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1.
Mol Pharm ; 13(5): 1711-22, 2016 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-26998644

RESUMO

PLGA nanoparticles are widely used in tumor targeting drug delivery systems. However, the naked PLGA nanoparticles (NNPs) not only have low drug loading but also can be rapidly removed from blood circulation by the immune system. The aim of this study was to prepare pH-triggered surface charge reversed lipid hybrid PLGA nanoparticles (LNPs) to enhance drug loading and drug delivery efficiency. CHO-Arg-His-OMe and FA-PEG-DSPE were synthesized to modify PLGA nanoparticles to prepare LNPs. The drug loading and encapsulation rate of LNPs were greatly improved as compared with NNPs. In pH 7.4 medium, doxorubicin (DOX)-loaded LNPs showed negative charge and released DOX slowly. In pH 5.0 medium, DOX-loaded LNPs exhibited positive charge and released DOX quickly. DOX-loaded LNPs delivered more DOX to the nucleus of KB cells and MBA-MD-231/ADR cells than did free DOX. In addition, DOX-loaded LNPs significantly inhibited the proliferation of KB cells and MBA-MD-231/ADR cells. Compared with free DOX, the same dose of the DOX-loaded LNPs delivered more DOX to tumor tissue. Thus, DOX-loaded LNPs significantly inhibited the growth of tumor in tumor-bearing nude mice and obviously reduced the systemic toxicity of DOX. In conclusion, pH-triggered surface charge reversed DOX-loaded LNPs significantly enhanced the antitumor activity of DOX in vitro and in vivo. DOX-loaded LNPs had great potential in tumor targeted chemotherapy.


Assuntos
Antineoplásicos/química , Doxorrubicina/química , Nanopartículas/química , Células A549 , Animais , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Humanos , Concentração de Íons de Hidrogênio , Células KB , Ácido Láctico/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilcolinas/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Ratos Sprague-Dawley
2.
Yao Xue Xue Bao ; 50(4): 486-91, 2015 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-26223133

RESUMO

A chiral LC-MS/MS method for the simultaneous analysis of desvenlafaxine (DVS) enantiomers in human plasma was developed and applied to a pharmacokinetic study on 12 Chinese healthy volunteers. d6-Desvenlafaxine was used as internal standard (IS). Chromatographic separation was performed on the Astec Chirobiotic V chiral column (150 mm x 4.6 mm, 5 µm). The assay was linear over the concentration range of 0.500-150 ng x mL(-1) for both enantiomers (r2 > 0.99). The method was successfully applied to a stereoselective pharmacokinetic study of 100 mg desvenlafaxine sustained release tablets on 12 Chinese healthy volunteers under fasting conditions. The results showed that the pharmacokinetic parameters were similar to both enantiomers in Chinese healthy volunteers. The AUC(0-t), and C(max) of the two enantiomers were about 1.5 times higher than those of blacks and whites reported in the literature.


Assuntos
Cicloexanóis/farmacocinética , Administração Oral , Área Sob a Curva , Povo Asiático , Cromatografia Líquida , Cicloexanóis/sangue , Preparações de Ação Retardada , Succinato de Desvenlafaxina , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Masculino , Plasma/química , Estereoisomerismo , Comprimidos , Espectrometria de Massas em Tandem
3.
PLoS One ; 9(5): e97358, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24828815

RESUMO

A PEG-based, folate mediated, active tumor targeting drug delivery system using DOX-hyd-PEG-FA nanoparticles (NPs) were prepared. DOX-hyd-PEG-FA NPs showed a significantly faster DOX release in pH 5.0 medium than in pH 7.4 medium. Compared with DOX-hyd-PEG NPs, DOX-hyd-PEG-FA NPs increased the intracellular accumulation of DOX and showed a DOX translocation from lysosomes to nucleus. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was much higher than that of free DOX, DOX-ami-PEG-FA NPs and DOX-hyd-PEG NPs. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was attenuated in the presence of exogenous folic acid. The IC50 of DOX-hyd-PEG-FA NPs and DOX-hyd-PEG NPs on A549 cells showed no significant difference. After DOX-hyd-PEG-FA NPs were intravenously administered, the amount of DOX distributed in tumor tissue was significantly increased, while the amount of DOX distributed in heart was greatly decreased as compared with free DOX. Compared with free DOX, NPs yielded improved survival rate, prolonged life span, delayed tumor growth and reduced the cardiotoxicity in tumor bearing mice model. These results indicated that the acid sensitivity, passive and active tumor targeting abilities were likely to act synergistically to enhance the drug delivery efficiency of DOX-hyd-PEG-FA NPs. Therefore, DOX-hyd-PEG-FA NPs are a promising drug delivery system for targeted cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Ácido Fólico/análogos & derivados , Ácido Fólico/farmacologia , Nanopartículas/administração & dosagem , Polietilenoglicóis/farmacologia , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Células KB , Camundongos , Camundongos Nus , Taxa de Sobrevida
4.
Anticancer Drugs ; 25(7): 751-66, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24590167

RESUMO

The experiment aimed to increase the drug-delivery efficiency of poly-lactic-co-glycolic acid (PLGA) nanoparticles. Lipid-polymer hybrid nanoparticles (LPNs-1) were prepared using PLGA as a hydrophobic core and FA-PEG-hyd-DSPE as an amphiphilic shell. Uniform and spherical nanoparticles with an average size of 185 nm were obtained using the emulsification solvent evaporation method. The results indicated that LPNs-1 showed higher drug loading compared with naked PLGA nanoparticles (NNPs). Drug release from LPNs-1 was faster in an acidic environment than in a neutral environment. LPNs-1 showed higher cytotoxicity on KB cells, A549 cells, MDA-MB-231 cells, and MDA-MB-231/ADR cells compared with free doxorubicin (DOX) and NNPs. The results also showed that, compared with free DOX and NNPs, LPNs-1 delivered more DOX to the nuclear of KB cells and MDA-MB-231/ADR cells. LPNs-1 induced apoptosis in KB cells and MDA-MB-231/ADR cells in a dose-dependent manner. The above data indicated that DOX-loaded LPNs-1 could kill not only normal tumor cells but also drug-resistant tumor cells. These results indicated that modification of PLGA nanoparticles with FA-PEG-hyd-DSPE could considerably increase the drug-delivery efficiency and LPNs-1 had potential in the delivery of chemotherapeutic agents in the treatment of cancer.


Assuntos
Antineoplásicos/farmacologia , Ácido Fólico/análogos & derivados , Nanopartículas/química , Fosfatidilcolinas/química , Polietilenoglicóis/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos , Ácido Fólico/química , Ácido Fólico/metabolismo , Humanos , Ácido Láctico/química , Ácido Láctico/metabolismo , Nanopartículas/metabolismo , Fosfatidilcolinas/metabolismo , Polietilenoglicóis/metabolismo , Ácido Poliglicólico/química , Ácido Poliglicólico/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
5.
Yao Xue Xue Bao ; 49(11): 1593-9, 2014 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-25757288

RESUMO

A rapid, sensitive and convenient LC-MS/MS method was developed for the determination of γ-aminobutyric acid (GABA) in human plasma. d2-γ-Aminobutyric acid (d2-GABA) was synthesized as internal standard (IS). After extraction from human plasma by protein precipitation with acetonitrile, all analytes were separated on a Luna HILIC column (100 mm x 3.0 mm, 3 µm) using an isocratic mobile phase of water: acetonitrile: formic acid (20 : 80 : 0.12) with a flow rate of 0.5 mL x min(-1). Acquisition of mass spectrometric data was performed in multiple reaction monitoring mode (MRM) in positive electrospray ionization using the transitions of m/z 104 --> 69 for GABA and m/z 106 --> 71 for d2-GABA. The method was linear in the concentration range of 5.00 to 1 000 ng x mL(-1). The intra- and inter-day precisions were within 9.9%, and accuracy ranged from 99.1% to 104%, within the acceptable limit across all concentrations. The method was successfully applied to a pharmacokinetic study of GABA tablets in healthy Chinese volunteers.


Assuntos
Ácido gama-Aminobutírico/sangue , Cromatografia Líquida , Humanos , Espectrometria de Massas em Tandem
6.
Chin Med J (Engl) ; 125(3): 481-5, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22490407

RESUMO

BACKGROUND: The key components of metabolic syndrome (MS) are waist circumference, blood pressure, fast blood glucose, high density lipoprotein cholesterol (HDL-c) and triglycerides (TG). These components have, separately and jointly, been associated with an increased risk of cardiovascular diseases. In this study, we aimed to explore the association between MS components and cancer risk in a population-based cohort in China. METHODS: We established a population-based cohort with 17 779 individuals aged 35 and above at baseline in 2004 and 2005 in Changzhou, Jiangsu Province, China. All participants were face-to-face interviewed to complete a questionnaire and were accepted physical examinations including blood tests for glucose and lipids and physical measurements for obesity and blood pressure. In 2009, a total of 16 284 subjects (6886 men and 9398 women, 91.6%) attended the flow-up interviews and the participants or their family members reported all the hospitalizations and diseases including cancer occurred during the follow-up period. Multivariate Cox regression was used to estimate the hazard ratios (HRs) of metabolic syndrome components and cancer incidence. RESULTS: There was a dose-response association between cancer risk and the number of MS components presented at baseline (P for trend = 0.012) and the HR (95% confidence interval (CI)) was 2.63 (1.27 - 5.45) for subjects carrying 3 or more metabolic syndrome components after adjustment for possible confounding factors. Specifically, the multivariate-adjusted HRs (95%CIs) for cancer risk in subjects with central obesity, high fasting glucose, low HDL-c were 1.94 (1.01 - 3.74), 2.04 (1.10 - 3.77) and 2.05 (1.09 - 3.88), respectively. CONCLUSIONS: In this population-based, prospective cohort study in China, we found MS components, e.g., central obesity, high fasting glucose, low HDL-c were risk factors for cancer development. Early intervention of MS components may be also beneficial to reduce cancer burden.


Assuntos
Síndrome Metabólica/epidemiologia , Adulto , Povo Asiático , Glicemia/fisiologia , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias/epidemiologia , Estudos Prospectivos , Triglicerídeos/sangue , Circunferência da Cintura/fisiologia
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