RESUMO
INTRODUCTION: Poor cell uptake and incomplete intracellular drug release are the two major challenges for polymeric prodrug-based drug delivery systems (PPDDSs) in cancer treatment. METHODS: Herein, a PPDDS with pH-induced surface charge-reversal and reactive oxygen species (ROS) amplification for ROS-triggered self-accelerating drug release was developed, which was formed by encapsulating a ROS generation agent (vitamin K3 (VK3)) in pH/ROS dual-sensitive polymetric prodrug (PEG-b-P(LL-g-TK-PTX)-(LL-g-DMA)) based micelle nanoparticles (denoted as PVD-NPs). RESULTS: The surface charge of the PVD-NPs can change from negative to positive for enhanced cell uptake in response to tumor extracellular acidity pH. After internalization by cancer cells, PVD-NPs demonstrate dual drug release in response to intracellular ROS-rich conditions. In addition, the released VK3 can produce ROS under the catalysis by NAD(P)H:quinone oxidoreductase-1, which facilitates tumor-specific ROS amplification and drug release selectively in cancer cells to enhance chemotherapy. CONCLUSION: Both in vitro and in vivo experiments demonstrated that the PVD-NPs showed significant antitumor activity in human prostate cancer.
Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Pró-Fármacos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Micelas , NAD(P)H Desidrogenase (Quinona)/metabolismo , Células NIH 3T3 , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Polímeros/síntese química , Polímeros/química , Pró-Fármacos/farmacocinética , Vitamina K 3/administração & dosagem , Vitamina K 3/farmacocinéticaRESUMO
A promising theranostic nanosystem VK3-CPT@Ru-CD is designed and fabricated by the host-guest driven self-assembly between the fluorescent adamantine-functionalized Ru(II) complexes and the ROS-labile-cyclodextrin modified thioketal linkers, in which anticancer drug camptothecin (CPT) and vitamin K3 (VK3) are effectively co-encapsulated. On account of the generative feedback between the intracellular redox cycling of VK3 and the high degree of ROS-triggered collapse of nanoparticles, VK3-CPT@Ru-CD can facilitate cancer-specific ROS amplification and drug release selectively in cancer cells, thus realizing the selective killing of tumor with minimal side-effects both in vitro and in vivo, the therapeutic effect of which is more prominent than the free anti-cancer drugs. More interestingly, the menadione structure of encapsulated VK3 can effectively quench the inherent fluorescence of Ru-CD, and a fluorescence lightening up phenomenon is observed accompanied with the ROS-triggered drug release, which can be utilized for real-time tracking of drug release in vitro and in vivo.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Camptotecina/administração & dosagem , Corantes Fluorescentes/química , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química , Vitamina K 3/administração & dosagem , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Complexos de Coordenação/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanomedicina Teranóstica/métodos , Vitamina K 3/farmacocinética , Vitamina K 3/uso terapêuticoRESUMO
We have reported that vitamin E intake lowers phylloquinone (PK) concentration in extrahepatic tissues of rats. In this study, we aimed to clarify the characteristic of the distribution of menaquinone-7 (MK-7), a vitamin K contained in fermented foods, by comparison with other vitamin K distributions and to clarify the effect of vitamin E intake on MK-7 concentration in rats. Rats were fed a vitamin K-free diet (Free group), a diet containing 0.75 mg PK/kg (PK group), a 0.74 mg menaquinone-4 (MK-4)/kg diet (MK-4 group), a 1.08 mg MK-7/kg diet (MK-7 group), or a 0.29 mg menadione (MD)/kg diet (MD group) for 16 wk. MK-7 mainly accumulated in the liver, spleen, and adrenal gland of the MK-7 group, although PK accumulated in the serum and all tissues of the PK group. Conversely, MK-4 was present in all tissues of the PK, MK-4, MK-7, and MD groups. MK-4 concentration in the serum, liver, adipose tissue, and spleen was higher in the MK-4 group than in the other groups; however, MK-4 concentration in the kidney, testis, tibia, and brain was lower in the MK-4 group than in the PK, MK-7, and MD groups. Next, vitamin E- and K-deficient rats were orally administered MK-7 with or without α-tocopherol. α-Tocopherol did not affect MK-7 or MK-4 concentration in the serum and various tissues. These results suggested that MK-7 is particularly liable to accumulate in the liver, and MK-7 concentration is not affected by vitamin E intake.
Assuntos
Fígado/efeitos dos fármacos , Estado Nutricional/efeitos dos fármacos , Vitamina K 2/análogos & derivados , alfa-Tocoferol/farmacologia , Animais , Dieta , Alimentos Fermentados , Fígado/metabolismo , Masculino , Ratos Wistar , Distribuição Tecidual , Vitamina K 1/metabolismo , Vitamina K 1/farmacocinética , Vitamina K 2/metabolismo , Vitamina K 2/farmacocinética , Vitamina K 3/metabolismo , Vitamina K 3/farmacocinética , Deficiência de Vitamina K/metabolismoRESUMO
Menadione (VK3), an essential fat-soluble naphthoquinone, takes very important physiological and pathological roles, but its detection and quantification is challenging. Herein, a new method was developed for quantification of VK3 in human plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after derivatization with 3-mercaptopropionic acid via Michael addition reaction. The derivative had been identified by the mass spectra and the derivatization conditions were optimized by considering different parameters. The method was demonstrated with high sensitivity and a low limit of quantification of 0.03 ng mL(-1) for VK3, which is about 33-fold better than that for the direct analysis of the underivatized compound. The method also had good precision and reproducibility. It was applied in the determination of basal VK3 in human plasma and a clinical pharmacokinetic study of menadiol sodium diphosphate. Furthermore, the method for the quantification of VK3 using LC-MS/MS was reported in this paper for the first time, and it will provide an important strategy for the further research on VK3 and menadione analogs.
Assuntos
Ácido 3-Mercaptopropiônico/química , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Vitamina K 3/sangue , Calibragem , Humanos , Concentração de Íons de Hidrogênio , Cinética , Modelos Químicos , Estrutura Molecular , Reprodutibilidade dos Testes , Temperatura , Vitamina K 3/química , Vitamina K 3/farmacocinética , Vitaminas/sangue , Vitaminas/química , Vitaminas/farmacocinéticaRESUMO
This chapter includes the aspects of Menadione (vitamin K). The drug is synthesized by the use of itaconic acid obtained through Friedel-Craft condensation or by direct oxidation of the 2-methyl-1,4-naphthquinone. Vitamin K generally maintains healthy blood clotting and prevents excessive bleeding and hemorrhage, it is also important for maintaining healthy bone structure and for carbohydrate storage in the body. In addition, it is given to newborn babies born in hospitals to prevent the development of life-threatening bleeding caused by low prothrombin levels. The chapter discusses the drug metabolism and pharmacokinetics and presents various method of analysis of this drug such as compendial tests, electrochemical analysis, spectroscopic analysis, and chromatographic techniques of separation. It also discusses its physical properties such as solubility characteristics, X-ray powder diffraction pattern, and thermal methods of analysis. The chapter is concluded with a discussion on its biological properties such as activity, toxicity, and safety.
Assuntos
Vitamina K 3/análise , Animais , Estabilidade de Medicamentos , Humanos , Solubilidade , Análise Espectral , Vitamina K 3/química , Vitamina K 3/farmacocinética , Vitamina K 3/farmacologiaRESUMO
SCOPE: The mechanism for increased bleeding and decreased vitamin K status accompanying vitamin E supplementation is unknown. We hypothesized that elevated hepatic α-tocopherol (α-T) concentrations may stimulate vitamin K metabolism and excretion. Furthermore, α-T may interfere with the side chain removal of phylloquinone (PK) to form menadione (MN) as an intermediate for synthesis of tissue-specific menaquinone-4 (MK-4). METHODS AND RESULTS: In order to investigate these hypotheses, rats were fed phylloquinone (PK) or menadione (MN) containing diets (2 µmol/kg) for 2.5 weeks. From day 10, rats were given daily subcutaneous injections of either α-T (100 mg/kg) or vehicle and were sacrificed 24 h after the seventh injection. Irrespective of diet, α-T injections decreased MK-4 concentrations in brain, lung, kidney, and heart; and PK in lung. These decreases were not accompanied by increased excretion of urinary 5C- or 7C-aglycone vitamin K metabolites, however, the urinary α-T metabolite (α-CEHC) increased ≥ 100-fold. Moreover, α-T increases were accompanied by downregulation of hepatic cytochrome P450 expression and modified expression of tissue ATP-binding cassette transporters. CONCLUSION: Thus, in rats, high tissue α-T depleted tissue MK-4 without significantly increasing urinary vitamin K metabolite excretion. Changes in tissue MK-4 and PK levels may be a result of altered regulation of transporters.
Assuntos
Suplementos Nutricionais/efeitos adversos , Vitamina E/efeitos adversos , Vitamina K 1/farmacocinética , Vitamina K 2/análogos & derivados , Vitamina K 3/farmacocinética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Biotransformação , Cromanos/urina , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Subcutâneas , Fígado/enzimologia , Fígado/metabolismo , Masculino , Propionatos/urina , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Vitamina K 1/administração & dosagem , Vitamina K 1/metabolismo , Vitamina K 1/urina , Vitamina K 2/metabolismo , Vitamina K 2/urina , Vitamina K 3/administração & dosagem , Vitamina K 3/metabolismo , Vitamina K 3/urina , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/efeitos adversos , alfa-Tocoferol/metabolismo , alfa-Tocoferol/urinaRESUMO
2,3-dimethoxy-1,4-naphthoquinone (CAS-RN 6959-96-3) (DMNQ) and 2-methyl-1,4-naphthoquinone (CAS-RN 58-27-5) (MNQ:menadione) are effective one electron redox cycling chemicals in vitro. In addition, in vitro MNQ forms a thioether conjugate with glutathione by nucleophilic attack at the third carbon. In contrast, here we demonstrate that in vivo the major metabolic route is directly to the dihydronaphthoquinone for both DMNQ and MNQ followed by conjugation to mono- and di-glucuronides and sulfate. Analysis of urine and bile showed that glutathione conjugation of MNQ was only a very minor route of metabolism. DMNQ was distributed to all tissues including the brain, and MNQ was much less widely distributed. For DMNQ tissue half-life, in particular for the heart, was considerably longer than the plasma half-life. For both DMNQ and MNQ, urine 8-oxo-7,8-dihydro-2'-deoxyguanosine and liver transcriptomic analysis failed to show any evidence of redox stress. Oxidized glutathione (GSSG) in liver increased significantly at the 10 min postdosing time point only. Metabonomic analysis 96 h after DMNQ administration indicated decreased liver glucose and increased lactate and creatine suggesting an impairment of oxidative metabolism. We conclude that in vivo DMNQ and MNQ are primarily two electron reduced to the dihydronaphthoquinones and undergo little one electron redox cycling. For DMNQ, disruption of cellular oxidative metabolism may be a primary mechanism of toxicity rather than redox stress.
Assuntos
Fígado/metabolismo , Naftoquinonas/farmacocinética , Vitamina K 3/farmacocinética , Animais , Cromatografia Líquida , Creatinina/urina , Elétrons , Fígado/efeitos dos fármacos , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Naftoquinonas/administração & dosagem , Naftoquinonas/metabolismo , Estresse Oxidativo , Espectrometria de Massas em Tandem , Distribuição Tecidual , Transcrição Gênica , Vitamina K 3/administração & dosagem , Vitamina K 3/metabolismoRESUMO
In human liver, the two-electron reduction of quinone compounds, such as menadione is catalyzed by cytosolic carbonyl reductase (CBR) and NAD(P)H:quinone oxidoreductase (NQO1) activities. We assessed the relative contributions of CBR and NQO1 activities to the total menadione reducing capacity in liver cytosols from black (n=31) and white donors (n=63). Maximal menadione reductase activities did not differ between black (13.0+/-5.0 nmol/min mg), and white donors (11.4+/-6.6 nmol/min mg; p=0.208). In addition, both groups presented similar levels of CBR activities (CBR(blacks)=10.9+/-4.1 nmol/min mg) versus CBR(whites)=10.5+/-5.8 nmol/min mg; p=0.708). In contrast, blacks showed higher NQO1 activities (two-fold) than whites (NQO1(blacks)=2.1+/-3.0 nmol/min mg versus NQO1(whites)=0.9+/-1.6 nmol/min mg, p<0.01). To further explore this disparity, we tested whether NQO1 activity was associated with the common NQO1(*)2 genetic polymorphism by using paired DNA samples for genotyping. Cytosolic NQO1 activities differed significantly by NQO1 genotype status in whites (NQO1(whites[NQO1*1/*1])=1.3+/-1.7 nmol/min mg versus NQO1(whites[NQO1*1/*2+NQO1*2/*2])=0.5+/-0.7 nmol/min mg, p<0.01), but not in blacks (NQO1(blacks[NQO1*1/*1])=2.6+/-3.4 nmol/min mg versus NQO1(blacks[NQO1*1/*2])=1.1+/-1.2 nmol/min mg, p=0.134). Our findings pinpoint the presence of significant interethnic differences in polymorphic hepatic NQO1 activity.
Assuntos
População Negra/genética , Citosol/enzimologia , Fígado/enzimologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Polimorfismo Genético , População Branca/genética , Adulto , Oxirredutases do Álcool/genética , Oxirredutases do Álcool/metabolismo , Aldeído Redutase , Aldo-Ceto Redutases , Feminino , Genótipo , Humanos , Fígado/citologia , Masculino , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/genética , Vitamina K 3/farmacocinéticaRESUMO
In previous works we demonstrated that 2-methyl-1,4-naphthoquinone (menadione) causes a marked increase in the force of contraction of guinea pig and rat isolated atria. This inotropic effect was significantly higher in the guinea pig than in the rat and was strictly related to the amount of superoxide anion (O(2)(*-)), generated as a consequence of cardiac menadione metabolism through mitochondrial NADH-ubiquinone oxidoreductase. The present study was designed to further elucidate the basis of these quantitatively different positive inotropic responses. To this purpose, we measured O(2)(*-) and hydrogen peroxide (H(2)O(2)) produced by mitochondria isolated from guinea pig and rat hearts in the presence of 20 microM menadione. Moreover, we evaluated the menadione detoxification activity (DT-diaphorase) and the antioxidant defences of guinea pig and rat hearts, namely their GSH/GSSG content, Cu/Zn- and Mn-dependent superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (Gpx) activities. Our results indicate that DT-diaphorase activity and glutathione levels were similar in both animal species. By contrast, guinea pig mitochondria produced greater amounts of O(2)(*-) and H(2)O(2) than those of rat heart. This is probably due to both the higher Mn-SOD activity (2.93 +/- 0.02 vs. 1.95 +/- 0.06 units/mg protein; P < 0.05) and to the lower Gpx activity (10.09 +/- 0.30 vs. 32.67 +/- 1.02 units/mg protein; P < 0.001) of guinea pig mitochondria. A lower CAT activity was also observed in guinea pig mitochondria (2.40 +/- 0.80 vs. 6.13 +/- 0.20 units/mg protein; P < 0.01). Taken together, these data provide a rational explanation for the greater susceptibility of guinea pig heart to the toxic effect of menadione: because of the greater amount of O(2)(*-) generated by the quinone and the higher mitochondrial Mn-SOD activity, guinea pig heart is exposed to more elevated concentrations of H(2)O(2) that is less efficiently detoxified, because of lower Gpx and CAT levels of mitochondria.