【作者】 杨利；

【导师】 王执民；

【作者基本信息】 第四军医大学 ， 影像医学与核医学， 2004， 硕士

【摘要】 近年来，热化疗栓塞才运用于肝癌的介入治疗。旨在集热疗、化疗、栓塞为一体，加大对癌细胞的杀伤。其疗效已被实验和临床所证实。但影响疗效的因素很多，而化疗栓塞制剂的特性及生物学分布的特征与其直接相关。本实验为加热阿霉素碘油栓塞制剂的研究，拟为临床应用提供实验基础。 目的：研究加热后阿霉素碘油传统制剂(混悬剂、普通乳剂)和纳米乳剂物理性状及混悬剂生物学分布特征改变的意义。 方法：“泵法”配制普通阿霉素碘油乳剂及混悬剂。在普通乳剂处方中加入Span-80、Tween-80，在机械和超声乳化机中乳化制成纳米乳剂。在25℃、40℃、50℃、60℃水浴箱中加热阿霉素碘油普通乳剂、纳米乳剂及混悬剂2h，观察乳析和分层时间，测定相对粘度，在显微镜及电镜下观测制剂微粒特性；用紫外分光光度法测定释放到透析液中阿霉素的浓度，计算包裹率、释放率。 将常温和60℃的UAS(4mg／ml)分别经肝动脉注入VX2肝癌模型中，用DSA、CT、超声诊断仪，病理切片油红染色普通光学显微镜和共聚焦显微镜观测碘油在肿瘤组织的分布；荧光分光光度法测定10h后肝脏肿瘤组织的阿霉素浓度，计算浓度比(测得第四军医大学硕士学位论文浓度与总灌注量之比值)。 结果:混悬剂和普通阿霉素碘油乳剂在加热后层析/沉淀出现早，显微镜下大颗粒/油滴增多。从25℃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〔P<0.05);25℃、40℃、50℃处理组释放速率近乎相同(P>.05);60℃条件下，混悬剂组和普通乳剂组与对照组的生理盐水组中阿霉素浓度几近相等 (P>0 .05)。 UANE外观呈粉红色乳液，性状稳定，在观测期(72h)内未发现乳析;透射电镜显示UANE呈圆整规则球形微粒，大小均匀，分散良好，粒径分布8一26nln，平均粒径(18.3士8.0)nrn。包封率92.6%。最大释放率93.39%。半量释放时间为7h。 UANE经过25℃、40 Oe、50℃、60 OC四种不同温度处理后，观测期内未见乳析出现。随着温度的升高，UANE的粘度下降了近一倍，药物释放速度减缓:从25℃到60℃，半量释放时间延迟，分别为7h、20h、72h、>72h;浓度平台期出现时间分别为24h、>72h、>72h、>72h;峰值浓度与25℃组峰值浓度比值分别为1 .00、0.77、0.53、0.43，释放速度明显减缓。 X线监视下，灌注过程中观察到60’CUAS明显比常温的容易推注，可控性明显好于常温组;加热组在流控状态下形成的油滴小;术前后DSA对比可见加热组瘤区栓塞较完全，瘤区血供完全阻断;CT检查显示加热组瘤区碘油沉积密度高;能量多普勒超声显示瘤区可测滋养血管在栓塞后以加热栓塞组较少;肿瘤组织病理切片油红染色显微镜下观察结果表明碘油主要滞留于肝血窦、肝脏组织间隙及25一250林m的小动脉内，加热后分布密度增加;普通光学显微镜和共聚焦显微镜观察结果阿霉素与碘油的分布相关。栓塞后10h加热组阿霉素在肝组织内的浓度比高。 结论:普通阿霉素碘油制剂在加热后粘度及其物理稳定性下降，而缓释性增强，延缓了阿霉素释放入血的速度，增加了碘油在瘤灶的沉积，使瘤灶内碘油密度增加。阿霉素碘油纳米乳剂与 第四军医大学硕士学位论文传统碘油乳剂相比，有着明显的稳定性、缓释性和高携药率。加热后，随着温度的升高，缓释性增强。更多还原

【Abstract】 Transcatheter arterial thermo-chemical embolism is a kind of interventional therapy method applied to the treatment of liver rumor in recent years, which has confirmed by experiment and clinical practice. This method has the mixed kill ability of the thermo-therapy, chemotherapy and embolismotherapy to the tumor. Its curative effect has direct relationship with the biodistribution and pharmacokinetics of the pharmaceutics, though it has several different facters. This research concentrates on the heated Lipiodol-Doxorubicin pharmaceutics, which would be the reference for the advanced experimental research and clinical application.Objective: To investigate the significance of the physicochemical properties of three types of Lipiodol-Adriamycin pharmaceutics (Emulsion , Suspension , Nanoemulsion) and the biodistribution of Suspension after heated.Methods: Ultra-fluid lipiodol Adriamycin emulsion (UFI-ADM Emulsion, UAE) and ultra-fluid lipiodol Adriamycin suspension (UFI-ADM Suspension, UAS) was prepared by "pumping technique". Ultra-fluid lipiodol Adriamycin Nanoemulsion (UFI-ADM Nanoemulsion, UANE) was prepared by mechanical and ultrasound emulsifier homogenizer after Tween-80 and Span-80 had added to the UAE.After heated up at different temperature of 25 C , 40C, 50C,60C for two hours, the time of delamination and sediment of the three types of pharmaceutics was counted, the viscosity was measured, the form of the particle was observed by the microscope and electron microscope, the concentration of ADM in liquid of dialysis was measured by ultraviolet spectrophotometic method for the ADM releasing rate and embedding ratio.UAS (4mg/ml) of normal temperature and 60C was infused into liver cancer model of vx2; Investigated by DSA, CT, Ultrasonograph, and observe pathological section dyed with oil red by microscope and confocal microscopy for the biodistribution of UFI in the tissue of the tumor. The concentration of ADM in the tissue of tumor measured by ultraviolet spectrophotometic method for the ratio of concentration of ADM. (the ratio of measured concentration to the total priming volume).Results: After heated up the delamination and sediment of UAS and UAE speeded up. In the sight of the microscope, the heated pharmaceutics had more big particulate/oil-drop. In comparison with the degree of 25 C, both the relative viscosity and the relative viscosity ratio of the two pharmaceutics reduced about two times at the degree of 60C, the releasing rate was lower. Among the groups at the degree of 25C 40C, 50C . each pharmaceutics had nearly the same releasing rate(P >0.05). In the group at the degree of 60 C , the releasing rate of UAS, USE and Adriamycin-Saline solution almost had no difference(p>0.05).The UANE had an appearance of pink, stable, creaming not observed within the observing period; under transmission electron microscopy , UANE showed a global , regular contour with homogenous size and distribution. The particles ranged from 8-26nm in diameter, with 18.3 + 8.0nm as the average diameter. The embedding ratio was 92.6%. The maximum releasing ratio was 93.39%, and the time of semis releasing was 7 hours.After heated up at different temperature of 25C, 40C, 50C,60C for two hours, no creaming was observed within the observing period(7h). With the increasing of temperature, the viscosity of UANE decreased about one time. The drug releasing ratio was decreased: ranged from 25 C to 60 C, the time of semis releasing was delayed, which was 7h, 20h, 72h, >72h; Platform period of concentration was 24h, >72h, >72h, >72h; the ratio of peak concentration to that of 25 C was 1.00, 0.77, 0.53, 0.43. Speed of drug releasing was slower. Result observed by X-ray in the operation indicated that the heated pharmaceutics had a character of easy controlling compared with the normal one. The heated one had little oil drop under the fluid condition. Post-operative DSA indicated that heated one had a high dense in the field of tumor. Power Doppler Ultrasonograph (PD-US) examining after operation ind更多还原