Multifunctional Polymeric Micelles for Enhanced Intracellular Delivery of Doxorubicin to Metastatic Cancer Cells

Purposes  To develop multifunctional RGD-decorated poly(ethylene oxide)-b-poly(ester) based micelles and assess their pH-triggered core degradation and targeted drug release in tumor cells that overexpress RGD receptors. Methods  Novel poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) based copolymers modified with RGD ligands on PEO and pendent functional groups on PCL, i.e., GRGDS-PEO-b-poly(α-benzylcarboxylate-ε-caprolactone) (GRGDS-PEO-b-PBCL) and GRGDS-PEO-b-poly(α-carboxyl-ε-caprolactone) (GRGDS-PEO-b-PCCL), were synthesized. Chemical conjugation of doxorubicin (DOX) to PCCL core produced GRGDS-PEO-b-P(CL-DOX) micellar conjugates, while GRGDS-PEO-b-PBCL were used to physically encapsulate DOX. For both systems, micellar core degradation, drug release, intracellular drug uptake/disposition, and cytotoxicity against B16F10 metastatic cells were investigated. Results  The PBCL and P(CL-DOX) cores were found resistant to degradation in pH 7.2, but showed 10% and 40% loss in core molecular weight in pH 5.0 within 144 h, respectively. Preferential release of DOX and DOX derivatives from PBCL and P(CL-DOX) cores was noted in pH 5.0, respectively. The GRGDS-modified micelles showed enhanced cellular internalization through endocytosis, increased intracellular DOX release, nuclear localization, and improved cytotoxicity against metastatic B16F10 cells compared to their unmodified counterparts. Conclusions  The results clearly suggest a promise for the development of multifunctional polymeric micelles with RGD ligand decorated shell and endosomal pH-triggered degradable core for selective DOX delivery to metastatic cancer cells.     

Synthesis and in Vitro and in Vivo Pharmacological Evaluation of New 4-Aminoquinoline-Based Compounds

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Estimation of C max and T max in Populations After Single and Multiple Drug Administrations

Following the oral administration of drugs, the plasma concentration generally reaches, in principle, a single, well-defined peak (Cmax) at the time of Tmax. A complication for the direct estimation of Cmax and Tmax is that measurements of concentrations are recorded only at discrete time points. Theoretical equations characterizing the population distribution of Cmax and Tmax are derived in relationship to the pharmacokinetic model, its parameters, their variabilities, and experimental errors. These equations can be solved by numerical integration. The resulting means, variances and other summary statistics of Cmax and Tmax are evaluated under various conditions involving single and multiple drug administrations. Results gained by the proposed numerical method agree closely with results gained by Monte-Carlo simulations. It is argued that the numerical method could be useful to study the statistical properties of the investigated measures and could, in some cases, provide a viable alternative to simulations. It is demonstrated that Cmax is estimated directly with positive bias, especially following repeated drug administrations. As a consequence, the recorded peak-trough fluctuation (PTF), measured in the steady state, can be excessively large (even by orders of magnitude) particularly when drug accumulation is high. These results have practical implications for the development of drugs and drug formulations.     

18F-Labeled Phenyldiazenyl Benzothiazole for in Vivo Imaging of Neurofibrillary Tangles in Alzheimer's Disease Brains

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Pyrimidinone Nicotinamide Mimetics as Selective Tankyrase and Wnt Pathway Inhibitors Suitable for in Vivo Pharmacology

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Positron Emission Tomography to Elucidate Pharmacokinetic Differences of Regioisomeric Retinoid X Receptor Agonists

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Bivalent Ligands Targeting Multiple Pathological Factors Involved in Alzheimer's Disease

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叶酸-羧甲基壳聚糖-超小超顺磁氧化铁纳米粒在大、小鼠体内的药代动力学、组织分布及磁共振响应特征

叶酸-羧甲基壳聚糖-超小超顺磁氧化铁纳米粒(folic acid-O-carboxymethyl chitosans ultrasmall super-paramagnetic iron oxide nanoparticles,FA-OCMCS-USPIO-NPs)是一种新型分子靶向的核磁共振造影剂。本文考察了其在正常大鼠和小鼠体内的药代动力学及磁共振响应特征,探讨该造影剂在动物体内的分布规律,为其肿瘤靶向造影提供依据。尾静脉给予高、低浓度的纳米粒后,采用邻二氮菲法测定大鼠血浆及小鼠组织内的铁含量并绘制药时曲线,求得两组药代动力学参数t1/2均大于7 h。组织分布结果显示只有少部分的纳米粒被肝、脾吞噬,而心、肺、肾内几乎没有分布,并且纳米粒的吞噬不随剂量的增加而增加。核磁共振结果显示,给药后4 h纳米粒开始由肾脏排泄,24 h时肝、肾的信噪比(SNR)恢复到正常水平,肺部没有纳米粒的分布。可见,部分纳米粒逃避了肝、脾的吞噬,具有低毒性和较长的半衰期,为肿瘤靶向造影奠定了基础。     

十一酸睾酮自微乳制剂的大鼠体内药代动力学研究

目的制备十一酸睾酮自微乳化制剂,并对其大鼠体内药代动力学进行研究。方法采用血清睾酮放免法测定给药后大鼠体内血清睾酮水平的变化,并计算药代动力学参数。结果十一酸睾酮原料药混悬液基本没吸收,而自微乳制剂和市售Andriol药物的吸收大大提高。以Andriol为参比制剂,自微乳制剂的相对生物利用度为96.4%。结论自微乳化给药系统能提高脂溶性药物十一酸睾酮的吸收。     

酮康唑对奥拉西坦在大鼠体内药代动力学的影响

目的建立测定大鼠血浆中奥拉西坦含量的高效液相色谱法,研究酮康唑对奥拉西坦在大鼠体内药代动力学的影响。方法色谱柱为DiamonsilRPC18柱(250mm×4.6mm,5μm),流动相为乙腈-水(3.2:96.8),流速为0.8mL/min,检测波长210nm,柱温40℃,进样量20μL。试验组大鼠连续灌胃给予酮康唑(50mg/kg,每日1次)7d后,单次灌胃给予奥拉西坦(200mg/kg),测定奥拉西坦血药浓度,计算药代动力学参数,并与单次灌胃给予奥拉西坦(200mg/kg)的对照组进行比较。结果奥拉西坦标准曲线方程为Y=0.0217X+0.1058(r=0.9992,n=7),质量浓度线性范围为2～100mg/L;低、中、高3种质量浓度的方法回收率分别为(102.25±8.51)%,(96.29±2.76)%和(98.14±1.62)%,日内及日间精密度的RSD均小于5.42%。对照组与试验组主要药代动力学参数,半衰期(t1/2)分别为(2.807±0.8751)h和(3.231±1.019)h,峰浓度(Cmax)分别为(52.80±16.94)mg/L和(47.33±8.317)mg/L,0～12h药时曲线下面积(AUC0-12h)分别为(257.2±77.84)mg.h/L和(258.9±67.30)mg.h/L,组间比较无显著性差异。结论酮康唑对大鼠体内奥拉西坦的药代动力学无显著影响。     

低分子右旋糖酐对甘露醇注射液在家兔体内药动学的影响

目的探讨低分子右旋糖酐对甘露醇注射液在家兔体内的药代动力学影响。方法用衍生化气相色谱法测定甘露醇注射液单用组和复方低分子右旋糖酐组甘露醇在家兔体内的血药质量浓度,比较两者的药动学参数。结果 2组的主要药动学参数差异均无统计学意义(P>0.05)。结论两药合用时,低分子右旋糖酐对甘露醇注射液在家兔体内的药代动力学没有显著影响。     

基于多元线性回归的癫痫患儿丙戊酸血药浓度影响因素分析

目的：探讨影响癫痫患儿丙戊酸（VPA）的血药浓度的因素。方法：回顾性分析我院218例VPA血药浓度监测报告,包括患儿性别、年龄、丙戊酸钠日总剂量、联合用药情况、丙氨酸氨基转移酶、天冬氨酸氨基转移酶、血浆白蛋白、血肌酐和稳态血药浓度。利用多元线性回归分析影响VPA血药浓度变化的因素。结果：多元线性回归分析显示,日总剂量与血药浓度呈正相关（P<0.05）,白蛋白含量与血药浓度呈负相关（P<0.05）,不同剂型对血药浓度有影响,丙戊酸钠缓释片与糖浆的血药浓度比较差异有统计学意义（P<0.05）。结论：丙戊酸钠的不同剂型、给药剂量和白蛋白含量会影响VPA血药浓度,患儿性别、年龄、是否联用左乙拉西坦或拉莫三嗪、丙氨酸氨基转移酶、天冬氨酸氨基转移酶、血肌酐与血药浓度无相关性     

载紫杉醇的PEG修饰的大黄酸偶联物胶束的细胞摄取及活体成像研究

目的 探究载紫杉醇(paclitaxel,PTX)的聚乙二醇(polyethyleneglycol,PEG)修饰的大黄酸偶联物胶束的细胞摄取及活体成像情况。方法 将环境响应型荧光探针P4/P2与药物PTX共载于mPEG-羧甲基壳聚糖-大黄酸(CRmP)偶联物胶束中,制备(P4+PTX)/CRmP胶束。以MCF-7细胞为细胞模型,利用激光共聚焦显微镜和流式细胞仪分析该胶束被MCF-7细胞摄取的情况;以H22皮下移植瘤小鼠为模型,在体和离体成像分析该胶束在体内的分布情况。结果 (P4+PTX)/CRmP胶束以完整的胶束形式被MCF-7细胞内吞摄入,分布于细胞质。(P2+PTX)/CRmP胶束在荷瘤小鼠的肝脏和肿瘤部位较多聚集,并于实验时间内在肿瘤部位不断累积。结论 该胶束以完整的胶束形式被肿瘤细胞摄取,在体内有一定的肝靶向性和肿瘤靶向性。     

阿克拉霉素A固体脂质纳米粒冻干针剂在家兔体内药动学

目的:研究阿克拉霉素A固体脂质纳米粒(ACM-SLN)冻干针剂在家兔体内的药物动力学。方法:用RP-HPLC法测定家兔耳缘静注ACM-SLN冻干针剂和阿克拉霉素A(ACM-A)注射剂后不同时间血浆中ACM-A的浓度,绘制药-时曲线,计算药物动力学参数。结果:ACM-SLN冻干针剂和ACM-A注射剂的体内过程均符合二室模型,ACM-SLN冻干针剂的t1/2β与MRT显著延长,AUC增高,CL降低。结论:ACM-SLN冻干针剂有利于增加药物与肝脏肿瘤组织的接触时间,从而提高ACM-A的抗肝癌作用。     

氨氯地平对映体在家兔体内手性药动学比较研究

目的:研究氨氯地平对映体在家兔体内的手性药动学过程。方法:家兔灌胃给予氨氯地平对映体10mg/kg,分别于灌胃前及灌胃后0.5、1、1.5、2、2.5、3、4、6、8、10、12、24h自耳动脉采血,采用反相高效液相色谱法结合手性高效液相色谱法测定血浆中(R)-和(S)-氨氯地平的浓度。结果:家兔体内氨氯地平2种对映体的药动学过程均呈二室模型;家兔体内不同时间点氨氯地平2种对映体的血浆浓度比较无显著性差异(t=0.78,P>0.05),主要药动学参数接近。结论:氨氯地平对映体在家兔体内的药动学过程并不存在立体选择性差异。     

Evaluation of In Vivo toxicity of Novel Biosurfactant from Candida parapsilosis loaded in PLA-PEG Polymeric Nanoparticles

The aim of this study was to evaluate the toxicological profile of biosurfactant encapsulated polymeric nanoparticles of Polylactic acid-Polyethylene glycol (PLA-PEG) in mice. Hematological, biochemical and histopathological samples of rodents were evaluated. Mice were selected randomly and divided into 3 treatment groups and one control group. Group I mice served as a control group, Group II were administrated with biosurfactant, Group III were treated with Polymeric nanoparticles of PLA-PEG. Group IV mice were injected with biosurfactant loaded polymeric nanoparticles of PLA-PEG. The formulations were administered intravenously via tail vein with 20 μg/mL dose concentration of biosurfactant. The normal control group was injected with only PBS. Blood samples were collected on 7th, 14th and 21st day and hematological and biochemical assays were performed. After the blood collection, mice were sacrificed for histopathological examination. The results showed that there were no significant difference in hematology parameter between the control and treated group. Some minute, non-significant changes were found in biochemical parameters which were not considered. Histopathological result of selected vital organs revealed that the biosurfactant and/or PLA-PEG polymeric nanoparticles can be considered as safe as no toxicological features were observed in histopathology of tissues. Hence, it can be deliberated that the biosurfactant encapsulated in PLA-PEG copolymeric nanoparticles are non toxic and can provide a safe, suitable platform for biomedical applications in future.     

HPLC-MS/MS法研究PVP包衣去甲斑蝥素壳聚糖纳米粒在大鼠体内的药代动力学

目的:建立HPLC-MS/MS方法测定大鼠血浆中去甲斑蝥素(NCTD)浓度,并考察PVP包衣去甲斑蝥素-壳聚糖纳米粒制剂(PVP coated NCTD-chitosan nanoparticles,PVP-NCTD-NP)在大鼠体内药代动力学及相对生物利用度。方法:使用电喷雾电离负离子源(ESI-),多重反应离子(MRM)模式检测药物;采用高氯酸作为蛋白沉淀剂,测定大鼠尾静脉注射PVP-NCTD-NP和原药NCTD溶液后的血药浓度;利用3P97软件计算药代动力学参数。结果:NCTD在0.102 5～10.25μg·mL-1范围内线性关系良好(r=0.999 2),最低检测限为50 ng·mL-1;经3P97软件拟合,NCTD的药代动力学过程符合二室模型,与原药相比,PVP-NCTD-NP相对生物利用度为325.5%。结论:本法灵敏、准确、选择性高,适用于NCTD药代动力学的研究;PVP-N-CTD-NP可促进药物的吸收,显著提高NCTD的生物利用度。     

纳米粒形状对体内药动学的影响及非球形纳米粒制备方法的研究进展

目的介绍非球形纳米粒的最新研究进展,并对其体内药动学行为及制备方法进行综述。方法参考近年来国内外的23篇文献,根据纳米粒形状对体内药动学影响及非球形纳米粒的制备方法分类并总结。结果形状这一影响因素同聚合物种类、颗粒大小和表面化学等一样影响着纳米粒子在体内的吞噬、转运、吸附等药动学行为,因此,可以根据需要将纳米粒设计成不同形状以达到缓释、靶向等作用;可以采用"PRINT"技术、介孔硅技术、膜拉伸技术等或联合应用多种技术制备非球形纳米粒;可以根据要求的不同,把制备的非球形纳米粒制成注射剂、肺部吸入剂及口服制剂等等。结论纳米粒的形状对体内药动学有着重要影响,并且逐渐受到越来越多的关注,制备非球形纳米粒的方法也在不断地涌现。在今后的研究中,仍需开发大规模且高效生产非球形纳米粒的方法,以及对粒子形状在生物学相关领域的影响上做系统性的研究,使非球形纳米粒在药物传递领域中发挥重要的作用。     

Effect of the Immunomodulator Tilorone on the in Vivo Acetylation of Procainamide in the Rat

Interferon and interferon inducers have been found to inhibit cytochrome P-450-dependent metabolism in animals and man. The effect of these agents on the acetylation of drugs has not been previously reported. Since these agents stimulate the reticuloendothelial system, together with the abundance of N-acetyltransferase in the reticuloendothelial system, it was hypothesized that these immunomodulators may affect drug acetylation. To test this hypothesis, the effect of tilorone (a synthetic interferon inducer) on the in vivo acetylation of procainamide was examined in the rat. Pretreatment with tilorone hydrochloride (50 mg/kg) 48 hr prior to the administration of procainamide hydrochloride (50 mg/kg) resulted in a 32% increase in the urinary recovery of N-acetylprocainamide and a 35% increase in the metabolic clearance of procainamide to N-acetylprocainamide. These data indicate that interferon inducers increase the N-acetylation of drugs in vivo.     

Anti-tumor Effect of All-<Emphasis Type="BoldItalic">Trans</Emphasis> Retinoic Acid Loaded Polymeric Micelles in Solid Tumor Bearing Mice

Purpose All-trans retinoic acid (ATRA) polymeric micelles were developed for parenteral administration. The distribution characteristics and antitumor activities of ATRA polymeric micelles were evaluated after intravenous administration to mice bearing CT26 solid tumors. Methods ATRA incorporated in poly(ethylene glycol)-poly(benzyl aspartate) block copolymer was prepared by the evaporation method. The levels of [³H]ATRA in blood and tissue including tumor were determined by measuring the radioactivity after injection into mice. The tumor volume and the survival of the mice were determined to assess the anticancer activity. Results The delivery of ATRA by polymeric micelles prolonged the blood circulation and enhanced the accumulation of ATRA in the tumor tissue compared with the administration of free ATRA. Tumor growth was significantly delayed and the survival time of mice was prolonged following the treatment by ATRA polymeric micelles demonstrating the improved anticancer activity of ATRA. Conclusion Polymeric micelles are a promising and effective carrier of ATRA in order to enhance tumor delivery and they have a promising potential application in the treatment of solid tumors.