranostic nanoplatforms is attracting considerable worldwide interest. Herein, a theranostic nanoplatform with multifunctions based on polydopamine (PDA) nanoparticles (NPs) was developed, owning dual-imaging and dual-therapy functions for cancer theranostic applications. PDA NPs were generated using a facile polymerization method under alkaline conditions, followed by poly(ethylene glycol) (PEG) modification. Then, the obtained NPs were loaded with IR820 and Fe3+ ions to produce the final PEGylated PDA/IR820/Fe3+ (PPIF) NPs. The PPIF NPs thus generated displayed increasingly brighter photoacoustic and magnetic resonance signals with increasing NP concentration and were demonstrated to be cytocompatible and effectively taken up and internalized into HeLa cells. Under near-infrared light irradiation, PPIF NPs can produce heat and reactive oxygen species for photothermal/photodynamic combined cancer therapy. In this study, the versatility of PDA NPs was demonstrated to be promising as a multifunctional nanoplatform for potential cancer theranostic applications.


Assuntos
Antineoplásicos/farmacologia , Verde de Indocianina/análogos & derivados , Ferro/química , Nanopartículas/química , Radiossensibilizantes/farmacologia , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos/efeitos da radiação , Células HeLa , Calefação , Humanos , Verde de Indocianina/farmacologia , Verde de Indocianina/efeitos da radiação , Indóis/síntese química , Indóis/química , Indóis/toxicidade , Raios Infravermelhos , Camundongos , Nanopartículas/toxicidade , Tamanho da Partícula , Técnicas Fotoacústicas/métodos , Polietilenoglicóis/química , Polietilenoglicóis/toxicidade , Polímeros/síntese química , Polímeros/química , Polímeros/toxicidade , Radiossensibilizantes/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo
17.
Ecotoxicol Environ Saf ; 162: 192-200, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-29990731

RESUMO

Nanographene oxide (nGO) has been recently proposed as a new antitumoral therapeutic agent, drug delivery carrier and gene transfection vehicle, among others. Treatment is carried out by hyperthermia induced by infrared irradiation. After treatment, the nanosystems will be inevitably excreted and released to the environment. To understand the potential impacts of pegylated nGO (nGO-PEG), three key species from different trophic levels were used: the green micro-algae Raphidocelis subcapitata (growth inhibition test), the cladocera Daphnia magna (acute and chronic tests), and the fish Danio rerio (fish embryo test). Besides a regular standard procedure to assess toxicity, and considering the mode of action of nGO-PEG in cancer treatment, a simultaneous infrared lamp exposure was carried out for D. magna and D. rerio. Additionally, and taking advantage of the phenotypic transparency of D. magna, nGO-PEG was fluorescently tagged to evaluate the potential uptake of nGO-PEG. The R. subcapitata growth inhibition test showed effects during the first 48 h, recovering till the end of the test (96 h). No acute or chronic effects were observed for D. magna, under standard or infrared light exposures although confocal microscope images showed nGO-PEG uptake. Very small percentages of mortality and abnormalities were observed in D. rerio exposed with and without the infrared lamp. Although low hazard may be expected for nGO-PEG in aquatic ecosystems, further studies with species with different life traits should be accomplished, in order to derive more accurate conclusions.


Assuntos
Grafite/toxicidade , Óxidos/toxicidade , Polietilenoglicóis/toxicidade , Animais , Antineoplásicos , Clorófitas/efeitos dos fármacos , Clorófitas/crescimento & desenvolvimento , Daphnia/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Embrião não Mamífero/efeitos dos fármacos , Cadeia Alimentar , Grafite/química , Óxidos/química , Polietilenoglicóis/química , Testes de Toxicidade/métodos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia
18.
Biol Pharm Bull ; 41(6): 899-907, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29863078

RESUMO

Microfluidics is a promising system for efficiently optimizing the experimental conditions for preparing nanomedicines, such as self-assembled nanoparticles. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are promising drug carriers allowing sustained drug release. Here, we encapsulated the model drug curcumin, which has many pharmacological activities, into PLGA nanoparticles and investigated the effects of experimental conditions on the resulting PLGA nanoparticles using a microfluidics system with a staggered herringbone structure that can stir solutions through chaotic advection. The total flow rate and flow rate ratio of the solutions in the microfluidics system affected the diameters, polydispersity index, and encapsulation efficiency of the resulting PLGA nanoparticles and produced small, homogenous PLGA nanoparticles. The incorporation of polyethylene glycol (PEG)-PLGA into the PLGA nanoparticles reduced the particle size and improved the encapsulation efficiency. Initial burst release from the PLGA nanoparticles was prevented by the incorporation of PEG2000-PLGA. Curcumin-loaded PEGylated PLGA nanoparticles showed cytotoxicity similar to that of other formulations. This microfluidics system allows high throughput and is scalable for the efficient preparation of PLGA nanoparticles and PEGylated PLGA nanoparticles. Our results will be useful for developing novel PLGA-based polymer nanoparticles by using the microfluidics.


Assuntos
Curcumina/química , Composição de Medicamentos/instrumentação , Dispositivos Lab-On-A-Chip , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Células A549 , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/toxicidade , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Nanopartículas/toxicidade , Poliésteres/toxicidade , Polietilenoglicóis/toxicidade
19.
Biol Pharm Bull ; 41(6): 908-914, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29863079

RESUMO

Gold nanoparticles (GNPs) have promising properties such as photothermal effects and could be useful for imaging and as multifunctional nanocarriers for various drugs. In this study, we synthesized polyethyleneglycol (PEG)-grafted GNPs and conjugated them with cyclodextrin (CD) to incorporate curcumin. Curcumin has anticancer effects but its therapeutic application is limited due to poor water solubility. Three types of CDs (α-, ß-, and γ-CDs) were conjugated with PEGylated GNPs and the curcumin-containing CD/PEG-conjugated GNPs (cur-CD-GNPs) were characterized. Transmission electron microscopy and dynamic light scattering results showed that these cur-CD-GNPs have a small gold nanocore (approximately 5 nm) and the average size of the three cur-CD-GNPs was approximately 25-35 nm. Curcumin was efficiently incorporated into the ß-CD solution and the loading efficiency of curcumin in ß-CD-GNPs was the highest of the three types of CD-GNPs prepared. The cytotoxic effect of cur-CD-GNPs was investigated using a human lung cancer cell line. All cur-CD-GNPs exhibited cytotoxic effects comparable to that of curcumin solution and CD-GNPs without curcumin were not cytotoxic. These results suggest that cur-CD-GNPs may be a useful multifunctional nanomedicine, although in vivo investigations are required.


Assuntos
Antineoplásicos/química , Curcumina/química , Ciclodextrinas/química , Ouro/química , Nanopartículas Metálicas/química , Polietilenoglicóis/química , Células A549 , Antineoplásicos/toxicidade , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Curcumina/toxicidade , Ciclodextrinas/toxicidade , Composição de Medicamentos , Ouro/toxicidade , Humanos , Nanopartículas Metálicas/toxicidade , Polietilenoglicóis/toxicidade
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