肿瘤动脉栓塞化疗用白蛋白微球的研究

用白蛋白制备了动脉栓塞用微球,该微球平均粒径为45±10μm,药物含量10.2%。通过渗透膜的体外释放试验中,7d 的总释药量为27%,而溶液剂6 h 的释药量达80%。动物实验表明,白蛋白微球可以栓塞末稍动脉。     

栓塞用明胶微球的制备及其性质评价(英文)

本文目的是研究栓塞用明胶微球的制备及其质量评价。采用乳化-化学交联法制备明胶微球,以光学显微镜观察微球的形态、测定微球的粒径,并测定了微球的吸水率和溶胀率;采用质构仪测定了微球的抗压弹性,为测量微球经导管推注时的压力设计了一种新型装置。在线测定了不同粒径微球的推注压力,以毛细管顶空气相色谱法测定了明胶微球中残留的丙酮量。所得微球冻干后呈椭圆形,表面有褶皱,在生理盐水中吸水后形状圆整,表面光滑。干燥微球的粒径范围在100-1000μm,平均粒径为430.5μm;吸水后微球的粒径范围在150-1425μm,平均粒径为601.2μm,符合栓塞剂的粒径需要。微球最大平衡吸水率为590.7%,平均溶胀率为103.0%。明胶微球的弹性良好,压缩形变到50%时,对于400-700μm微球的压力为(0.771±0.064)N,对于700-850μm微球的压力为(0.814±0.153)N。三组明胶微球(湿球100-450,450-700,700-940μm)都能够以较小的压力通过导管。残余的丙酮含量低于中国药典2010版的限度。本研究制备的明胶微球体外性质良好,适于作栓塞剂使用;建立的评价明胶微球性质的方法有助于此类栓塞剂的体外评价。     

莪术油明胶微球用于肝动脉栓塞

目的　制备符合肝动脉栓塞要求的莪术油明胶微球(ZT-GMS)。方法　用正交设计优化了微球的制备工艺,对微球的制备工艺、粉体学性质、体外释药、初步稳定性和初步药效进行了研究。结果　球径在40～160 μm的微球占97.16%,平均产率为89.73%,平均含药量为2.13%,平均包封率为19.36%(均以莪术醇计)。体外释药12 h达80%,符合一级动力学模型,释药机理为溶蚀加扩散。稳定性考察实验结果表明其稳定性较好。肝动脉栓塞荷瘤大鼠实验结果表明大鼠平均生存率显著延长(P<0.01),肿瘤体积显著减小(P<0.01)。结论　微球的制备工艺及粒径分布较好,体外释药有明显的缓释作用,有一定疗效。     

顺铂壳聚糖微球的制备及特性研究

对顺铂壳聚糖微球的制备、载药量、大小及分布、形态及表面状态、体外释放及降解性进行了研究。微球用乳化-化学交联技术制备,平均粒径为74.80μm,顺铂含量为20.83%±0.36%。电镜扫描显示,微球球形圆整,表面粗糙。生理盐水中放置1h微球轻微溶胀,其体外释药符合一级方程,微球经⁶⁰Co辐射灭菌达到无菌要求。犬肝动脉栓塞后一个月,病理切片可见栓塞区仍有壳聚糖微球存在。     

顺铂白及胶微球的制备及栓塞特性

目的:顺铂白及胶微球的制备及栓塞特性的考察.方法:采用乳化-冷凝-化学交联技术制备顺铂白及胶微球,利用正交试验设计法优选顺铂白及胶微球的制备条件和工艺;对微球的载药量、大小及分布、形态及表面状态、体外释放以及栓塞特性等进行了研究.结果:微球平均粒径为(108.3±35.2)μm,顺铂含量为(20.7±6.2)%;电镜扫描显示,微球球形圆整,表面粗糙;微球经60Co辐射灭菌要求;其体外释药实验表明顺铂白及胶微球有明显的缓释性能;动物栓塞试验以及对肿瘤患者的栓塞治疗均显示良好的栓塞效果.结论:该微球制备工艺可行,制得的顺铂白及胶微球可达到介入栓塞和化疗的双重目的,适用于肝癌患者的介入栓塞治疗.     

不同直径海藻酸钠微球介入栓塞治疗子宫肌瘤疗效分析

目的 观察不同直径海藻酸钠微球(KMG)栓塞剂在子宫肌瘤介入栓塞治疗中的治疗效果.方法 选取2011年1月至2014年3月行子宫动脉栓塞手术的子宫肌瘤患者220例,采用selding's穿刺技术,用5F Cobra导管或4F微导管超选择至双侧子宫动脉,根据栓塞剂直径大小不同分为对照组和观察组,每组110例.对照组选择300～700 μm海藻酸钠微球(KMG)进行栓塞治疗,观察组先选择500～700 μm海藻酸钠微球(KMG)进行栓塞治疗,再用700～900 μm海藻酸钠微球补充栓塞,比较2组月经量增多、贫血改善、肌瘤体积缩小及对卵巢功能影响,比较2组术后发热、疼痛发生率差异无统计学意义(P>0.05).结果 海藻酸钠微球介入栓塞后,子宫肌瘤患者月经量均明显减少,2组月经量增多、贫血的改善比较差异无统计学意义(P>0.05);栓塞后6个月复查彩超提示对照组肌瘤平均体积由 (90.21±65.54)cm3缩小为 (49.38±10.59)cm3,观察组肌瘤平均体积由 (93.26±66.70)cm3缩小为 (40.05±10.74)cm3,2组子宫肌瘤患者介入治疗前后差异有统计学意义(P<0.01).术后6个月2组患者血清 FSH、LH、E2 较术前相应值变化情况差异无统计学意义(P>0.05).结论 海藻酸钠微球(KMG)介入栓塞治疗子宫肌瘤后6个月,肌瘤体积缩较前明显缩小,贯穿应用直径500～700 μm及700～900 μm栓塞剂治疗子肌瘤,术后肌瘤坏死缩小程度优于单用直径500～700 μm栓塞剂,介入栓塞术中不同直径栓塞剂栓塞子宫肌瘤疗效确切,值得推广.     

白及微球用于门静脉分支栓塞术的实验研究

［摘要］目的探讨以白及微球为栓塞剂行门静脉栓塞治疗的可行性。 方法分别以无水乙醇和白及微球对大白兔行门静脉不同分支栓塞。栓塞后定期进行影像学检测和组织病理检查。结果手术后病理检查显示：无水乙醇组肝实质呈不规则散不全性液化坏死；白及微球组肝实质呈大片状完全性气化坏死。结论白及微球作为门静脉的栓塞剂具有一定的可行性。     

磁性微球的磁响应性及狗肾动脉栓塞实验研究

研究了磁性明胶微球(MG-ms)的磁响应性及狗肾动脉栓塞效果。磁响应性实验表明,介质流速越慢,磁场强度越大,磁性微球中磁铁粒子含量越高,越容易定位磁性微球。狗肾动脉灌注10～30um磁性微球,血管造影和病理切片结果表明:磁性微球在外磁场作用下可以进一步栓塞至肾小球、肾脏的微细动脉,而且栓塞均匀、完全,而不加磁场时栓塞不完全。这些结果提示磁性明胶微球可以作为治疗肾癌的栓塞剂,将有利于增强化疗效果、减少毒副反应。     

丝裂霉素葡聚糖微球的研究

本文报告了丝裂霉素葡聚糖微球的制备与性质,也研究了丝裂霉素葡聚糖微球(简称(MMC-DMS)在狗体内的药物动力学特征和栓塞效果。微球的平均粒径为75±19μm,MMC含量为5%。在体外实验中,药物释放速度证明微球有缓释的性质。丝裂霉素葡聚糖微球与常规丝裂霉素通过导管分别输入狗的肝动脉内进行栓塞。用高效液相色谱(HPLC)法测定血药浓度,结果表明常规丝裂霉素峰浓度比MMC-DMS大1.6倍。血管造影显示肝的外周血管显著减少。组织病理学检查表明微球嵌入肝动脉内并在栓塞部分显示结节性坏死。MMC-DMS 在临床上试用于100例患肝癌的病人,肝动脉栓塞后病人瘤块缩小,症状改善,存活期延长。这些结果提示丝裂霉素葡聚糖微球是治疗肝癌很有用的栓塞剂,将有利于增强癌症化疗效果减少全身毒副反应。     

米托蒽醌肝动脉栓塞羧甲基淀粉微球的研究

为进一步研究栓塞微球的制备工艺、体外释药规律及药动学与药效学之间的关系,以米托蒽醌为模型药物、羧甲基淀粉钠为载体材料、对苯二甲酰氯为交联剂,经均匀设计法优化了制备空白羧甲基淀粉微球的工艺,用吸附法制备了米托蒽醌载药羧甲基淀粉微球。对载药微球的理化性质进行了研究。并以家兔为模型动物研究了载药微球经肝动脉栓塞给药后的药代动力学情况。结果表明:载药微球的平均算术粒径为75.71μm,含药量为13.21%,吸水膨胀率为71.94%,体外释药符合单指数模型。药动学研究表明,米托蒽醌制成微球经肝动脉栓塞给药后可延长药物驻留于靶位的时间,提示有利于肝癌的治疗。     

Formulation and testing of vancomycin loaded albumin microspheres prepared by spray-drying

Microparticles are widely employed as carriers of biologically active compounds with many possible applications. For targeted drug delivery and sustained release purposes, biopolymers (i.e. polysaccharides and proteins) have been proposed. In this study, microsphere formulations of vancomycin were prepared by the spray-drying method. Bovine serum albumin (BSA) was used as a polymer matrix and was cross-linked with glutaraldehyde after microsphere preparation. The product yield obtained from the spray-drying method was ～75%. The mean particle size was 5?±?1.6?µm, with the majority of particles between 4 and 8?µm. The extent of cross-linking affected the release of vancomycin from microspheres. Moreover, both rate and extent of vancomycin release from microspheres decreased with increasing glutaraldehyde concentration. Encapsulation of vancomycin did not alter the bioactivity of the drug and it was more effective in killing Staphylococcus aureus than the solution form.     

Interaction of platinum agents,cisplatin, carboplatin and oxaliplatin against albumin in vivo rats and in vitro study using inductively coupled plasma‐mass spectrometory

The protein binding rates (PBR) of platinum‐containing agents cisplatin (CDDP), carboplatin (CBDCA) and oxaliplatin (L‐OHP) have been reported as 98%, 25–50% and 98%, respectively. To investigate the protein‐binding properties of albumin with cisplatin, carboplatin and oxaliplatin, inductively coupled plasma mass spectrometry (ICP‐MS) was used to measure their plasma concentration in rats over time. The study also examined the effects of cisplatin, carboplatin and oxaliplatin‐binding on albumin in vitro, using CD spectrometry and native‐polyacrylamide gel electrophoresis (native PAGE). The ratios of PBR to irreversible PBR, of cisplatin and oxaliplatin were 98%:98% and 90%:87%, respectively, indicating a higher affinity for irreversible binding with albumin. That of carboplatin was 25%:10%, indicating 60–70% reversible binding with albumin. The plasma protein binding rate concentrations of cisplatin, carboplatin and oxaliplatin after in vivo administration were 96%, 15% and 80%, respectively. The CD spectrometry of albumin was unaffected by cisplatin, carboplatin and oxaliplatin binding. Though similar protein binding rates were observed with oxaliplatin and cisplatin, oxaliplatin had a higher mobility rate during PAGE. It was confirmed that the binding of cisplatin and oxaliplatin with albumin affected its electric charge but not the structure. In conclusion, cisplatin and oxaliplatin bind irreversibly with albumin in plasma and may irreversibly interact with tissue protein and/or DNA. The difficulties involved with predicting the tissue concentrations of cisplatin and oxaliplatin from their plasma concentration inhibits their therapeutic drug monitoring. On the contrary, carboplatin, like some generic drugs, reversibly binds to plasma proteins. It is, therefore, possible to conduct therapeutic drug monitoring for carboplatin.     

Adsorption of Fluorescein Dyes on Albumin Microspheres

The surface characteristics of bovine and egg albumin microspheres were examined using four anionic dyes; sodium fluorescein, eosin, erythrosin, rose bengal, and the cationic dye rhodamine B. The adsorption isotherms of the dyes on unloaded albumin microspheres exhibited Langmuir behavior for dilute solutions of rose bengal, erythrosin, and eosin, suggesting monolayer formation in the initial stages of the sorption process. The adsorption capacity of the microspheres for the dyes (k ₂) and the affinity constants of the dyes for the microspheres (k ₁) were found to depend on both the polarizability and the hydrophobic properties of the dye, presumably reflecting the heterogeneous character of the microsphere surface. Further, the extent of sorption at higher dye concentrations was found to depend on the ability of the dye to form stable aggregates inside the microspheres and on environmental long-range forces acting at these sites. At both low and high dye concentrations, the amount adsorbed to the microsphere surface increased with increasing hy-drophobicity of the dyes. The lowest adsorption was observed for the nonsubstituted dye fluorescein, whereas the most hydrophobic dye used, rose bengal, was completely adsorbed onto the microsphere surface. The data suggest that the bovine albumin microsphere surfaces are highly hydrophobic and less porous than egg albumin microsphere surfaces.     

The development of embolizing materials for chemo-embolization therapy of hepatocellular carcinoma

We developed chitin-containing cisplatin (CDDP) albumin microspheres (MS). We also investigated physical properties of MS in vitro, anti-tumor effect of MS in VX2 tumor model rabbits in vivo and clinical evaluation of MS. The CDDP contents, specific surface areas and yield of MS increased with an increase in the concentration of chitin. These findings suggest that accumulation of chitin on the surface of microsphere was the cause of expansion of the coated area as the concentration of chitin increased. In vitro CDDP releases decreased as the concentration of chitin increased. The initial burst effect of the drug was to be controlled by the increase of concentration of chitin. The chitin-containing CDDP microspheres showed similar CDDP release patterns irrespective of the concentration of chitin between 1 and 6 h after the administration of CDDP microspheres. After 6 h, the blood Pt levels increased with an increase in the concentration of CDDP microspheres suggesting a significant effect of the concentration of chitin on microsphere decomposability in vivo. Tumor growth rate was increasingly suppressed as the concentration of chitin increased. Clinical findings indicated that antitumor activity of chitin-containing CDDP albumin microspheres would have a chemoembolic effect by embolizing the hepatic artery. In the tumor and necrosis portions phagocytosis of microspheres by macrophage-like giant cell was shown. Consequently, the biocompatibility and decomposable properties of chitin-containing CDDP albumin microspheres were demonstrated.     

Amphotericin B microspheres: A therapeutic approach to minimize toxicity while maintaining antifungal efficacy

Amphotericin B microsphere formulations with and without addition of polyethylene glycol 2000 in cross-linked bovine serum albumin were prepared. Amphotericin B microspheres were characterized for particle size (<5 µm), zeta potential (～30 mV) and drug interaction by DSC and FTIR and were found to be stable formulations. Drug release profiles for these microspheres revealed that the release was primarily by diffusion. In vitro toxicity as assessed by release of haemoglobin and potassium demonstrated no toxic effect as compared with conventional solution formulation. Antifungal activity in vitro was comparable to solution formulation when tested by broth dilution method.     

Stabilization of pH-Induced Degradation of Porcine Insulin in Biodegradable Polyester Microspheres

The purpose of this research project was to stabilize the pH-induced degradation of porcine insulin encapsulated within biodegradable polyester microspheres through the incorporation of a basic additive. Insulin microspheres fabricated using Poly(L-lactide) (L-PLA) and Poly(DL-lactide-co-glycolide) (50:50 DL-PLGA) were subjected to in vitro release studies and the stability of unreleased insulin encapsulated within microspheres was investigated. The intramicrosphere pH was estimated by encapsulating acid-base indicators covering a wide pH transition range within 50:50 DL-PLGA microspheres. Finally, a basic excipient sodium bicarbonate was incorporated in 50:50 DL-PLGA microspheres to minimize acid-induced insulin degradation. The in vitro release was slow and incomplete (<30% in 30 days). Extraction and analyses of the unreleased insulin within the microspheres revealed that an average of ～11% remained intact. The degradation products observed consisted of ～15% of three distinct deamidated hydrolysis products including A-21 Desamido insulin, ～22% Covalent Insulin Dimer and trace amounts of High Molecular Weight Transformation Products. Comparison of the degradation profile of unreleased insulin contained in various microsphere formulations with the in vitro release kinetics indicated that an increase in covalent dimer formation within the microspheres prior to release is associated with a decrease in the cumulative percent insulin released during a 30-day incubation period. In an attempt to correlate insulin degradation with the drop in intra-microsphere pH due to polymer hydrolysis, it was determined that the pH within a degrading microsphere reaches a value of ～1.8 after 4 weeks. The incorporation of a basic excipient, sodium bicarbonate, in 50:50 DL-PLGA microspheres resulted in an improved in vitro release profile (cumulative release ～47.3% in 30 days) as well as a significant reduction in covalent dimerization of the unreleased insulin to barely detectable levels. The low pH microenvironment within a degrading microsphere is one of the major factors leading to protein instability, and the degradation of proteins encapsulated within polyester microspheres can be minimized by the incorporation of a basic excipient.     

An improvement of double emulsion technique for preparing bovine serum albumin-loaded PLGA microspheres

A modified double emulsion technique was adopted to prepare bovine serum albumin (BSA) loaded poly (D,l-lactic-co-glycolic acid) (PLGA) microspheres. In the formulations, polysorbates (Tween) such as Tween20®, Tween40® or Tween80®, instead of frequently used poly (vinyl alcohol) (PVA), was used as the emulsifier. Microspheres with porous surface, large particle size, low microsphere yield (～65.4%) and BSA entrapment efficiency (～25.2%) were obtained when Tween80® aqueous solution alone was used as the outer aqueous phase. However, microspheres with smooth surface, high yield and BSA entrapment efficiency could be produced successfully by introducing sodium chloride or glucose into the outer aqueous phase. Adding 5.0%(w/v) sodium chloride into the continuous phase led to increase in microsphere yield and BSA entrapment efficiency from 65.4% and 25.2% to ～100% and 76.6%, respectively. Microsphere yield and BSA entrapment efficiency increased from 64.5% and 25.2% to 97.2% and 89.3%, respectively, when 15.0%(w/v) glucose was added into the continuous phase. In constrast to the microspheres prepared in the presence of additive, a more marked burst release was observed for microspheres prepared without additive in the continuous phase, which may be attributed to the porous morphology of the latter.     

Formation and characterization of cisplatin loaded poly(d,l-lactide) microspheres for chemoembolization

Cisplatin, a slightly water soluble anticancer drug, has been incorporated into biodegradable poly(d,l-lactide) microspheres using the solvent evaporation process. The optimal experimental conditions to produce spherical and separate drug-loaded particles (45% cisplatin) were as follows: the dispersing phase was a mixture of 0.05% methylcellulose and 4% polyvinyl alcohol (8 mPa-s grade); and the optimal poly(d,l-lactide) concentration in the organic phase was found to be greater than or equal to 7.16%. Microscopic studies showed that increasing the drug content in the microspheres produced the appearance of rod-like crystals at the microparticle surface. In addition, the cisplatin crystals were found homogeneously distributed in the polymer matrix, even at a high drug content. Increased viscosities of the organic phase enhanced the mean microsphere size, while increasing the emulsifier concentration in the aqueous phase decreased the average particle size. The drug incorporation efficiency was markedly improved after saturation of the dispersing phase with cisplatin. It was also noted that the amount of drug incorporated increased with increasing mean microsphere diameter. The methylene chloride content entrapped within the microspheres was found to depend upon the microsphere size distribution and the cisplatin content. An increase of the microsphere system porosity, by the addition of 10% cyclohexane in the organic phase, caused a reduction in the residual methylene chloride content. Finally, the in vitro release kinetics of cisplatin were influenced by the drug loading.     

不均等分割放疗联合化疗治疗晚期鼻咽癌的效果

目的　观察不均等分割放射治疗联合化疗对晚期鼻咽癌的治疗效果。方法　 5 3例初治晚期鼻咽癌患者分为不均等分割放疗加化疗组 2 9例 (研究组 )和常规分割放疗加化疗组 2 4例 (常规组 )。常规组外照射 (面颈联合野 )DT3 6～ 4 0Gy/ 2 0F、4w后 ,研究组不均等分割放射 (双侧耳前野 )DT3 0～3 3Gy/ 3 0F、3w ,同期加照鼻前野 9Gy/ 6F、3w ,总剂量 75～ 82Gy/ 5 6F、7w ;常规组设双侧耳前野及鼻前野 ,三野交替 ,DT2 7～ 3 0Gy/ 15F、3w ,总剂量 63～ 70Gy/ 3 5F、7w ,两组的化疗方案相同。顺铂 (DDP)2 0mg/m2 ·d ,d1-3,5 氟尿嘧啶 ( 5 FU) 5 0 0mg/m2 ·d ,d1-5,放疗前 1周期、放疗后 2周期。结果　①研究组、常规组鼻咽肿瘤完全消退率分别为 93 .1%、75 .0 % (P <0 .0 5 ) ,颈淋巴结完全消退率分别为96.0 %、75 .0 % (P <0 .0 5 ) ;② 3年生存率两组分别为 82 .7%、70 .8% (P >0 .0 5 ) ;③急性粘膜反应及胃肠道反应两组相似。结论　不均等分割放疗联合DDP + 5 FU方案 ,能显著提高鼻咽部及颈淋巴肿瘤的消退率 ,对晚期鼻咽癌的局部控制率明显高于常规放疗加化疗 ,近期疗效较好 ,是治疗晚期鼻咽癌的有效方法。但 3年生存率无统计学差异 ,其不良反应相似。     

Biodegradation rate of embolized protein microspheres in lung, liver and kidney of rats

The targeting and sustained release characteristics of cytotoxic drug-loaded protein microspheres may prove useful in the therapeutic chemoembolization of solid tumours. Because biodegradation rate of embolized particles will influence rate of incorporated drug release and duration of exposure, this parameter was studied for microspheres (10-30 microns mean diam.) prepared from the proteins albumin and casein, that we have previously used as carriers for doxorubicin. As a measure of microsphere loss in-vivo the radionuclide 125I was chosen because it can be covalently bound to proteins and also homogeneously distributed throughout the matrix. Radiolabelled microspheres were administered to rats both intravenously (lung as target organ, 1.4-2.2 mg/100 g) and via the hepatic artery (liver as target organ, 0.4-0.8 mg/100 g). In both cases it was observed that the casein system biodegraded more slowly than the albumin in-vivo. Thus, time taken for loss of 50% of embolized microspheres from lung was: albumin 2.0 days; casein 3.5 days and from liver:albumin 3.6 days; casein 6.8 days. Microsphere "debris" did not markedly accumulate in other organs. In-vitro experiments showed that microspheres were stable in serum and that albumin microspheres were not innately more sensitive to enzymic digestion than casein. The results may be useful in estimating duration of exposure of target organs to drug-loaded microsphere systems prepared from these proteins.