RESUMO
The high expression of reduced glutathione (GSH) and low pH in tumor sites have encouraged new ideas for targeted drug release. The tumor microenvironment is a crucial target for studying the anti-tumor efficiency of photothermal therapy because the microenvironment plays a key role in cancer progression, local resistance, immune escaping, and metastasis. Herein, active mesoporous polydopamine nanoparticles loaded with doxorubicin and functionalized with N,N'-bis(acryloyl)cystamine (BAC) and cross-linked carboxymethyl chitosan (CMC) were used to induce simultaneous redox- and pH-sensitive activity to achieve photothermal enhanced synergistic chemotherapy. The inherent disulfide bonds of BAC were able to deplete glutathione, thus increasing the oxidative stress in tumor cells and enhancing the release of doxorubicin. Additionally, the imine bonds between CMC and BAC were stimulated and decomposed in the acidic tumor microenvironment, improving the efficiency of light conversion through exposure to polydopamine. Moreover, in vitro and in vivo investigations demonstrated that this nanocomposite exhibited improved selective doxorubicin release in conditions mimicking the tumor microenvironment and low toxicity towards non-cancerous tissues, suggesting there is high potential for the clinical translation of this synergistic chemo-photothermal therapeutic agent.
Assuntos
Quitosana , Hipertermia Induzida , Nanopartículas , Neoplasias , Humanos , Terapia Fototérmica , Quitosana/uso terapêutico , Fototerapia , Doxorrubicina/química , Neoplasias/tratamento farmacológico , Nanopartículas/química , Oxirredução , Concentração de Íons de Hidrogênio , Microambiente TumoralRESUMO
Chronic allograft rejection, which is manifested as chronic allograft vasculopathy (CAV), continues to refrain the long-term success of small bowel transplantation (SBTx). The pathway mediated by the receptor for advanced glycation end products (RAGE) and its ligand, high mobility group box-1 (HMGB1), may contribute to the pathogenesis of CAV, given that they were involved in the process of allograft rejection. n-3 polyunsaturated fatty acids (PUFAs), which have been discovered to attenuate CAV, may have potential impacts on this pathway. The present study investigated whether n-3 PUFAs attenuated CAV via the regulation of the HMGB1-RAGE pathway in a chronic rejection model of rat SBTx. We revealed that the expression of HMGB1 and RAGE was increased in CAV-bearing vessels as well as endothelial cells isolated from these vessels. Oral administration of fish oil with high levels of n-3 PUFAs following SBTx significantly reduced the HMGB1 and RAGE expression, which coincided with the amelioration of CAV. In contrast, feeding of corn oil that contained low levels of n-3 PUFAs had no favorable effects on CAV development and failed to decrease the HMGB1 and RAGE expression. These results indicate that protective effects of n-3 PUFAs on allograft vessels exist via down-regulation of the HMGB1-RAGE pathway.
Assuntos
Regulação para Baixo , Ácidos Graxos Ômega-3/farmacologia , Rejeição de Enxerto/prevenção & controle , Proteína HMGB1/metabolismo , Intestino Delgado/efeitos dos fármacos , Receptores Imunológicos/metabolismo , Animais , Doença Crônica , Óleo de Milho/administração & dosagem , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Óleos de Peixe/administração & dosagem , Proteína HMGB1/genética , Intestino Delgado/metabolismo , Intestino Delgado/transplante , Masculino , Ratos , Ratos Endogâmicos Lew , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genéticaRESUMO
OBJECTIVE: To establish a RP-HPLC method for simultaneous determination of total quercetin, kaempferol and isorhamnetin in rat plasma after oral administration of Folium Mori extract (FME). METHODS: After a single dose of FME (110 mg/kg) was taken, rat plasma samples were collected. The samples were hydrolyzed with hydrochloric acid (c=3.0 mol/L), the mixed solution was extracted with ether acetone mixture. The total quercetin, kaempferol and isorhamnetin in plasma samples were determined by HPLC, pharmacokinetic parameters were calculated by DAS 3.0 software. RESULTS: The method was linear over the concentration ranges of 0.0545-8.70, 0.0954-14.7 and 0.0545-8.55 µg/ml for quercetin, kaempferol and isorhamnetin, respectively (r=0.9979, 0.9993, 0.9981). The absolute recoveries were 85.3%-86.1%, 79.4%-86.7% and 62.8%-89.7%, respectively and the assay recoveries were all from 94.7% to 107%. The relative standard deviation (RSD) of intra-and inter-day were less than 9.5% and 9.8%, respectively. The main pharmacokinetic parameters were as follows: T(1/2z) was 92.7, 67.9 and 54.2 h; Tmax was 0.400, 0.400 and 3.87 h; AUC(0-∞) was 68.0, 67.5 and 32.8 mg/h/L; MRT(0-∞) was 128, 85.2 and 72.0 h for quercetin, kaempferol and isorhamnetin, respectively. CONCLUSION: The method established in this study is accurate, reliable and reproducible, and can be applied for determination of total quercetin, kaempferol and isorhamnetin in rat plasma after oral administration of FME; the pharmacokinetic studies showed that the distribution of drugs is rapid and elimination is very slow.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Flavonóis/farmacocinética , Quempferóis/farmacocinética , Quercetina/farmacocinética , Administração Oral , Animais , Flavonóis/sangue , Quempferóis/sangue , Masculino , Extratos Vegetais/farmacocinética , Quercetina/sangue , Ratos , Ratos Sprague-DawleyRESUMO
A method coupling liquid chromatography with electrospray ionization time-of-flight mass spectrometry (LC/ESI-TOF/MS) has been developed for rapid and sensitive analysis of rat urinary metabolite profile of Danggui Buxue Tang (DBT), a well-known Chinese herbal formula. After oral administration of DBT, urine samples were collected during 0-24 h, and then pretreated by solid-phase extraction. A total of 68 compounds including 13 parent compounds and 55 metabolites were detected in the drug-containing urines compared with blank urines. The total analytical time was less than 20 min. Metabolites of DBT were identified using dynamic adjustment of the fragmentor voltage to produce structure-relevant fragment ions. By using this approach, the mass accuracy of precursor and fragment ions was typically within +/-5 ppm of the theoretical values, and enabled the identification of 43 metabolites including 27 isoflavanoid and 16 phthalide metabolites. Our results indicated that glucuronidation and sulfation were the major metabolic pathways of isoflavonoids, while glutathione conjugation, glucuronidation and sulfation were the main metabolic pathways of phthalides. No saponin-related metabolites were detected. The results of the present study provided important structural information relating to the metabolism of DBT. Furthermore, this work demonstrated the potential of the LC/ESI-TOF/MS approach for identification of metabolites from Chinese herbal medicines in urine.
Assuntos
Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/química , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Astragalus propinquus/química , Medicamentos de Ervas Chinesas/metabolismo , Extratos Vegetais/urina , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To explore the utility of principle component analysis (PCA) on chromatographic data for quality control to Dannanxing (Pinellia Cum Bile). METHOD: Chromatographic fingerprints of sample were determined by TLC, PCA and multivariat analysis were used for data processing. RESULT: The quantitative differences among samples procesed with different biles and heating time were found with the method. CONCLUSION: PCA could be used in data processing for chromato-gramphic fingerprints of Dannanxing.