PLGA/TPGS Nanoparticles for Controlled Release of Paclitaxel: Effects of the Emulsifier and Drug Loading Ratio

PURPOSE: We successfully manufactured nanoparticles of biodegradable polymers for controlled release of paclitaxel. TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) could be a novel material to make nanoparticles of high drug encapsulation efficiency (EE) and desired physicochemical and pharmaceutical properties of the drug loaded nanoparticles. Among various controlling parameters in the process, the present work is to elucidate the effects of the surfactant stabilizer and the drug loading ratio. METHODS: Paclitaxel loaded PLGA nanoparticles were formulated at various drug-loading ratios by a modified single emulsion solvent extraction/evaporation technique. TPGS was introduced either as the emulsifier or as a matrix material component by using different technique. Polyvinyl alcohol (PVA) was also used for a comparison. The nanoparticles of various recipes were characterized by various state-of-the-art instrument technology for their properties. RESULTS: The EE and the in vitro release behavior were found significantly influenced by the drug loading ratio and the surfactant stabilizer encountered. TPGS involved nanoparticles can have high EE and other favorable properties. CONCLUSIONS: TPGS could be a novel and effective emulsifier, which can result in high EE and desired properties of paclitaxel-loaded polymeric nanoparticles.     

Effects of anticancer drugs on the metabolism of the anticancer drug 5,6-dimethylxanthenone-4-acetic (DMXAA) by human liver microsomes

AIMS: To investigate the effects of various anticancer drugs on the major metabolic pathways (glucuronidation and 6-methylhydroxylation) of DMXAA in human liver microsomes. METHODS: The effects of various anticancer drugs at 100 and 500 microM on the formation of DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA) in human liver microsomes were determined by high performance liquid chromatography (h.p.l.c.). For those anticancer drugs showing significant inhibition of DMXAA metabolism, the inhibition constants (Ki) were determined. The resulting in vitro data were extrapolated to predict in vivo changes in DMXAA pharmacokinetics. RESULTS: Vinblastine, vincristine and amsacrine at 500 microM significantly (P < 0.05) inhibited DMXAA glucuronidation (Ki = 319, 350 and 230 microM, respectively), but not 6-methylhydroxylation in human liver microsomes. Daunorubicin and N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide (DACA) at 100 and 500 microM showed significant (P < 0.05) inhibition of DMXAA 6-methylhydroxylation (Ki = 131 and 0.59 microM, respectively), but not glucuronidation. Other drugs such as 5-fluoroucacil, paclitaxel, tirapazamine and methotrexate exhibited little or negligible inhibition of the metabolism of DMXAA. Pre-incubation of microsomes with the anticancer drugs (100 and 500 microM) did not enhance their inhibitory effects on DMXAA metabolism. Prediction of DMXAA-drug interactions in vivo based on these in vitro data indicated that all the anticancer drugs investigated except DACA appear unlikely to alter the pharmacokinetics of DMXAA, whereas DACA may increase the plasma AUC of DMXAA by 6%. CONCLUSIONS: These results indicate that alteration of the pharmacokinetics of DMXAA appears unlikely when used in combination with other common anticancer drugs. However, this does not rule out the possibility of pharmacokinetic interactions with other drugs used concurrently with this combination of anticancer drugs.     

雷公藤中具有抗癌活性的二萜类化合物

目的研究雷公藤的化学成分及其细胞毒活性。方法用硅胶柱色谱、凝胶柱色谱分离,制备高效液相色谱纯化,得到单体化合物,用各种有机波谱鉴定化合物结构;以MTT法测试各化合物的抗癌活性。结果分离得到5个萜类化合物,鉴定为雷酚萜L(3-epi-triptobenzeneB,Ⅰ)、雷酚萜B(3β,14-dihydroxy-abieta-8,11,13-triene,triptobenzeneB,Ⅱ)、雷酚萜E(wilforolE,Ⅲ)、雷酚萜酸(triptohairicacid,Ⅳ)、雷酚萜酸甲醚[11-hydroxy-14-methoxy-18(4→3)-abeo-abietan-3,8,11,13-tetraen-18-oic-acid,hypoglicacid,Ⅴ]。结论化合物Ⅰ为新化合物,命名为雷酚萜L(triptobenzeneL),化合物Ⅳ为首次分离得到。细胞毒实验表明各化合物均有一定的抗癌活性。     

围抗癌化疗期几组止吐药物效果的比较

目的从几组化疗止吐剂中筛选一帖经济有效、便于推广应用的抗癌止吐处方。方法胃复安为对照组；利多卡因、恩丹西酮、综合防治用药为观察组进行自身前、后对照，以止吐效果为主要指标的多侧面观察比较。结果急性期和延迟期消化道反应防治（０°－Ⅰ°，下同）有效率分别是：胃复安３４％、２８％；利多卡因８２％、Ｘ％；恩丹西酮８８％、８４％；综合防治用药９４％、１００％。结论以安定、地塞米松、胃复安联合按需用药是较理想的抗癌化疗止吐处方。     

表达蛋白质组学在抗肿瘤药物研发中的应用

表达蛋白质组学主要对正常、疾病或药物处理细胞或亚细胞中的所有蛋白质进行定性或定量研究。近年来表达蛋白质组学对抗肿瘤药物的研发起到了一定的推动作用。本文通过检索相关数据库文献,对其进行梳理、总结和归纳,阐述了表达蛋白质组学在抗肿瘤药物研发中的应用,包括抗肿瘤药物靶点发现、药物作用机制阐明、临床诊断以及基于网络药理学的药物研发理念的实现等。尽管表达蛋白质组学本身还存在一些缺陷,但随着其技术的不断发展,必将进一步促进抗肿瘤创新药物的研发。     

抗肿瘤药物西美替尼在Caco-2细胞模型中的吸收转运

目的研究抗肿瘤药物西美替尼在Caco-2细胞模型中的吸收转运。方法建立Caco-2细胞转运模型,采用HPLC法测定药物浓度,计算表观渗透系数(P_app),研究西美替尼的Caco-2细胞跨膜转运情况。结果西美替尼在转运过程中没有明显的浓度依赖性。在低浓度范围内,药物的转运速率随着浓度的增加而增加;在较高浓度时达到饱和。西美替尼不同浓度的P_app值(3.91×10^-5、3.29×10^-5、1.90×10^-5和0.95×10^-5cm·s^-1)基本都大于难吸收药物的临界值(1×10^-5cm·s^-1)。西美替尼在Caco-2细胞中的转运呈现较强的方向性,从肠腔面到基底面的P_app值显著大于从基底面到肠腔面的P_app值（2.36～7.58倍）。ATP抑制剂叠氮化钠能显著降低西美替尼的正向转运程度,并升高其反向转运程度。当加入葡萄糖后,从肠腔面到基底面的跨膜转运程度显著降低。结论西美替尼主要是以转运载体介导的主动转运方式被吸收,其小肠吸收情况较好。     

肿瘤糖疫苗的研究进展

肿瘤细胞表面异常表达的糖抗原为肿瘤糖疫苗的研究提供了合适的靶标, 然而由于这些糖抗原的免疫原性较差, 这又给糖疫苗的发展带来了很大的困难。本文概述了近年来科学工作者在提高肿瘤糖疫苗的免疫原性方面所做的努力: 半合成的肿瘤糖疫苗将糖抗原与蛋白共价连接, 已经有很多疫苗进入了临床试验; 随后发展的全合成的肿瘤糖疫苗将糖抗原、T细胞表位和内源性佐剂共价连接, 使疫苗的结构和组成更加确定; 基于细胞代谢糖工程的肿瘤糖疫苗将非天然的糖疫苗与细胞表面代谢糖工程相结合, 得到了强烈的免疫应答; 某些基于天然糖抗原结构修饰的疫苗产生的抗体也可以与天然糖抗原发生交叉反应, 这为肿瘤糖疫苗的发展提供了新的方向。     

扶正培本系列方药在胃癌综合治疗中的临床与机理研究

[目的]探索扶正培本系列方药在胃癌综合治疗中的临床疗效。[方法]针对胃癌患者不同阶段临床特点和治疗的主要环节,在扶正培本治则指导下的系列治法与方药的临床作用的研究,有针对化疗毒付反应的健脾益肾冲剂、预防转移复发的扶正防癌口服液和针对晚期带瘤患者提高生活质量的养胃抗瘤冲剂。[结果]扶正培本系列方药对化疗药物具有明显的增效减毒作用,提高机体免疫功能,清除有害自由基,提高SOD活性,降低术后复发与转移,提高带瘤患者的生活质量延长生存期等作用[结论]扶正培本系列方药防治复发转移作用的可能分子机制在于：可以促进肿瘤细胞凋亡信号转导基因Fas蛋白和mRNA表达,降低FasL蛋白和mRNA表达;进而提高起始型Caspase-8的活性;同时提高凋亡调控基因Bax蛋白和mRNA表达,降低Bcl-2/Bax比例,从而减弱Bcl-2蛋白和mRNA表达抑制细胞凋亡的作用,降低肿瘤细胞线粒体膜电位△ψm和降低细胞内PH值,使细胞酸化,通过线粒体途径有效地放大了凋亡信号;最终活化Caspase-3导致细胞凋亡。     

菌株Streptomyces capillispiralis 1070代谢产物的抗肿瘤机制

目的考察菌株Streptomyces capillispiralis 1070的代谢产物抑制肿瘤细胞A549增殖的作用机制。方法采用MTT法考察菌株Streptomyces capillispiralis 1070的活性代谢产物对A549细胞增殖的抑制作用,采用吖啶橙活细胞染色荧光显微镜观察法、罗丹明123活细胞染色流式细胞检测技术及扫描电镜技术、透射电镜技术观察A549细胞增殖受到抑制后的各种变化。采用全波长扫描与Molish反应对活性物质的成分做初步判断。结果该活性物质可使A549细胞存活率降低至25.79%,可使A549细胞线粒体膜电位明显下降,能使A549细胞胞浆内出现酸性自噬泡,但细胞膜结构完整、无细胞内容物外漏。结论推测该活性物质是通过诱导细胞自噬而发挥其抗肿瘤作用。菌株Streptomyces capillispiralis 1070的活性代谢产物为多糖类物质。     

苦荞内生真菌产物EE-2抑制HepG2生长及诱导其细胞凋亡

目的研究苦荞内生真菌KQH-2代谢醇提物EE-2对人肝癌细胞的抑制作用及其作用机制。方法采用MTT法考察EE-2对人肝癌细胞HepG2体外增殖的抑制作用,显微镜观察EE-2对HepG2细胞形态的影响,琼脂糖凝胶电泳检测细胞DNA完整性,并利用流式细胞仪检测HepG2细胞凋亡及细胞周期变化情况。结果用EE-2处理过的HepG2细胞,显微镜观察可见细胞脱壁圆缩,出现凋亡小体;细胞核降解。流式细胞仪检测发现,处理组的DNA直方图上有比对照组加强的SubG1峰,且可将HepG2细胞阻滞于G0/G1期。结论苦荞内生真菌KQH-2代谢醇提物EE-2可诱导人肝癌HepG2细胞的凋亡,且具有细胞周期阻滞作用。