阿霉素磁性明胶微球的制备及特性检测

目的制备阿霉素磁性明胶微球检测其特性。方法采用乳化-交联法制备阿霉素磁性明胶微球。高倍显微镜观察微球粒径大小及形态,紫外分光光度法检测微球中阿霉素的含量,测定微球磁吸附率,计算求和值S,确定最佳投料比（药物∶载体）,绘制药物微球体外释放曲线。结果制备的阿霉素磁性明胶微球最佳投料比为1∶15,磁吸附率为100%。微球外形圆整,分散性好。阿霉素60min释放70%左右,240min持续释放90%以上。结论制备的阿霉素磁性明胶微球缓释性好,磁响应性强,可作为一种治疗顽固性疼痛的靶向神经损毁剂。     

表阿霉素脂质体的制备与质量评价

目的:制备盐酸表阿霉素脂质体,建立HPLC含量测定方法并优选包封率测定方法.方法:采用薄膜分散-pH梯度法制备盐酸表阿霉素脂质体;采用HPLC测定药物含量;采用葡聚糖凝胶色谱、超滤及透析3种分离方法测定脂质体的包封率.结果:制备的表阿霉素脂质体粒径较小、分布较窄;3种方法测得盐酸表阿霉素脂质体的包封率分别为96.1%,98.4%,92.9%;结论:薄膜分散-pH梯度法适于制备盐酸表阿霉素脂质体,含量测定方法可靠.超滤法可以准确、快速地测定脂质体包封率.     

常用的蛋白质保护剂对NGF-PLGA微球性质的影响

目的研究常用的蛋白质保护剂对微球性质的影响特点。方法复乳化溶剂挥发法制备NGF-PLGA微球,分别添加葡萄糖,聚乙二醇,卵清蛋白作保护剂,观察微球的形态,载药量、包封率及体外释放特点,研究保护剂的作用特点。结果保护剂对微球的粒径、包封率和载药量影响不明显,粒径集中分布在10-40μm,载药量0．0007％-0．0011％,包封率7％～11％。保护剂主要影响微球的形态和体外释放。添加不同的保护剂,微球表面的光滑度和孔隙差别较大;体外释放的突释较小,存在明显的缓慢释放期,进入快速释放期的起始时间和释药速度受保护剂影响显著,一个月内的累积释放药量达到80％以上。结论保护剂的分子量可能是微球形态和释放不同的原因,添加分子量大的保护剂形成的微球的表面比添加分子量小的保护剂时致密光滑,体外的缓慢释放期长。     

氟尿嘧啶大粒径明胶微球的制备与性质

目的　制备大粒径明胶微球 ,研究其体外和颈动脉栓塞化疗的药物释放特性。方法　用改良的双相乳化冷凝法制备大粒径氟尿嘧啶明胶微球 ,紫外分光光度法测定药物含量、药物包裹率、载药量和体内外药物释放特性。用显微照像仪测定了大粒径微球的平均粒径。在X射线监控下 ,将大粒径氟尿嘧啶明胶微球栓塞在兔颈外动脉 ,以氟尿嘧啶溶液为对照 ,不同时间点取血样测试血药浓度进行统计分析。结果　大粒径氟尿嘧啶明胶微球粒径均匀 ,平均粒径 (2 32± 32 ) μm ,药物包裹率85 % ,载药量 12 .2 % ,体外 4 8h缓释 95 %。颈动脉栓塞后 ,可使较小用药剂量在局部较长时间内维持较高的药物浓度。结论　大粒径氟尿嘧啶明胶微球颈动脉栓塞可以显著提高肿瘤化疗效果     

盐酸多西环素牙周用微球温敏性凝胶的制剂学研究简

目的构建盐酸多西环素牙周用微球温敏性凝胶缓释系统。方法通过乳化一交联固化法制备盐酸多西环素羧甲基壳聚糖微球（DXY-CMCTS-MS）。采用壳聚糖和卢．甘油磷酸钠（β-GP）制备凝胶。用扫描电镜和光学显微镜观察微球表面形态;体外动态透析法测定释药性能。结果制备的DXY—CMCTS—MS形态圆整,粒径分布较为均匀,平均粒径约25μm,载药量18．9％,包封率64．6％。DXY微球凝胶在室温下为自由流动的液体,37℃的平均凝胶时间为（1．1±0．3）min,明显低于凝胶剂的凝胶时间。微球凝胶复合载体的释药速度明显低于微球剂,体外释药曲线符合Higuchi拟合方程。结论盐酸多西环素微球温敏凝胶复合载体的处方和制备工艺可行,作为牙周用缓释制剂值得进一步研究。     

牛血清白蛋白乳酸-羟乙酸共聚物微球的制备

目的 以牛血清白蛋白为模型蛋白,以乳酸-羟乙酸共聚物（PLGA）为包裹材料,探索粒径小于10μm的微球的制备方法并优化工艺。方法采用复乳溶剂挥发法制备蛋白质微球,以BCA法及微量BCA法测定微球的蛋白含量及蛋白从微球的释放。考察BSA浓度,内外相体积比,PLGA浓度,超声功率,匀浆转速,PVA浓度,PVA体积,PLGA分子量等因素对微球包封率、粒径、载药量及突释量的影响。结果通过控制不同的因素,可以得到较高的载药量及包封率、粒径在5μm左右的微球。结论采用复乳溶剂挥发法通过控制不同的因素,可得到粒径5μm左右不同载药量及突释量的具有较高包封率的微球。     

干扰素α-2b缓释微球的制备及影响因素考察

目的:制备以明胶粉形式固化的干扰素α-2b(IFNα-2b)聚乙二醇/聚对苯二甲酸丁二醇酯共聚物(PEG/PBT)-乳酸-羟基乙酸共聚物(PLGA)缓释微球,并考察微球制备方法,基质材料,IFNα-2b存在形式[包括液态含人血清白蛋白(HSA),固态含HSA及液态不含HSA]及胶粉粒径对微球性质的影响.方法:将IFNα-2b溶于明胶溶液后,冷冻干燥,研磨制备胶粉,然后用S/O/O法、W/O/W法或S/O/W法制备微球;以粒径、包封率及释放为指标,考察微球的制备方法、基质材料、IFNα-2b形式及胶粉粒径对微球性质的影响;采用ELISA法测定IFNα-2b.结果:以液态不含HSA形式的IFNα-2b为原料药,胶粉粒径为14.5 μm,以PEG/PBT及PLGA( 9∶ 1)为混合基质材料,S/O/W法制备的微球最为理想,该微球突释约为20%,体外可持续释放19 d以上,累积释放量可达80%以上.结论:微球制备方法、基质材料、IFNα-2b形式及胶粉粒径对微球性质影响很大;将IFNα-2b以胶粉形式固化后制备微球可增加其稳定性,利于其连续释放.本研究为蛋白多肽类药物微球的制备提供了新思路.     

卡铂-乳酸/羟基乙酸共聚物微球的制备和体外性质

目的制备卡铂-乳酸/羟基乙酸共聚物(PLGA)微球,比较不同方法所得微球的形态、载药量和体外释药特点。方法采用相分离法和溶剂挥发法制备卡铂-PLGA微球,显微镜下测定微球的粒径和粒径分布,电子扫描显微镜观察微球表面形态。用电感耦合等离子体发射光谱法(ICP-AES)测定微球含药量,计算包封率,考察微球体外释药行为。结果两种方法所得微球球形较好,相分离法制得的卡铂-PLGA微球,平均粒径为22~31μm,含药量为42~61μg·mg-1、包封率21%~31%;体外释放试验中药物于24h完全溶出。溶剂挥发法所得微球平均粒径为38~54μm,含药量为7.2μg·mg-1、包封率约为20%;体外药物突释率约为39%,缓释期药物释放符合Higuchi模型,PLGA75/25、η=0.19和PLGA50/50、η=0.18的微球药物释放速度常数分别为2.40h-1/2和0.85h-1/2;体外14d累计释药分别达到71%和54%。结论相分离法制备卡铂-PLGA微球含药量高,但体外释药快,没有缓释作用;溶剂挥发法所得微球药物突释率较低,体外能控制药物缓慢释放。     

重组人骨形态发生蛋白-2缓释凝胶微球的研制及其溶胀、降解、载药、释药特征

目的制备载人骨形态发生蛋白-2(rhBMP-2)的甲基丙烯酸缩水甘油酯右旋糖酐(dex-GMA)凝胶微球并初步考察其体外溶胀、降解、载药与释药特征。方法以液体石蜡为油相,Span-80为乳化剂,采用乳化化学交联技术制备载rhBMP-2的凝胶微球(BMP-HMs)并通过正交设计法优化其制备工艺;观察BMP-HMs形态和粒径,测定其包封率与载药量;用微球的吸水能力表示微球的溶胀率(Rs),扫描电镜观察微球的体外降解,动态观察体外释药特征及其与微球溶胀、降解的关系。结果所制备的BMP-HMs形态规整,粒径40～50μm,分布均匀;rhBMP-2载药量(10.6±4.8)%,包封率(88.9±1.0)%,BMP-HMs冻干剂4℃以下存放6个月性能稳定,但在磷酸盐缓冲液(PBS)中20～40d内可以完全降解。微球Rs随反应促进剂四甲基乙二胺(TEMED)用量的增大而减小,0.3mlTEMED制备的BMP-HMs体外释药实验表明80%的rhBMP-2在前20d左右释放。结论BMP-HMs对rhBMP-2具有确定的缓释作用,并可以通过制备工艺的改变控制其释药。     

鼠疫耶尔森菌亚单位疫苗鼻腔免疫微球的制备与性质

目的：制备F1，V，F1-V3种鼠疫耶尔森菌亚单位疫苗鼻腔免疫微球，研究其体外释放性质、抗原活性等性质。方法：采用复乳溶剂挥发法制备鼠疫疫苗微球，以激光粒度测定仪测定微球的平均粒径，以BCA法及微量BCA法测定微球的疫苗含量及疫苗从微球的释放，以ELISA法考察从微球中释放出的鼠疫疫苗的活性。结果：鼠疫耶尔森菌亚单位疫苗微球粒径均匀，F1，V，F1-V疫苗微球平均粒径分别为4．2，4．6和5．9μm，包裹率分别为68．2％，61．3％和51．0％，载药量分别为9．7％，8．7％和6．2％，微球中包裹的疫苗与原溶液相比活性降低不明显。结论：采用复乳溶剂挥发法，通过控制一定的因素，可以得到具有较高包封率的鼠疫耶尔森菌亚单位疫苗微球。     

Cardiotoxicity of doxorubicin and other anthracycline derivatives

Conclusion  Doxorubicin cardiotoxicity has posed a formidable challenge in the fields of oncology, cardiology, pharmacology, biochemistry, pathology, and molecular biology Whereas development of a noncardiotoxic doxorubicin analogue has eluded scientists so far, careful monitoring of left ventricular ejection fraction with radionuclide angiocardiography during the course of doxorubicin therapy has substantially reduced the incidence and severity of overt congestive heart failure. Use of intracellular iron chelating agents and liposomal doxorubicin have the potential for substantially improving the safety margin of doxorubicin and for allowing the use of higher cumulative doses of doxorubicin. However, the current guidelines for left ventricular ejection fraction monitoring using equilibrium radionuclide angiocardiography should still be followed until a large volume of experience is accumulated with iron chelating agents and liposomal doxorubicin used either alone or in combination.     

Monitoring cardiac function in patients receiving doxorubicin

Despite its well-known cardiotoxicity, doxorubicin continues to be an effective and widely used antineoplastic agent. Many efforts have focused on understanding the mechanism of doxorubicin-induced cardiotoxicity and on preventing it completely. Currently protective agents, eg, liposomal doxorubicin formulation, which results in less myocardial uptake, and the use of dexrazoxane, an intracellular iron chelator reducing the formation of radical complexes, have shown evidence of reducing incidences of cardiotoxicity at high dose of doxorubicin. However, they have not been able to completely eliminate cardiotoxicity. Therefore, it is crucial that careful monitoring to identify those patients who are at risk of developing unpredictable and sometimes-irreversible cardiac dysfunction is conducted while allowing other patients who respond to doxorubicin-containing therapy to receive their maximal therapeutic dose. Serial measurement of left ventricular ejection fraction by radionuclide angiocardiography remains a useful and widely adopted modality in monitoring patients that are receiving doxorubicin. Efforts are continuing on finding a more sensitive and reliable predictor of eventual clinical cardiac dysfunction.     

Indication of doxorubicin cardiotoxicity by impairment of 131I-pIPPA utilization

The present study was designed to evaluate if doxorubicin (D) can impair myocardial fatty acid utilization. To this end we studied the myocardial utilization of ¹³¹I-pIPPA in untreated (Co, n=6) and D (20 mg/kg intraperitoneal) treated rats. D was given 24 h (24 D, n=6) and 48 hours (48 D, n=6) before tracer administration. One min after i.v. ¹³¹I-pIPPA (50 μCi) injection, the hearts were rapidly removed, frozen in liquid nitrogen, weighed, and counted. Following lipid extraction of homogenized heart extracts 131 I radioactivity distribution was analyzed by thin-layer chromatography (TLC). In additional rat experiments, high energy phosphates (12 rats/group) and carnitine (20 rats/group) were determined enzymatically in heart extracts. The mean pIPPA uptake in rat heart (%dose/g) was 2.49 in Co, 1.74 in 24 D, and 2.36 in 48 D rats. Usually five peaks were separated by TLC, that with a mean Rf value of 0.92 corresponding to ¹³¹I-pIPPA, the remaining four representing catabolites of pIPPA metabolism. The mean relative amount of unmetabolized ¹³¹I-pIPPA as compared to the sum of ¹³¹I-pIPPA catabolites was less in Co than in 24 D or 48 D rats (P<0.05) (\(\bar x\): 46.5% vs 72.4% vs 59.4%, respectively). The mean carnitine content of heart extracts was higher in Co (0.55 μM/g) than in D treated rats (24 D, 0.42 μM/g; 48 D, 0.46 μM/g) P<0.05). The total amount of higher energy phosphates was not different between the groups. However the mean ATP/AMP ratio was higher in Co (35.9) than in 24 D (22.3) or 48 D (27.1) rats (P<0.05). We conclude that D therapy is accompanied by a partial reversible impairment in myocardial pIPPA utilization, possibly mediated by carnitine deficiency. Thus, ¹³¹I-pIPPA might be useful in patients on D therapy to evaluate eventual D-induced effects on myocardial fatty acid utilization.

     

Radionuclide evaluation of doxorubicin cardiotoxicity: the need for cautious interpretation

Serial radionuclide angiography is a sensitive technique for the identification of asymptomatic cardiac dysfunction secondary to doxorubicin hydrochloride chemotherapy. However, the results of serial studies must be interpreted with caution in order to avoid labeling variations in the left ventricular ejection fraction (LVEF) due to artifact as doxorubicin cardiotoxicity. The use of sequential gated cardiac studies in the evaluation of a thirteen-year-old boy on doxorubicin hydrochloride is presented. Reassessment of the results of these studies showed that technical and biologic factors were the cause of recurring fluctuations in the LVEF, rather than drug toxicity.     

18F-ML-10监测多柔比星诱发心脏毒性的可行性探讨

目的 探讨放射性核素凋亡显像剂18F-ML-10无创监测多柔比星诱发心脏毒性的可行性.方法 36只KM小鼠随机分为对照组、低剂量(15mg/kg)多柔比星模型组和高剂量(20 mg/kg)多柔比星模型组,每组12只.对照组腹腔注射生理盐水,多柔比星模型组腹腔注射一定剂量的多柔比星,48 h后进行小动物超声检测左室射血分数(left ventricular ejection fraction,LVEF),以及放射性显像剂18F-ML-10与18F-FDG在小鼠体内的生物分布并测定每克组织放射性摄取值(％ID/g),处死的小鼠取出心脏进行caspase 3免疫组化检测心肌细胞的凋亡情况.结果 超声结果显示低剂量组[LVEF=(59.49±5.32)％]与高剂量组LVEF=(52.41±6.47)％小鼠左室射血分数明显低于对照组LVEF=(70.58±5.06)％,18F-FDG在低剂量组(％ ID/g=21.67±3.69)与高剂量组(％ID/g=15.58 ±1.92)的摄取也明显低于对照组(％ID/g =36.18 ±3.65),而凋亡显像剂18F-ML-10在低剂量组(％ID/g =0.50 ±0.11)与高剂量组(％ID/g=1.100.55)的摄取明显明显高于对照组(％ID/g=0.02 ±0.02),差异均有统计学意义(P＜0.05),caspase 3免疫组化显示模型组心肌细胞发生明显凋亡,与18F-ML-10在心脏的摄取相一致.结论 心肌细胞的凋亡是多柔比星诱导心脏毒性的重要途径,特异性凋亡显像剂18 F-ML-10用于多柔比星诱发心肌细胞凋亡的毒性监测具有较好的应用前景.     

加热处理阿霉素碘油制剂临床意义的实验研究

目的　研究普通阿霉素碘油乳剂和阿霉素碘油混悬剂热处理后的物理性状改变的临床意义。方法　用“泵法”(pumpingtechnique)制成普通阿霉素碘油乳剂 (UFL -ADMEmulsion ,UAE)和阿霉素碘油混悬剂 (UFL -ADMSuspension ,UAS) ,分别在 2 5℃、40℃、5 0℃、60℃水浴箱中加热 2h后 ,观察乳析和分层时间 ,测定相对粘度 ,在显微镜下观察制剂微粒的状况 ,用紫外分光光度法(ultravioletspectrophotometicmethod)测定释放到透析液中阿霉素的浓度 ,计算释放率。结果　混悬剂和普通乳剂在加热后层析 /沉淀出现早 ,显微镜下大颗粒 /油滴增多。从 2 5℃到 60℃ ,相对粘度和相对粘度比下降了近 2倍 ,溶出速率明显降低 (Ρ <0 .0 5 ) ;2 5℃、40℃、5 0℃处理组间释放速率近乎相等 (Ρ >0 .0 5 ) ;60℃条件下 ,混悬剂组和普通乳剂组与作为对照组的生理盐水组中的阿霉素浓度几近相等 (Ρ >0 .0 5 )。结论　阿霉素碘油混悬剂和普通乳剂在热处理后 ,物理稳定性下降 ,粘度减小 ,阿霉素释放速度减慢 ,具有一定的临床应用价值     

Optimization of doxorubicin loading for superabsorbent polymer microspheres: in vitro analysis

Purpose  

This study was designed to establish the ability of super-absorbent polymer microspheres (SAP) to actively uptake doxorubicin and to establish the proof of principle of SAP’s ability to phase transfer doxorubicin onto the polymer matrix and to elute into buffer with a loading method that optimizes physical handling and elution characteristics.     

The predictive value of myocardial radioisotope scanning in animals treated with doxorubicin

Thirty-four New Zealand white rabbits were treated with doxorubicin and imaged weekly with Tc-99m pyrophosphate to define the value of abnormal myocardial images in predicting doxorubicin-induced cardiac toxicity. Increased myocardial uptake was detected in most animals on sustained treatment with doxorubicin. A greater proportion of the heart was involved with doxorubicin-related histologic changes in animals with strongly positive myocardial images than in treated animals with moderately positive or normal scans. The myocardial images returned to normal levels 2--6 wk after doxorubicin was discontinued. Five of seven rabbits that received doxorubicin after they had three moderately positive myocardial scans, died from congestive heart failure. Three rabbits whose doxorubicin was discontinued because of scan findings, survived for 6 wk or more before dying from renal failure. The three rabbits who received the highest total dose of doxorubicin died of renal failure without developing abnormal myocardial scans.     

缺血修饰白蛋白作为多柔比星心肌毒性诊断指标研究

目的探讨缺血修饰白蛋白(IMA)可否成为多柔比星(DOX)心肌毒性反应的早期诊断指标。方法取乳鼠心肌细胞与6种不同浓度的DOX相互作用,观察DOX导致心肌毒性模型中活性细胞百分率、细胞凋亡百分率情况,并检测细胞培养液中肌酸激酶同工酶(CK-MB)、肌钙蛋白(c Tn T)及IMA变化情况。结果随DOX浓度增加及培养时间延长,活性细胞百分率逐渐下降(F=23.3,P<0.05),细胞凋亡百分率也逐渐下降(F=30.4,P<0.05)。运用SPSS分析软件的斯伯曼/斯皮尔曼相关系数进行分析,结果显示,IMA与细胞凋亡情况在3 h就开始存在相关性(r=0.891,P<0.05),而c Tn T与细胞凋亡情况12 h开始相关(r=0.658,P<0.05);CK-MB与细胞凋亡情况48 h开始相关(r=0.711,P<0.05)。结论 IMA成为DOX心肌毒性反应的早期诊断指标具有实验室基础。