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1.
Int J Pharm ; 575: 118980, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31899320

RESUMO

Cardiac glycosides (CGs) have been used to treat cancer for hundreds of years. However, the narrow therapeutic window and system toxicity have hindered their wide clinical applications. Herein, the small molecule prodrug strategy and nanotechnology were integrated into one drug delivery system with enhanced therapeutic effect. Using periplocymarin (PPM) as a target agent, we designed a novel redox-responsive prodrug conjugated with linoleic acid (PPM-ss-LA), which was capable of self-assembling independent of exogenous excipients. This prodrug could co-assemble with DSPE2k to form PEGylated prodrug nanoparticles (PPM-ss-LA/DSPE2k-NPs) with enhanced colloidal stability and blood circulation. Compared with free PPM, PPM-ss-LA/DSPE2k-NPs retained high anti-proliferative activity and showed increased cell uptake and therapeutic efficacy. Furthermore, the PPM-ss-LA/DSPE2k-NPs acquired a greatly enhancement of 50% lethal dose (LD50) in mice and reduced system toxicity compared with the free drug. Overall, the on-demand release of nanoprodrug delivery system could improve the therapeutic window and anticancer efficacy of CGs.

2.
Food Chem Toxicol ; 137: 111126, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31954714

RESUMO

Syringic acid (SA), a natural polyphenol found in fruits and vegetables, is claimed to show notable hepatoprotection. Nevertheless, low solubility and bioavailability hamper the application of SA. This study aimed to investigate the potential of TPGS/F127/F68 mixed polymeric micelles as a sustained and liver-targeting nanocarrier for SA. Herein, the prepared SA-loaded TPGS/F127/F68 mixed polymeric micelles (SA-TPGS-Ms) were spherically-shaped and homogeneously-distributed nanoparticles with high entrapment efficiency (94.67 ± 2.05%) and sustained release. Besides, in-vitro cell culture studies revealed that SA-TPGS-Ms substantially promoted cellular uptake with excellent biocompatibility. After oral administration, SA-TPGS-Ms demonstrated an increased bioavailability (2.3-fold) and delayed in-vivo elimination compared with the free SA. Furthermore, the alleviation of oxidative stress and amelioration of hepatic injury in CCl4-induced hepatotoxicity mice further demonstrated the excellent hepatoprotection of SA-TPGS-Ms. Collectively, SA-TPGS-Ms could be a promising nanocarrier for the utilization of SA in functional foods, with enhanced bioavailability and hepatoprotection.

3.
Fitoterapia ; 138: 104348, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31470062

RESUMO

Gastrodigenin rhamnopyranoside (GR) is a hepatoprotective compound that exists in Moringa oleifera seeds. However, the UPLC-MS/MS method for the determination of GR (in-vitro/in-vivo) is lacking clarification. Herein, this study established the UPLC-MS/MS technique, which was effective and sensitive for the investigation of the pharmacokinetics and biodistribution of GR in rats and mice. The separation was achieved with a Shim-pack XR-ODS III C18 column (2.0 × 75 mm, 1.6 µm) at 40 °C, while the mobile phase (Acetonitrile/0.1% Formic acid =12:82, v/v) was at an eluting rate of 0.2 mL/min. The Multiple Reaction Monitoring (MRM) was selected for quantification, i.e., m/z [M + HCOO]- 314.9 → 269 for GR and m/z [M + HCOO] - 182.85 → 137 for Tyrosol as the internal standard. The calibration curves were linearly ranged from 10 to 2500 ng/mL (r ≥ 0.999) with a lower-limit-of-quantification (LLOQ) of 10 ng/mL in the various biological samples (plasma, liver, heart, lung, spleen, brain, kidney). The intra- and inter-day precision was within 5%, while accuracy ranged from -11.4% - 8.33%. Recovery and matrix effect were with 80.32 to 101.31% and 90.36 to 103.76%, respectively, in a reasonable range. After oral and intravenous administration, GR was detected within 3 h but decreased rapidly in plasma, indicating fast elimination. Also, GR was quickly distributed in the various tissues, particularly in the kidney and spleen. The results demonstrated that the established UPLC-MS/MS method was highly linear, precise and accurate with the potential to be used for the quantitative analysis of GR in-vivo.


Assuntos
Glicosídeos/farmacocinética , Moringa/química , Sementes/química , Animais , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
4.
Food Chem Toxicol ; 131: 110531, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31136780

RESUMO

1-O-(4-hydroxymethylphenyl)-α-L-rhamnopyranoside (MPG) is a phenolic glycoside that exists in Moringa oleifera seeds with various health benefits, whereas its hepatoprotective effect is lacking clarification. Herein, MPG was isolated from Moringa oleifera seeds, and its hepatoprotection against CCl4-induced hepatotoxicity in L02 cells and ICR mice was investigated. Toxicity studies showed that MPG did not induce significant changes in organ coefficients and histological analysis, as well as exhibited no cytotoxicity. In vitro studies indicated that MPG substantially increased cell viability and intracellular SOD activities, and significantly inhibited LDH leakage in CCl4-treated cells. In vivo studies demonstrated that MPG significantly alleviated CCl4-induced hepatotoxicity in mice, as indicated by diagnostic indicators of hepatic injury, as well as the histopathological analysis. Moreover, MPG reduced the lipid peroxidation levels and regulated the inflammatory cytokines. Notably, MPG substantially suppressed the significant elevation of ROS production in hepatocytes of mice intoxicated with CCl4. Moreover, TUNEL assay demonstrated that MPG obviously inhibited hepatic apoptosis induced by CCl4. Altogether, these results suggested that MPG has excellent liver-protecting effects against hepatocytotoxicity induced by CCl4 in mice and L02 cells, which can be further developed as a valuable functional food additive or drug for the treatment of hepatic injury.


Assuntos
Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Glicosídeos/farmacologia , Moringa oleifera/química , Sementes/química , Administração Oral , Animais , Antioxidantes/administração & dosagem , Antioxidantes/isolamento & purificação , Antioxidantes/toxicidade , Tetracloreto de Carbono/toxicidade , Linhagem Celular , Citocinas/metabolismo , Feminino , Glicosídeos/administração & dosagem , Glicosídeos/isolamento & purificação , Glicosídeos/toxicidade , Fígado/patologia , Masculino , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos
5.
Drug Dev Ind Pharm ; 45(8): 1265-1276, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30990749

RESUMO

The prevalence of hyperuricemia is relatively high worldwide, and a great number of patients are suffering from its complications. 6-shogaol, an alkylphenol compound purified from the root of ginger (Zingiber officinale Roscoe), has been proved to possess diverse pharmacological activities. However, its poor aqueous solubility usually leads to low bioavailability, and further clinical applications will be greatly discounted. The current study aimed to formulate a 6-shogaol-loaded-Self Microemulsifying Drug Delivery System (SMEDDS) to amend low aqueous solubility and bioavailability orally, as well as, potentiate the hyperuricemic activity of the 6-shogaol. SMEDDS was developed with central composite design established on a two system components viz., 18.62% W/W ethyl oleate (oil phase) and ratio of tween 80 (surfactant) to PEG 400 (co-surfactant) (1.73:1, W/W). Based on quadratic model, the navigation of the design space could generate spherically-shaped and homogenous droplets with respective mean particle diameter, polydispersity and of 20.00 ± 0.26 nm and 0.18 ± 0.02. The 6-shogaol-SMEDDS showed significant elevation of cumulative release compared with the free 6-shogaol and more importantly a 571.18% increment in the relative oral bioavailability of the drug. The predominant accumulation of 6-shogaol-SMEDDS in the liver suggested hepatic-targeting potentiality of the drug. Oral administration of 6-shogaol-SMEDDS in hyperuricemic rats also significantly decreased uric acid level and xanthine oxidase activity. Histological studies confirmed formulation groups indeed could provide better protection of kidney than free drug groups. Collectively, these findings indicated that the SMEDDS hold much promise in enhancing the oral delivery and therapeutic efficacy of 6-shogaol.


Assuntos
Catecóis/administração & dosagem , Catecóis/química , Emulsões/administração & dosagem , Emulsões/química , Hiperuricemia/tratamento farmacológico , Administração Oral , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Masculino , Camundongos , Tamanho da Partícula , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Solubilidade/efeitos dos fármacos , Tensoativos/química
6.
Pharmaceutics ; 11(3)2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30845761

RESUMO

:6-shogaol is a promising anti-cancer and anti-inflammatory agent. However, the treatment effectiveness of 6-shogaol is limited by poor water solubility, poor oral absorption and rapid metabolism. Herein, 6-shogaol loaded in micelles (SMs) were designed to improve 6-shogaol's solubility and bioavailability. The micelles of a PEG derivative of linoleic acid (mPEG2k-LA) were prepared by the nanoprecipitation method with a particle size of 76.8 nm, and entrapment of 81.6 %. Intriguingly, SMs showed a slower release in phosphate buffer saline (PBS) (pH = 7.4) compared to free 6-shogaol while its oral bioavailability increased by 3.2⁻fold in vivo. More importantly, the in vitro cytotoxic effect in HepG2 cells of SMs was significantly higher than free 6-shogaol. Furthermore, SMs could significantly improve the tissue distribution of 6-shogaol, especially liver and brain. Finally, SMs showed a better hepatoprotective effect against carbon tetrachloride (CCl4)-induced hepatic injury in vivo than free 6-shogaol. These results suggest that the novel micelles could potentiate the activities of 6-shogaol in cancer treatment and hepatoprotection.

7.
AAPS PharmSciTech ; 20(3): 98, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30719694

RESUMO

In this study, syringic acid-loaded TPGS liposome (SA-TPGS-Ls) was successfully prepared to improve oral bioavailability of syringic acid (SA). SA is a natural and notable antioxidant activity compound with its limited bioavailability ascribable to its poor aqueous solubility and fast elimination. Recently, TPGS has become a perfect molecular biomaterial in developing several carrier systems with sustained, controlled, and targeted the drug delivery. SA-TPGS-Ls was prepared via thin-film dispersion method and characterized in terms of particle size, stability, morphology, and encapsulation efficiency (EE). The results showed that SA-TPGS-Ls had regular spherical-shaped nanoparticles with EE of 96.48 ± 0.76%. The pharmacokinetic studies demonstrated a delayed MRT and prolonged t1/2, while relative oral bioavailability increased by 2.8 times. Tissue distribution showed that SA-TPGS-Ls maintained liver drug concentration while delayed elimination was also observed in the kidney. In CCl4-induced hepatotoxicity study, the activities of hepatic T-AOC, GSH-Px, CAT, GSH, and SOD were greatly elevated, while serum biological markers ALT, AST, and AKP were reduced after treatment of mice with SA-TPGS-Ls. Histopathological studies confirmed that SA-TPGS-Ls could remarkably improve the status of hepatic tissues. Collectively, SA-TPGS-Ls significantly improved the drug encapsulation efficiency, stability coupled with bioavailability of SA, hence increasing in vivo antioxidant activity of the drug.


Assuntos
Antioxidantes/administração & dosagem , Antioxidantes/farmacocinética , Ácido Gálico/análogos & derivados , Lipossomos , Vitamina E/administração & dosagem , Vitamina E/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Intoxicação por Tetracloreto de Carbono/enzimologia , Intoxicação por Tetracloreto de Carbono/metabolismo , Ácido Gálico/administração & dosagem , Ácido Gálico/farmacocinética , Meia-Vida , Masculino , Camundongos , Nanopartículas , Tamanho da Partícula , Polietilenoglicóis , Ratos , Ratos Sprague-Dawley , Solubilidade , Distribuição Tecidual
8.
Int J Pharm ; 555: 270-279, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30471374

RESUMO

The anti-tumor efficacy of curcumin can be markedly improved by nano-drug self-delivery systems with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, a type of novel, glutathione (GSH)-responsive, PEGylated prodrug nano-micelles (PPNMs) was prepared by self-assembly of curcumin-s-s-vitamin E/mPEG2k-DSPE mixture. The PPNMs (entrapment efficiency: 96.7%) was acceptably stable in water with a mean particle size of 29.84 nm. Compared with curcumin-loaded mPEG2k-DSPE nano-micelles (CUR-NMs), PPNMs showed a higher drug loading (1.68% vs 27.3%) and remarkably improved the chemical stability of curcumin in phosphate buffer saline (PBS) (pH = 7.4), 10% FBS culture medium, and rat plasma. In vitro release study showed that PPNMs could redox responsively control the release of curcumin from the prodrug. Moreover, PPNMs showed a cytotoxicity in HepG2 cells similar to that of the free curcumin; however, when the HepG2 cells were pretreated with 1 mM GSH, PPNMs displayed a markedly enhanced cytotoxicity and cellular uptake than the free curcumin. After intravenous injection, PPNMs showed an increased half-life in blood circulation (10.6-fold) and bioavailability (107-fold) compared with the free curcumin injection. Altogether, the prodrug nano-micelles represent a promising preparation for sustained and controlled delivery of curcumin with enhanced antitumor activity.


Assuntos
Antineoplásicos/administração & dosagem , Curcumina/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Curcumina/farmacocinética , Curcumina/farmacologia , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Glutationa/metabolismo , Células Hep G2 , Humanos , Masculino , Micelas , Oxirredução , Tamanho da Partícula , Polietilenoglicóis/química , Pró-Fármacos , Ratos , Ratos Sprague-Dawley
9.
Int J Biol Macromol ; 123: 801-809, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445085

RESUMO

In this present study, we investigated the anti-hyperuricemic and anti-gouty arthritis effect of a puried water-soluble polysaccharide (LJP-1) obtained from Lonicera japonica. A series of characterization of the purified polysaccharide were carried out in this paper. Monosaccharide analysis showed that LJP-1 composed of glucuronic acid, glucose, galactose, arabinose, and xylose at the ratio of 2.43:1:2.09:1.95:1.96, respectively. The estimated molecular weight of LJP-1 was 17.5 kDa. LJP-1 belonged to pyranose and possessed α- and ß -glycosidic configurations. Congo red test showed that LJP-1 had a spatial triple helix structure. In pharmacodynamic experiments, the anti-hyperuricemic activity of LJP-1 was studied using hyperuricemic SD rat model induced via potassium oxonate and hypoxanthine. The result showed that LJP-1 could obviously decrease the serum uric acid level and suppress xanthine oxidase (XOD) activity. Moreover, in the gouty arthritis model established by sodium urate crystals, the degree of swelling of the ankle joint, IL-1ß, IL-6, TNF-α and COX-2-related inflammatory factors levels in murine serum all declined. Taken together, these results demonstrated that LJP-1 has anti-gouty arthritis effect. Therefore, LJP-1 could serve as a promising candidate for developing novel natural anti-gouty agent.


Assuntos
Artrite Gotosa/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Lonicera/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/uso terapêutico , Animais , Modelos Animais de Doenças , Inflamação/patologia , Espectroscopia de Ressonância Magnética , Masculino , Peso Molecular , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier
10.
AAPS PharmSciTech ; 19(8): 3661-3669, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30324361

RESUMO

In this study, an optimized nanostructured lipid carriers (NLCs) were developed and investigated for improving the solubility and oral availability of 6-Gingerol (6G), an active and abundant component of ginger with limited applications due to its poor water solubility plus oral biological availability. The NLCs consisted of a solid lipid (glyceryl monostearate), another liquid lipid (decanoyl/octanoyl-glycerides) and mixed surfactants (Tween 80 and Poloxamer 188), and was prepared by high pressure homogenization method. The optimal 6G-NLC formulation was evaluated through physical properties such as appearance, mean particle size, zeta potential, encapsulation efficiency, and in vitro drug release, alongside techniques viz., transmission electron microscopy (TEM), differential scanning calorimetry (DSC), as well as powder X-ray diffraction (XRD). Pharmacokinetics were also evaluated in rats. The 6G-NLCs prepared with optimal formulation exhibited a homogenous spherical shape with mean particle size and zeta potential of 63.59 ± 5.54 nm and - 12.18 ± 1.06 mV. Encapsulation efficiency and drug loading were 76.71 ± 1.11 and 1.17 ± 0.35%, respectively. In vitro release profile of 6G from NLCs was sustained and fitted with Weibull equation. After oral administration of the 6G-NLCs, drug concentrations in serum, MRT, and AUC0-t were significantly higher as compared with the free 6G suspension. All these results indicated that the developed NLC formulation could be effective and promising drug carriers to improve the water solubility of 6G while sustaining the drug release as well as prolonging in vivo acting time of the drug coupled with oral bioavailability enhancement.


Assuntos
Catecóis/química , Álcoois Graxos/química , Lipídeos/química , Animais , Disponibilidade Biológica , Catecóis/farmacocinética , Portadores de Fármacos/química , Álcoois Graxos/farmacocinética , Glicerídeos , Masculino , Nanoestruturas/química , Ratos , Ratos Sprague-Dawley , Solubilidade
11.
Int J Biol Macromol ; 117: 167-178, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29802924

RESUMO

In this study, two polysaccharide fractions (RRP1: Mw = 5.5 kDa, and RRP2: Mw = 425.7 kDa) were isolated from Rhodiola rosea to investigate their antioxidation and hepatoprotective effects. Physicochemical analysis showed that RRP1 was composed of mannose, rhamnose, galacturonic acid, glucose, galactose and arabinose with a relative molar ratio of 0.69:0.11:0.15:1:0.51:7.5 and RRP2 was consisted of mannose, rhamnose, galacturonic acid, glucose, galactose and arabinose (relative molar ratio = 0.15:0.19:1.01:0.18:0.47:1). Periodate oxidation and Smith degradation analysis revealed that, in RRP1, part of the arabinose and glucose residues were 1 → 3,6/1 → 3/1 → 2,3/1 → 3,4/1 → 2,4/1 → 2,3,4-linked, and the mannose, rhamnose and galactose residues were 1 → 2,6/1 → 6/1 → 2/1→/1 → 4,6/1 → 4-linked. In RRP2, the rhamnose, glucose and galactose residues were linked by 1 → 3,6/1 → 3/1 → 2,3/1 → 3,4/1 → 2,4/1 → 2,3,4 linkages, and the arabinose and mannose residues were 1 → 2/1 → 6/1 → 4-linked. The methylation analysis confirmed the structure information of the two fractions. Importantly, fraction RRP1 demonstrated stronger antioxidative activities than RRP2 by scavenging DPPH, hydroxyl and superoxide anion radicals in vitro. Correspondently, RRP1 showed more significant effects than RRP2 on decreasing the levels of ALT, AST and MDA, and increasing the GSH, SOD and CAT levels in the CCl4-treated mice. These data demonstrated that the polysaccharide RRP1 could be developed as a promising candidate for preventing and treating liver damage induced by toxic chemicals.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Polissacarídeos/química , Polissacarídeos/farmacologia , Rhodiola/química , Animais , Antioxidantes/isolamento & purificação , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Testes de Função Hepática , Masculino , Metilação , Camundongos , Peso Molecular , Monossacarídeos/química , Compostos Fitoquímicos/química , Polissacarídeos/isolamento & purificação , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
12.
Int J Pharm ; 513(1-2): 68-77, 2016 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-27567929

RESUMO

An optimized perillaldehyde-loaded liposomal nanoformulation (PAH-LNF) was successfully applied to improve the pharmacological effect of perillaldehyde (PAH) in poloxamer 407-induced hyperlipidemia. Oral administration of PAH-LNF (240mg/kg per body weight) in rats significantly enhanced solubility and relative bioavailability (270.7%) compared to the free PAH with about 2.7-, 1.5-, 1.3-, 1.3- and 1.5-fold increase in AUC, T1/2, MRT, Cmax and Tmax, respectively. Tissue distribution study also revealed the accumulation of PAH in the liver, lungs, spleen, kidney, brain and heart in order of decreasing affinity. Moreover, a significant decrease in serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) with simultaneous increase in high-density lipoprotein cholesterol (HDL-C) level was observed in the chemically-induced hyperlipidemic mice which further confirmed PAH's anti-hyperlipidemic properties. Additionally, PAH-LNF also significantly increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) with a concurrent decrease in malondialdehyde (MDA) to affirm the antioxidant and hepatoprotective effects of PAH. Thus, liposomal nanoformulation promises to be a useful drug delivery system for the development of PAH.


Assuntos
Antioxidantes/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Monoterpenos/administração & dosagem , Administração Oral , Animais , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Área Sob a Curva , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Meia-Vida , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Lipídeos/sangue , Lipossomos , Masculino , Camundongos , Monoterpenos/farmacocinética , Monoterpenos/farmacologia , Nanopartículas , Poloxâmero/toxicidade , Ratos , Ratos Sprague-Dawley , Solubilidade , Superóxido Dismutase/metabolismo , Distribuição Tecidual
13.
Int J Pharm ; 512(1): 186-193, 2016 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-27567930

RESUMO

The aim of this study was to develop a novel drug delivery system using two biocompatible copolymers of Solutol(®)HS15 and Soluplus(®) to improve solubility, oral bioavailability and anticancer activity of paclitaxel (PTX). The PTX-loaded mixed micelles (PTX-M) were prepared by ethanol thin-film hydration method. The optimal PTX-M were provided with small size (164.8±2.0nm) and spherical shape at ratio of 1: 3 (Solutol(®)HS15: Soluplus(®)), thus increasing the solubility to 15.76±0.15mg/mL in water. The entrapment efficiency and drug loading of PTX-M were 98.48±0.91% and 10.59±0.09% respectively. In vitro release study indicated a sustained release of PTX-M. Transcellular transport study showed that the efflux ratio were decreased by 89.72% dramatically in Caco-2 cell transport models, and the pharmacokinetics study of PTX-M compared with PTX, showed a 3.68-fold increase in relative oral bioavailability, indicating the mixed micelles may promote absorption in the gastrointestinal tract. In addition, the MTT assay demonstrated that the IC50 value of PTX-M was reduced by 40.21% (PTX-M: 22.6±2.1µg/mL, PTX: 37.8±1.4µg/mL), and in vivo anti-tumor study (15days' therapy) showed PTX-M achieved higher anti-tumor efficacy (57.66%) compared with PTX (41.13%). Furthermore, a gastrointestinal safety assay also provided the reliability and safety of PTX-M. Collectively, these findings present an oral micelle formulation with increased solubility, oral bioavailability and anticancer activity of PTX.


Assuntos
Portadores de Fármacos/administração & dosagem , Micelas , Paclitaxel/farmacologia , Paclitaxel/farmacocinética , Polietilenoglicóis/química , Polivinil/química , Ácidos Esteáricos/química , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Liberação Controlada de Fármacos , Masculino , Camundongos , Paclitaxel/administração & dosagem , Paclitaxel/química , Polímeros/química , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Pharm ; 501(1-2): 342-9, 2016 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-26861689

RESUMO

In the present study, a formulation system consisting of cholesterol and phosphatidyl choline was used to prepare an effective chlorogenic acid-loaded liposome (CAL) with an improved oral bioavailability and an increased antioxidant activity. The developed liposomal formulation produced regular, spherical and multilamellar-shaped distribution nanoparticles. The pharmacokinetic analysis of CAL compared with chlorogenic acid (CA), showed a higher value of Cmax(6.42 ± 1.49 min versus 3.97 ± 0.39 min) and a delayed Tmax(15 min versus 10 min), with 1.29-fold increase in relative oral bioavailability. The tissue distribution in mice also demonstrated that CAL predominantly accumulated in the liver which indicated hepatic targeting potential of the drug. The increased activities of antioxidant enzymes (Total Superoxide Dismutase (T-SOD) and Glutathione Peroxidase (GSH-Px)) and total antioxidant capacity (T-AOC), in addition to decreased level of malondialdehyde (MDA) in CCl4-induced hepatotoxicity study further revealed that CAL exhibited significant hepatoprotective and antioxidant effects. Collectively, these findings present a liposomal formulation with significantly improved oral bioavailability and an increased in vivo antioxidant activity of CA.


Assuntos
Antioxidantes/administração & dosagem , Ácido Clorogênico/administração & dosagem , Nanopartículas/administração & dosagem , Administração Oral , Animais , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/uso terapêutico , Disponibilidade Biológica , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ácido Clorogênico/química , Ácido Clorogênico/farmacocinética , Ácido Clorogênico/uso terapêutico , Colesterol/química , Glutationa Peroxidase/sangue , Glutationa Peroxidase/metabolismo , Lipossomos , Masculino , Malondialdeído/sangue , Malondialdeído/metabolismo , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Ratos Sprague-Dawley , Superóxido Dismutase/sangue , Superóxido Dismutase/metabolismo
15.
Biomed Chromatogr ; 30(3): 432-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26184450

RESUMO

For quantitative and other related bioactive studies of hydnocarpin, there is a need to establish an efficient, specific and sensitive analytical method (in vitro and in vivo). In this paper, an efficient HPLC method has been established and validated to analyze hydnocarpin in a nanomicelle formulation for the first time. Various chromatographic conditions for in vitro and in vivo determinations were investigated, with the application examined by pharmacokinetics and tissue distribution studies. The analysis was carried out using an HPLC system with a Waters symmetry C18 column (4.6 × 150 mm, 5 µm) at 25°C with a detecting wavelength of 342 nm. Eluting at a rate of 1.0 mL/min, a 65% methanol and 35% acetic acid solution (0.1%) served as the mobile phase for the in vitro determinations while a 62% methanol and 38% acetic acid solution (0.1%) was used for in vivo analysis with isoliquiritigenin as internal standard. The established in vitro linearity range for hydnocarpin was 0.2-20 µg/mL (R(2) = 0.9996), with the biological (in vivo) samples following the same trend. The accuracy of the method was >99% (in vitro) and 92.4-105.3% (in vivo). Also, the precision met the acceptance criterion. These results indicate that the established method exhibited high specificity, accuracy, linearity and precision. Additionally, this efficient HPLC method was applied to pharmacokinetics and tissue distribution studies.


Assuntos
Flavonolignanos/sangue , Micelas , Nanoestruturas/análise , Animais , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Flavonolignanos/farmacocinética , Modelos Lineares , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual
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