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1.
目的以人血清白蛋白为载体包载替尼泊苷,经过包衣修饰后制备包载替尼泊苷的多层包衣纳米粒(teniposide-encapsulated multilayer nanoparticles,P-CS-NP),以期降低药物的不良反应并改善其体外抗肿瘤活性。方法以粒径、多分散指数和载药率为评价指标,采用单一因素法筛选出替尼泊苷白蛋白纳米粒的最优处方工艺,通过加入壳聚糖和聚谷氨酸聚乙二醇共聚物进一步制备多层包衣白蛋白纳米粒,筛选得到最优包衣量。以游离的替尼泊苷作为参比,用MTT法测定纳米粒对人肺癌A549细胞的体外细胞毒性,并用流式细胞仪和共聚焦显微镜测定和观察多层包衣纳米粒的细胞摄取率和细胞摄取行为。结果确定了多层包衣纳米粒的处方及制备工艺。多层包衣纳米粒的体外细胞毒性比游离的替尼泊苷小,摄取具有时间依赖性,与壳聚糖共孵育的纳米粒的细胞摄取量增加,入胞后纳米粒主要分布在细胞质。结论白蛋白纳米粒能被壳聚糖和聚谷氨酸聚乙二醇共聚物包衣修饰,多层包衣纳米粒可以作为替尼泊苷的药物递送载体,其体外细胞毒性降低。  相似文献   

2.
目的 制备载蛋白降解靶向嵌合体(PROTAC)分子的白蛋白纳米粒并优化处方,考察纳米粒对胶质瘤细胞增殖活性及烟酰胺腺嘌呤二核苷酸(NAD+)代谢的抑制。方法 以热驱动法制备载NPT-B2的白蛋白纳米粒并表征,建立NPT-B2的高效液相色谱(HPLC)检测方法,以CCK8法和蛋白免疫印迹法分别考察NPT-B2和白蛋白纳米粒(B2-BSA-NPs)对胶质瘤细胞的增值活性抑制作用,及肿瘤细胞限速酶-烟酰胺磷酸核糖转移酶(NAMPT)的降解。结果 HPLC方法线性良好,精密度、回收率符合测定要求。纳米粒粒径为55.48 nm、电位-12.9 mV,包封率94.74%,载药量8.61%。NPT-B2对胶质瘤细胞的IC50为61.16 nmol/L,同时具有NAMPT降解作用。B2-BSA-NPs对胶质瘤细胞的IC50为41.21 nmol/L,对NAMPT具有非常显著降解效果。结论 构建了载PROTAC分子的白蛋白纳米粒,优化处方提高药物包封率,改善PROTAC分子水溶性差的问题,纳米粒对胶质瘤细胞增殖活性及NAD+能量代谢有显著抑制作用。  相似文献   

3.
目的 通过观察三氧化二砷(As2O3)对人类慢性髓系白血病(CML)细胞株K562细胞的作用.探讨其治疗CML的作用机制.方法 将K562细胞与不同浓度As2O3共同孵育,于24、48、72 h用MTT方法检测K562细胞存活率,用AnnexinV-FITC检测凋亡细胞,同时用酶联免疫吸附法(ELISA)检测K562细胞上清液中血管内皮因子(VEGF)的浓度.结果 As2O3<2 μmol·L-1时,对K562细胞增殖抑制和诱导凋亡的作用与空白对照组比较,无统计学意义(P>0.05);As2O3>2 μmol·L-1时则具统计学意义(P<0.05);在相同作用时间下,AS2O3 浓度升高对K562细胞的增殖抑制率及细胞凋亡率亦升高;当As2O3>8 μmol·L-1时,对K562细胞的抑制及细胞凋亡率不再上升. As2O3<2 μmol·L-1时上清液中VEGF浓度与空白对照组比较无显著性(P>0.05);As2O3>2 μmol·L-1时VEGF的浓度差异有显著性(P<0.05),且随As2O3 浓度的增加VEGF浓度上升;当As2O3>8 μmol·L-1时则变化不显著(P>0.05).结论 As2O3可抑制K562细胞增殖,并具诱导凋亡作用, As2O3在2.0~10.0 μmol·L-1梯度浓度,作用在24~72 h时段,表现为时间和剂量依赖性,还可下调VEGF表达水平.  相似文献   

4.
目的:探讨米非司酮(mifepristone)联合三氧化二砷(As2O3)对K562/ADM的逆转作用及机制研究。方法:不同浓度米非司酮、As2O3处理细胞72h,采用MTT法检测细胞增殖活性;流式细胞仪检测细胞凋亡、分光光度法检测细胞谷胱甘肽(GSH)含量。结果:10μmol.L-1的米非司酮对K562/ADM细胞无明显杀伤,可有效逆转K562/ADM细胞耐药性,此浓度米非司酮联合As2O3(2.0μmol.L-1)作用于K562/ADM细胞后,逆转倍数明显增高(P<0.01),GSH含量明显低于同浓度单用药组(P<0.05)。对细胞增殖抑制及其诱导凋亡的效果均明显高于同浓度单用药组(P<0.05)。结论:米非司酮联合As2O3逆转作用增强,机制可能与凋亡加强及GSH含量改变有关。  相似文献   

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目的:探讨c-Jun氨基末端激酶(JNK)信号通路在三氧化二砷(As2O3)诱导K562细胞凋亡中的作用及机制。方法:体外培养K562细胞,用As2O3及特异性JNK抑制剂SP600125对K562细胞进行处理;倒置相差显微镜下观察细胞形态学变化;MTT法检测不同时间点细胞增殖抑制率;AnnexinV/PI染色结合流式细胞术检测细胞凋亡率;ELISA检测p-JNK蛋白表达的变化;流式细胞术检测突变型P53表达。结果:ELISA显示4μmol/LAs2O3作用48h后p-JNK蛋白表达增强,经SP600125预处理后,As2O3诱导的K562细胞p-JNK蛋白表达明显减弱(P<0.01),As2O3诱导的细胞增殖抑制率和细胞凋亡率均下降,与As2O3单作用组相比突变型P53表达增加(P<0.05)。结论:JNK信号转导通路在As2O3诱导K562细胞凋亡过程中发挥重要作用,是As2O3诱导K562细胞凋亡的主要途径之一。  相似文献   

6.
目的 利用泊洛沙姆188对PLGA进行化学修饰,制备包载阿霉素的纳米粒,并评价纳米粒在人耐药乳腺癌细胞中的摄取能力及毒性。方法 通过EDC/NHS法合成泊洛沙姆188-PLGA,通过核磁共振对其结构进行表征并测定临界胶束浓度;通过纳米沉淀法制备包载阿霉素的纳米粒,通过粒度仪对纳米粒的粒径及分布进行分析,通过细胞摄取实验及细胞毒性实验对纳米粒的摄取效果及毒性进行评价。结果 成功合成了泊洛沙姆188-PLGA,并制备了粒径在140 nm左右的纳米粒,该纳米粒在人耐药乳腺癌细胞中有较好的摄取效果及较强的毒性。结论 泊洛沙姆188能够逆转耐药,增强耐药细胞对化疗药物的敏感程度。  相似文献   

7.
目的:探讨三氧化二砷(As2O3)诱导K562/ADM细胞凋亡中活性氧(ROS)的作用和其与耐药基因radr1及其编码的P-糖蛋白(P—gP)表达的关系。方法:应用噻唑蓝(MTT)比色法检测K562/ADM细胞增殖活性;Annexin V/PI染色法检测细胞凋亡;RT-P(鼠检测mdr1基因mRNA的表达;流式细胞术测定P-gP表达、ROS活性和细胞内阿霉素(ADM)含量。结果:As2O3显著抑制K562/ADM细胞的增殖,Annexin V/PI双染检测显示凋亡细胞明显增加:ROS活性明显下降;mdr1 mRNA和P-gP表达明显降低,P-gP功能受抑,细胞内ADM含量显著增高。结论:As2O3抑制K562/ADM耐药细胞的增殖活性和促进其凋亡,其机制可能为通过降低细胞ROS水平、抑制radr1/P-gp的表达和功能,进而逆转mdr1/P-gP介导的多药耐药和凋亡抑制。  相似文献   

8.
MEK抑制剂联合三氧化二砷对髓系白血病细胞凋亡的研究   总被引:1,自引:0,他引:1  
目的:研究MEK抑制剂PD98059联合三氧化二砷(As2O3)对髓系白血病细胞凋亡的影响及其作用机制。方法:将PD98059、As2O3单独或联合作用于髓系白血病细胞系HL-60、K562细胞,用AnnexinV-FITC法检测细胞凋亡,用流式细胞术检测Bcl-2、Caspapse-3表达。结果:联合组与单用组相比,细胞凋亡率明显增高。Bcl-2在HL-60、K562细胞均高水平表达。As2O3明显抑制HL-60细胞Bcl-2表达,对K562细胞Bcl-2无明显抑制作用。单用PD98059、As2O3及两药合用在诱导HL-60、K562细胞凋亡过程中,活化caspapse-3均明显上升,两药合用较单用PD98059或As2O3活化caspapse-3明显升高。结论:PD98059联合As2O3同时抑制ERK/MAPK和Bcl-2,激活Caspase酶,对HL-60细胞有协同促凋亡效应。两药联合同时靶向作用ERK/MAPK和BCR/ABL,活化Caspase酶,协同诱导K562细胞凋亡。PD98059可增强As2O3对髓系白血病细胞的凋亡诱导作用。  相似文献   

9.
目的制备、表征载四氧化三铁(Fe3O4)的乳铁蛋白修饰的两亲性壳聚糖(Lf-QMC)磁性纳米粒,研究其对海马神经细胞的亲和力及磁场介导下的体内脑靶向性。方法以Lf-QMC纳米粒为基础,采用溶剂挥发法将油酸(OA)改性的磁性Fe3O4(OA-Fe3O4)包载,形成载OA-Fe3O4的Lf-QMC纳米粒,载药量为1.5%;通过傅里叶红外光谱(FTIR)、透射电镜(TEM)、动态光散射(DLS)、X射线衍射(XRD)和振动磁强计(VSM)对其进行表征;刃天青法检测载OA-Fe3O4的Lf-QMC纳米粒对HT-22海马细胞活性的影响;TEM考察该纳米粒被HT-22海马神经细胞摄取的情况;荧光分析法检测载该纳米粒的体内脑靶向性。结果成功构建了载OA-Fe3O4的Lf-QMC纳米粒,其饱和磁化强度为1.2 emu·g-1;该磁性纳米粒在2200μg·m L-1对HT-22海马细胞无显著毒性;TEM观察显示该磁性纳米粒对HT-22海马细胞有较好的亲和性并能通过有效的途径进入细胞;在磁场的介导下,OA-Fe3O4-Lf-QMC纳米粒可以实现更好的脑靶向效果。结论载OA-Fe3O4的Lf-QMC纳米粒有望在磁场和乳铁蛋白的双重靶向作用下透过血脑屏障向神经细胞递送药物。  相似文献   

10.
目的 制备转铁蛋白受体特异结合肽T7修饰载紫杉醇纳米粒(T7-NPs-PTX),研究其对结肠癌RKO细胞的靶向抑制作用.方法 采用薄层法利备纳米粒共聚焦显微镜观察结肠癌RKO细胞和血管内皮HUVEC细胞对T7-NPs-PTX的摄取情况.MTT实验研究T7-NPs-PTX对结肠癌RKO细胞的毒性;流式细胞仪检测T7-NPs-PTX对结肠癌RKO细胞的凋亡诱导作用.构建RKO细胞肿瘤球模型,研究T7-NPs-PTX对肿瘤球的生长抑制能力.构建结肠癌裸鼠异位模型,研究T7-NPs-PTX对裸鼠肿瘤生长抑制作用.结果 RKO细胞对经过T7修饰后的T7-NPs-PTX摄取显著增加,但HUVEC细胞对T7-NPs-PTX的摄取无显著变化.T7-NPs-PTX对结肠癌RKO细胞的增殖抑制作用和细胞凋亡诱导作用显著强于NPs-PTX和PTX溶液.结论 经过T7修饰后能够增强纳米粒与结肠癌RKO细胞的亲和力,T7-NPs-PTX是一种潜在、高效的结肠癌靶向给药系统.  相似文献   

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This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.  相似文献   

14.
In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.  相似文献   

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This article assesses pain within the context of the dose response. A substantial number of studies indicate that the dose response for pain-related endpoints is commonly biphasic, being independent of the type of biological model employed, endpoint measured, or agent tested. The quantitative features of the dose response are also remarkably consistent regardless of the receptor pathway that mediates the nociceptive response, indicating a likely downstream message convergence. These findings have important implications for drug discovery, development, and clinical evaluation.  相似文献   

18.
The current USP National Formulary contains 65 Monographs for drug formulations containing neomycin. All 65 Monographs prescribe a bioassay for neomycin assay. This bioassay, based on cell culture, is labor intensive, has poor precision, and cannot be adapted for purity or identification. High-performance anion-exchange chromatography with integrated pulsed amperometric detection (HPAE-IPAD), a liquid chromatography technique, has been shown to be suitable for neomycin purity analysis and neomycin assay of an over-the-counter first aid cream (Hanko and Rohrer [17]). Here we propose that an HPAE-IPAD assay can replace the bioassay in the 65 neomycin-containing Monographs. We applied the HPAE-IPAD assay to four neomycin-containing drug products representing the four classes of formulations found in the 65 Monographs, liquid, solid, suspension, and cream. Each drug was analyzed with two chromatography systems, and on 3 separate days. For all products, HPAE-IPAD measurements were precise and accurate with respect to the label concentrations. There was also high accuracy for spike recovery of neomycin from the four drug products throughout 70–150% of the labeled concentration. These results suggest that an HPAE-IPAD assay would be an accurate assay for neomycin, and would be faster and more precise than the current bioassay.  相似文献   

19.
Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.
Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.
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20.
This review briefly summarizes the information on the molecular mechanisms of action, pharmacokinetic profiles and drug interactions of novel (third-generation) antiepileptic drugs, including brivaracetam, carabersat, carisbamate, DP-valproic acid, eslicarbazepine, fluorofelbamate, fosphenytoin, ganaxolone, lacosamide, losigamone, pregabalin, remacemide, retigabine, rufinamide, safinamide, seletracetam, soretolide, stiripentol, talampanel, and valrocemide. These novel antiepileptic drugs undergo intensive clinical investigations to assess their efficacy and usefulness in the treatment of patients with refractory epilepsy.  相似文献   

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