加热处理阿霉素碘油制剂的实验研究
|
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。
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
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。
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
引文
[1] Suitd. Conference on hyperthermia in cancer treatment. Cancer Res, 1979, 39(6): 2231-340.
[2] 于安伦，于金明．热疗的临床应用进展．国外医学肿瘤学分册，1996，23 (4)：235．
[3] Strauss AA, Appel M, Saphir O, Rabinovitz AJ. Immunologic resistance to carcinoma produced by electrocoagulation [J]. Surgery Gynecology and Obstetrics, 1965;35: 989-996.
[4] Stchlin JS. Hyperthermia perfusion of extremities for melanoma and soft tissue sarcoma [J]. Recent Results Cancer Res, 1997;59: 171-185.
[5] Issels RD, Fink RM, Lengfelder E. Effects of hypertherrnic conditions on the reactivity of oxygen radicals. Free Radic Res commun, 1986; 2(1-2): 7-18.
[6] Bumdon RH, Gill VM, Rice-Evans C. Oxidative stress and heat shock protein induction in human cells. Free Radic Res Commun, 1987;3: 129.
[7] Omar RA, Yano S, Kikkawa Y. Antioxident enzymes and survival of normal and simian virus 40-transformed mouse embryo cells after hyperthermia. Cancer Res, 1987;47: 3473.
[8] Freeman ML, Spita DR, Meredith MJ. Does heat shock enhance oxidative stress? Studies with ferrous and ferrio iron. Radiat Res, 1990;124: 228.
[9] Li J J, Oberley LW. Overexpression of manganese-containing superoxide dismutase confers resistance to the cytotoxicity of tumor necrosis factor alpha and/or hyperthermia. Cancer Res, 1997 May 15, 57(10): 1991-8.
[10] Cavalie R, Liocatto E C. Selective heat sensitivity of cancer cells: Biochemixal and clinical studies. Cancer, 1967, 20(2): 1351 - 1355.
[11] Sekiba K. Hyperthermia in gynecological malignancy. Jpn J Cancer Chemother. 1988, 15(4 pt 2-2): 1387-92.
[12]Satou T. Warm drug solution injected into vessel may enhance antitumor effect. Jpn J Cancer Chemother. 1990, 17: 1763-7.
[13]Ebe K, Suda H. Absolute ethano injection into solid tumors and additional hyperthermia therapy: evaluation with 133Xe tumor blood flow. J Jpn Soc Cancer Ther. 1992, 27: 759.
[14]王执民；曹玮；梁志会；张洪新；王义清；关彦；李文献；齐连君．兔肝癌介入性热化疗的疗效观察[J]．实用放射学杂志，2001，17 (11)：805-807．
[15]Hahn GM, Strand DE Cytotoxic effects of hyperthermia and adriamycin on Chinese Hamaster Cells[J]. J Natl Cancer Inst, 1976;57: 1063- 1067.
[16]何子强．热敏性微脂粒与局部温热疗法．国外医学肿瘤学分册．1990，4：224-226．
[17]Masunaga-S, Ono-K, AkaboshiM, KawaiK, Suzuki M, Kinashi Y, Takagaki M. Augmentation in chemosensitivity of intratumor quiescent cells by combined treatment with nicotinamide and mild hyperthermia. Jpn-J-Cancer-Res, 1997 Aug: 88(8): 770-7.
[18]Hettinga-JV, Konings-AV, Kampinga HH. Reduction of cellular cisplatin resistance by hyperthermia-a revies. Int-J-Hyperthermia. 1997 Sep-Oct; 13(5): 439-57.
[19]张洪新，郭卫平，王执民，王义清，刘燕，高巍，李文献，倪代慧，梁志会，曹伟，关彦．阿霉素化疗与热化疗对人肝癌细胞耐药模型作用的比较．第四军医大学学报，200021(8)：964—967．
[20]Tsumura M, Yoshiga K, Takada K. Enhancement of antitumor effect of 1-hexylcarbamoyl-5-fluorouracil combined with hyperthermia on cherlich ascites tumors tumor in vivo and Nakahara-Fukuoka sarcoma cell in vitro. Cancer Res, 1988, 48(14): 3977-3980.
[21]Herman TS, Teicher BA. Sequencing of trimodality therapy as determined by tumor growth delay and tumor cell survival in the FSa Ⅱc fibrosarcoma. Cancer Res, 1988, 48(14): 2693-2697.
[22]李骊耕．加温和抗癌药物消瘤疥对恶性Hep-2细胞的毒性作用[J]．
中华肿瘤杂志，1989；11：31-33．
[23]Beketic Ol, Jaksic M, Oreskovic S, Osmak M. Hyperthermic modulation of resistance to cis-diamminedichloroplatinum(Ⅱ) in human larynx carcinoma cells[J]. Int J Hyperthermia, 1997;13(2): 205-214.
[24]川崎祥二，等．日本医学放射线学会杂志，1984，44：526．
[25]Murray TG, Ciociarelli N, McCabe CM, Ksander B, Feuer W, Schiffrnan J, Mieler WF, O'Brien JM. In vitro eddicacy of carboplatin and hyperthermia in a murine retinoblastoma cell line[J]. Invest Ophthalmol Vis Sci, 1997;38(12): 2516-2522.
[26]张洪新；王执民；郭卫平；王义清；吴智群；李文献；陈江浩；关燕．阿霉素化疗与热化疗对兔毛细胞VX2细胞体外作用的比较．癌症，1999，18(3)：276-278．
[27]Goldstein HM, Wallace S, Anderson JH, Bree RL, Gianturco C. Transcatheter occlusion of abdominal tumors. Radiology. 1976, 120(3): 539-545.
[28]Bastian P, Bartkowski R, Kohler H, Kissel T. Chemo-embolization of experimental liver metastases. Part Ⅰ: distribution of bildegradable microspheres of different sizes in an animal model for the locoregional therapy. Eur. J. Pharm. Biopharm. 1998, 46(3): 243 254.
[29]李天晓，樊青霞，王瑞林，恶性肿瘤介入治疗学．2000年第一版，79：80．
[30]吴道澄，朴项浩，王执民，张国民，徐山淡，文爱东．阿霉素脂质体犬肝动脉栓塞后的体内分布与药动学研究．现代应用药学．1997，14(1)：24—26．
[31]韩国宏，郭庆林，郭宇良，邓敬兰，杜镐，盛启光．阿霉素不同剂型经肝动脉给药治疗肝癌的体内药动学研究．癌症．1998，17(3)：194-196
[32]韩国宏，郭庆林，郭宇良，邓敬兰，杜镐，盛启光．阿霉素经肝动脉给药的药动学和生物学分布．第四军医大学学报．1998，19(3)：
293-2953
[33]文爱东，蒋永培，樊亚萱．阿霉素犬肝动脉栓塞后的靶向性及药动学．西北药学杂志．1997．4，12：27-28．
[34]Lin SY, Wu WH, Lui WY. In vitro release, pharmacokinetic and tissue distribution studies of doxorubicin hydrochloride (Adriamycin HC1 ) encapsulated in lipiodolized w/o emulsions and w/o/w multiple emulsions. Pharmazie. 1992 Jun; 47(6): 439-43
[35]Isshiki K, Kishimoto W, Nonami T, Kato H, Haba T, Nakao A, Harada A, Takagi H, Kato M, Mizoguchi M.Studies on drug release from anti-cancer drug suspended Lipiodol. Gan To Kagaku Ryoho 1989Aug; 16(8 Pt 2): 3019- 23.
[36]Hahn KA, Frazier DL, Cox SK, Legendre AM. Effect of infusion regime on doxorubicin pharmacokinetics in the cat. J Am Anim Hosp Assoc 1997 Sep-Oct; 33(5): 427-33.
[37]安杰，安国斌，韩淑英，朱丽莎．p可霉素与异博定配伍使用的药动学研究．数理医药学杂志．2002年，15(4)：340-341．
[38]Gabizon A. Liposomes as in vivo carriers of adriamycin reduced cardiac uptake and preserved antitumor acrivity in mice [J]. Cancer Res, 1982, 42: 4734-4738.
[39]Van Hoesel QG, Steerenbery PA, Commelin D J, van Dijk A, van Oort W, Klein S, Douze JM, de Wildt D J, Hillen FC. Reduced cardiotoxicity and nephrotoxicity with preservation of antitumor activity of doxorubicin entrapped in stable liposomes [J. cancer Res. 1984, 44: 3698-3705.
[40]Raham A, More N, Schein PS. Doxorubicin-induced chronic cardiotoxicity and its protection by liposomal administration [J]. CancerRes, 1982, 42: 1817-1825.
[41]Rahman A, Fumagatlli A, Schein PS. Potential of liposomes to ameliorate anthraycline induced cardiotoxicity [J]. Semin. Oncol. 1984, 11: 44-49.
[42]赵刚，祁静蒽，胡增华，杨晓红，黄力明，沈晓梅．国产阿霉素
相同剂量不同用药方案静脉滴注药动学及疗效与毒副反应的研究。中国肿瘤临床．1992，19(5)：375—379
[43]陈江浩；王执民；吴道澄；徐山淡；陈海微；文爱东．阿霉素毫微粒肝动脉灌注后在荷肝肿瘤鼠体内的分布研究．中华放射学杂志．1999．3；33(3)：164-167．
[44]韩国宏；郭庆林；郭宇良；邓敬兰；杜镐；盛启光．阿霉素不同剂型经肝动脉给药治疗肝癌的体内药动学研究．癌症．1998；17(3)：194-196．
[45]Kodama T, Arima K, Sakamoto H, Suga M, Yachi A. Pharmacological and clinical studies on lipiodol emulsion for hepatocellular carcinoma. Gan To Kagaku Ryoho.1988 Aug;15(8 Pt 2): 2544-8.
[46]Nakakom K. An attempt for increasing effects of hepatic artery ligation for advanced hepatoma. Jap-deutsche Med Berichte 1979; 24: 672
[47]Knonno T, Maeda H, Iwai K, Tashiro S, Maki S, Morinaga T, Moehinaga M, Hiraoka T, Yokoyama I. Effect of arterial administration of high-molecular-weight antieancer agent SMANCS with lipid lymphographic agent on hepatoma, a preliminary report. EurJ Cancer Clin Oncol 1983; 190: 1053-1065.
[48]Miller DL, O'Leary YJ, Girton M. Distribution of iodized oil within the liver after hepatic arterial injection. Radiology 1987; 162(3): 849-52.
[49]Raoul JL, Bourguet P, Bretagne JF, Duvauferrier R, Coornaert S, Darnault P, Ramee A, Herry JY, Gastard J. Hepatic artery injection ofI131-1abeled lipilodol. Radiology 1988; 168: 541-5.
[50]Knonno T, Maeda H, Iwai K, Tashiro S, Maki S, Morinaga T, Mochinaga M, Hiraoka T, Yokoyama I. Effect of arterial administration of high-molecular- weight anticancer agent amahs with lipid lymphographic agent on hepatoma, a preliminary report. Eur J Cancer Clin Oncol 1983; 190: 1053-1065.
[51]Nakakuma K, Tashiro S, Hiraoka T, Uemura K, Konno T, Miyauchi Y, Yokoyama I. Studies on antieaneer treatment with an oily antieancer drug injected into the ligated feeding hepatic artery for liver cancer.Cancer.1983: 52: 2193-2200.
[52]Miller DL, O'Leary TJ, Girton M. Distribution of iodized oil within the liver after hepatic arterial injection. Radiology 1987; 162: 849-52
[53]Abramas H L.The response of neoplastic ranal vessels to epinephrine in man. Radiology 1964; 82: 217
[54]Iwai K, Maeda H, Konno T.Use of oily contrast medium for selective drag targeting to tumor: enhanced therapeutic effect and X-ray image. Cancer Research 1984; 44(5): 2115-2121.
[55]Nakakuma K, et al. An attempt for increasing effects of hepatic artery ligation for advanced hepatoma. Jap-Deutsche Med Berichte 1979; 24: 672
[56]Konno T, Maeda H, Iwai K, Maki S, Tashiro S, Uchida M, Miyauchi Y. Selective targeting of anti-cancer drag and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium. Cancer1984; 54: 2367-74.
[57]Senger DR, Galli S J, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrets a vascular permeability factor that promotes accumulation of Ascites fluid. Science 1983; 219: 983-985.
[58]李麟菘主编，临床介入治疗学．1994；58．
[59]李天晓，樊青霞，王瑞林主编，恶性肿瘤介入治疗学。2000年第一版，79：80．
[60]殷恭宽．物理药学(第一版)[M]．北京：北京医科大学出版社，1993：393-398．
[61]刘恒戈，张辉文，古拉扎提·木哈买提哈里．阿霉素在常用输液中的稳定性考察．新疆医科大学学报．2001Dec，24(4)：357—358．
[62]王立非，韩长春，杨立，徐风华，吕晓川，威景春．碘化油．阿霉素混悬剂物理稳定性的实验研究．中国药业．1999：8(12)：15—16
[63]施海彬、李麟荪、谈恒山．碘油抗癌药物乳剂与混悬剂的基础实验研究．介入放射学杂志，1994，3(1)：33—35．
[64]Katagiri Y, Mabuchi K, Itakura T, Naora K, Iwamoto K, Nozu Y, Hirai S, Ikeda N, Kawai T. Adriamycin-Lipiodol suspension for i.a. chemotherapy of hepatocellular carcinoma. Cancer Chemother Pharmacol 1989;23: 238-242.
[65]周步良，李萍，谈恒山．碘油抗癌药造影栓塞乳剂配制比例的实验研究．苏州医学院学报2000；20(6)：534—540．
[66]Heresbach D, Raoul JL, Bentue-Ferrer D, Bretagne JF, Van den Driessche J, Gastard J. Chemotherapy combined with Lipiodol. In vitro study of the kinetics of release of adriamycin. Gastroenterol Clin Biol 1989 Oct; 13(10): 775-8.
[67]许海燕，孔桦，杨子彬．纳米材料及其在生物医学工程中的应用．国外医学生物医学工程分册．1998；21(5)262—266
[68]张志荣，魏振平．载药毫微粒制备方法及药物靶向性．华西药学杂志．1996，11：123—126．
[69]K.reuter J. Nanoparticles and microparticles for drug and advance delivery. J.A.nat, 1996, 189(3): 503-505.
[70]彭冬先，何援利．纳米技术在临床医学中的应用研究进展及前景．医学综述．20017(11)：698—700．
[71]Gulyaev AE, Gelperina SE, Skidan IN, Antropov AS, Kivman GY, Kreuter J. Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticle. [J]. Pharm Res, 1999, 16(10): 1564-9.
[72]Soma CE, Dubernet C, Bentolila D, Benita S, Couvreur P. Reversion of multidrug resistance by co-encapsulation of doxorubcin and cyclosporin A in polyalkylcyanoacrylate nanoparticles. [J]. Biomaterials, 2000, 21(1): 1-7.
[73]高学云；张劲松；张立德；汪思应．纳米红色元素硒对C57小鼠Lewis肺癌移植瘤形成与转移的影响．中国公共卫生．2000．02．10；16(2)：109-110．
[74]吴道澄，陈江浩，王执民．多柔比星纳米微粒—碘油乳剂肝动脉栓塞治疗大鼠肝癌的药效学研究．中国医药工业杂志，1999；30(4)：162—165
[75]吴道澄，席晓莉，陈江浩等．阿霉素纳米微粒碘油乳剂肝动脉栓塞治疗肝癌[A]．第三届全国“超微颗粒制备与应用”研讨会论文集[C]．兰州：中国化学会物理化学专业委员会，1998：58-59．
[76]王浩，赵文宽，方佑龄．二氧化钛光催化杀灭肿瘤细胞的研究[J]．催化学报，1999，20(3)：373 374．
[77]陈克正，王丽平，刘兴斌．纳米微粒在生物医药领域中的应用研究．药学进展．2000，24(4)：193—196．
[78]张洪新；王执民；任炜；刘振堂；刘燕；郭卫平；刘毅勇；曹玮；王义清；李文献；倪代会；韩瑞炀．介入性热化疗与介入性化疗治疗中晚期肝癌的疗效对比[J]．实用放射学杂志，2003，19(4)：339-342
[79]Hino T., Kawashima Y., Shimabayashi S. Basic study for stabilization of w/o/w emulsion and its application to transcatheter arterial embolization therapy [J]. Advanced Drug Delivery Reviews, 2000, 45: 27-45.
[80]程洪艳，李素文，李艳平，张鸿卿，薛绍白．抗癌药物阿霉素的荧光发射光谱分析[J]，1999．6，35(2)：262-265．
[81]王立非；韩长春；杨立；徐风华；吕晓川；威景春．碘化油-阿霉素混悬剂物理稳定性的实验研究．药物研究[J]，1999，8(12)：15-16．
[82]刘福全；岳振东；李阳；石晓露；李炎秋；殷其谭．碘油乳剂的制作及其对肝脏增强的实验研究[J]，1998，5(1)：3-5．
[83]晁明；蒋定尧；任志达；方兵．微导管在肝癌介入治疗上的应用．实用放射学杂志[J]，2001，17(4)：247-249．
[84]李常青；徐道振；许东海；李秀兰；张伟；刘悦德．高温碘油热栓塞治疗原发性肝癌患者．中华肝脏病杂志，2002，10(3)：174-177．
[85]周步良，李萍，谈恒山．碘油抗癌药造影栓塞乳剂配制比例的实验研究．苏州医学院学报2000；20(6)：534-540．
[86]陆彬主编．药剂学．中国医药科技出版社2003年1月(第一版)
[87] 曹玮，王执民，张洪新，王义清，郭卫平，李文献，倪代会，梁志会，齐连君．兔Vx2肝癌改良模型的建立及其DSA影像分析．
[88] 曹晓明，王执民，张洪新，曹玮，刘毅勇．经肝动脉热疗对兔肝VX2肿瘤血管渗透性的影响．第四军医大学学报，2002．09．15；23(17)：1587-1589．
[89] MugitaniT, Taniguchi H, TakadaA, YamaguchiA, MasuyamaM, Hoshima M, Takahashi T. TNP-470 inhibits collateralization to complement the anti-tumor effect of hepatic artery ligation [J]. Br J Cancer. 1998; 77(4): 638-642.
[90] Fety R, Lucas C, Solere P, et al. Hepatic intra-arterial infusion of fotemustine: pharmacokinetics. Cancer Chemother Pharmacol. 1992; 31: 118-122.
[2] 于安伦，于金明．热疗的临床应用进展．国外医学肿瘤学分册，1996，23 (4)：235．
[3] Strauss AA, Appel M, Saphir O, Rabinovitz AJ. Immunologic resistance to carcinoma produced by electrocoagulation [J]. Surgery Gynecology and Obstetrics, 1965;35: 989-996.
[4] Stchlin JS. Hyperthermia perfusion of extremities for melanoma and soft tissue sarcoma [J]. Recent Results Cancer Res, 1997;59: 171-185.
[5] Issels RD, Fink RM, Lengfelder E. Effects of hypertherrnic conditions on the reactivity of oxygen radicals. Free Radic Res commun, 1986; 2(1-2): 7-18.
[6] Bumdon RH, Gill VM, Rice-Evans C. Oxidative stress and heat shock protein induction in human cells. Free Radic Res Commun, 1987;3: 129.
[7] Omar RA, Yano S, Kikkawa Y. Antioxident enzymes and survival of normal and simian virus 40-transformed mouse embryo cells after hyperthermia. Cancer Res, 1987;47: 3473.
[8] Freeman ML, Spita DR, Meredith MJ. Does heat shock enhance oxidative stress? Studies with ferrous and ferrio iron. Radiat Res, 1990;124: 228.
[9] Li J J, Oberley LW. Overexpression of manganese-containing superoxide dismutase confers resistance to the cytotoxicity of tumor necrosis factor alpha and/or hyperthermia. Cancer Res, 1997 May 15, 57(10): 1991-8.
[10] Cavalie R, Liocatto E C. Selective heat sensitivity of cancer cells: Biochemixal and clinical studies. Cancer, 1967, 20(2): 1351 - 1355.
[11] Sekiba K. Hyperthermia in gynecological malignancy. Jpn J Cancer Chemother. 1988, 15(4 pt 2-2): 1387-92.
[12]Satou T. Warm drug solution injected into vessel may enhance antitumor effect. Jpn J Cancer Chemother. 1990, 17: 1763-7.
[13]Ebe K, Suda H. Absolute ethano injection into solid tumors and additional hyperthermia therapy: evaluation with 133Xe tumor blood flow. J Jpn Soc Cancer Ther. 1992, 27: 759.
[14]王执民；曹玮；梁志会；张洪新；王义清；关彦；李文献；齐连君．兔肝癌介入性热化疗的疗效观察[J]．实用放射学杂志，2001，17 (11)：805-807．
[15]Hahn GM, Strand DE Cytotoxic effects of hyperthermia and adriamycin on Chinese Hamaster Cells[J]. J Natl Cancer Inst, 1976;57: 1063- 1067.
[16]何子强．热敏性微脂粒与局部温热疗法．国外医学肿瘤学分册．1990，4：224-226．
[17]Masunaga-S, Ono-K, AkaboshiM, KawaiK, Suzuki M, Kinashi Y, Takagaki M. Augmentation in chemosensitivity of intratumor quiescent cells by combined treatment with nicotinamide and mild hyperthermia. Jpn-J-Cancer-Res, 1997 Aug: 88(8): 770-7.
[18]Hettinga-JV, Konings-AV, Kampinga HH. Reduction of cellular cisplatin resistance by hyperthermia-a revies. Int-J-Hyperthermia. 1997 Sep-Oct; 13(5): 439-57.
[19]张洪新，郭卫平，王执民，王义清，刘燕，高巍，李文献，倪代慧，梁志会，曹伟，关彦．阿霉素化疗与热化疗对人肝癌细胞耐药模型作用的比较．第四军医大学学报，200021(8)：964—967．
[20]Tsumura M, Yoshiga K, Takada K. Enhancement of antitumor effect of 1-hexylcarbamoyl-5-fluorouracil combined with hyperthermia on cherlich ascites tumors tumor in vivo and Nakahara-Fukuoka sarcoma cell in vitro. Cancer Res, 1988, 48(14): 3977-3980.
[21]Herman TS, Teicher BA. Sequencing of trimodality therapy as determined by tumor growth delay and tumor cell survival in the FSa Ⅱc fibrosarcoma. Cancer Res, 1988, 48(14): 2693-2697.
[22]李骊耕．加温和抗癌药物消瘤疥对恶性Hep-2细胞的毒性作用[J]．
中华肿瘤杂志，1989；11：31-33．
[23]Beketic Ol, Jaksic M, Oreskovic S, Osmak M. Hyperthermic modulation of resistance to cis-diamminedichloroplatinum(Ⅱ) in human larynx carcinoma cells[J]. Int J Hyperthermia, 1997;13(2): 205-214.
[24]川崎祥二，等．日本医学放射线学会杂志，1984，44：526．
[25]Murray TG, Ciociarelli N, McCabe CM, Ksander B, Feuer W, Schiffrnan J, Mieler WF, O'Brien JM. In vitro eddicacy of carboplatin and hyperthermia in a murine retinoblastoma cell line[J]. Invest Ophthalmol Vis Sci, 1997;38(12): 2516-2522.
[26]张洪新；王执民；郭卫平；王义清；吴智群；李文献；陈江浩；关燕．阿霉素化疗与热化疗对兔毛细胞VX2细胞体外作用的比较．癌症，1999，18(3)：276-278．
[27]Goldstein HM, Wallace S, Anderson JH, Bree RL, Gianturco C. Transcatheter occlusion of abdominal tumors. Radiology. 1976, 120(3): 539-545.
[28]Bastian P, Bartkowski R, Kohler H, Kissel T. Chemo-embolization of experimental liver metastases. Part Ⅰ: distribution of bildegradable microspheres of different sizes in an animal model for the locoregional therapy. Eur. J. Pharm. Biopharm. 1998, 46(3): 243 254.
[29]李天晓，樊青霞，王瑞林，恶性肿瘤介入治疗学．2000年第一版，79：80．
[30]吴道澄，朴项浩，王执民，张国民，徐山淡，文爱东．阿霉素脂质体犬肝动脉栓塞后的体内分布与药动学研究．现代应用药学．1997，14(1)：24—26．
[31]韩国宏，郭庆林，郭宇良，邓敬兰，杜镐，盛启光．阿霉素不同剂型经肝动脉给药治疗肝癌的体内药动学研究．癌症．1998，17(3)：194-196
[32]韩国宏，郭庆林，郭宇良，邓敬兰，杜镐，盛启光．阿霉素经肝动脉给药的药动学和生物学分布．第四军医大学学报．1998，19(3)：
293-2953
[33]文爱东，蒋永培，樊亚萱．阿霉素犬肝动脉栓塞后的靶向性及药动学．西北药学杂志．1997．4，12：27-28．
[34]Lin SY, Wu WH, Lui WY. In vitro release, pharmacokinetic and tissue distribution studies of doxorubicin hydrochloride (Adriamycin HC1 ) encapsulated in lipiodolized w/o emulsions and w/o/w multiple emulsions. Pharmazie. 1992 Jun; 47(6): 439-43
[35]Isshiki K, Kishimoto W, Nonami T, Kato H, Haba T, Nakao A, Harada A, Takagi H, Kato M, Mizoguchi M.Studies on drug release from anti-cancer drug suspended Lipiodol. Gan To Kagaku Ryoho 1989Aug; 16(8 Pt 2): 3019- 23.
[36]Hahn KA, Frazier DL, Cox SK, Legendre AM. Effect of infusion regime on doxorubicin pharmacokinetics in the cat. J Am Anim Hosp Assoc 1997 Sep-Oct; 33(5): 427-33.
[37]安杰，安国斌，韩淑英，朱丽莎．p可霉素与异博定配伍使用的药动学研究．数理医药学杂志．2002年，15(4)：340-341．
[38]Gabizon A. Liposomes as in vivo carriers of adriamycin reduced cardiac uptake and preserved antitumor acrivity in mice [J]. Cancer Res, 1982, 42: 4734-4738.
[39]Van Hoesel QG, Steerenbery PA, Commelin D J, van Dijk A, van Oort W, Klein S, Douze JM, de Wildt D J, Hillen FC. Reduced cardiotoxicity and nephrotoxicity with preservation of antitumor activity of doxorubicin entrapped in stable liposomes [J. cancer Res. 1984, 44: 3698-3705.
[40]Raham A, More N, Schein PS. Doxorubicin-induced chronic cardiotoxicity and its protection by liposomal administration [J]. CancerRes, 1982, 42: 1817-1825.
[41]Rahman A, Fumagatlli A, Schein PS. Potential of liposomes to ameliorate anthraycline induced cardiotoxicity [J]. Semin. Oncol. 1984, 11: 44-49.
[42]赵刚，祁静蒽，胡增华，杨晓红，黄力明，沈晓梅．国产阿霉素
相同剂量不同用药方案静脉滴注药动学及疗效与毒副反应的研究。中国肿瘤临床．1992，19(5)：375—379
[43]陈江浩；王执民；吴道澄；徐山淡；陈海微；文爱东．阿霉素毫微粒肝动脉灌注后在荷肝肿瘤鼠体内的分布研究．中华放射学杂志．1999．3；33(3)：164-167．
[44]韩国宏；郭庆林；郭宇良；邓敬兰；杜镐；盛启光．阿霉素不同剂型经肝动脉给药治疗肝癌的体内药动学研究．癌症．1998；17(3)：194-196．
[45]Kodama T, Arima K, Sakamoto H, Suga M, Yachi A. Pharmacological and clinical studies on lipiodol emulsion for hepatocellular carcinoma. Gan To Kagaku Ryoho.1988 Aug;15(8 Pt 2): 2544-8.
[46]Nakakom K. An attempt for increasing effects of hepatic artery ligation for advanced hepatoma. Jap-deutsche Med Berichte 1979; 24: 672
[47]Knonno T, Maeda H, Iwai K, Tashiro S, Maki S, Morinaga T, Moehinaga M, Hiraoka T, Yokoyama I. Effect of arterial administration of high-molecular-weight antieancer agent SMANCS with lipid lymphographic agent on hepatoma, a preliminary report. EurJ Cancer Clin Oncol 1983; 190: 1053-1065.
[48]Miller DL, O'Leary YJ, Girton M. Distribution of iodized oil within the liver after hepatic arterial injection. Radiology 1987; 162(3): 849-52.
[49]Raoul JL, Bourguet P, Bretagne JF, Duvauferrier R, Coornaert S, Darnault P, Ramee A, Herry JY, Gastard J. Hepatic artery injection ofI131-1abeled lipilodol. Radiology 1988; 168: 541-5.
[50]Knonno T, Maeda H, Iwai K, Tashiro S, Maki S, Morinaga T, Mochinaga M, Hiraoka T, Yokoyama I. Effect of arterial administration of high-molecular- weight anticancer agent amahs with lipid lymphographic agent on hepatoma, a preliminary report. Eur J Cancer Clin Oncol 1983; 190: 1053-1065.
[51]Nakakuma K, Tashiro S, Hiraoka T, Uemura K, Konno T, Miyauchi Y, Yokoyama I. Studies on antieaneer treatment with an oily antieancer drug injected into the ligated feeding hepatic artery for liver cancer.Cancer.1983: 52: 2193-2200.
[52]Miller DL, O'Leary TJ, Girton M. Distribution of iodized oil within the liver after hepatic arterial injection. Radiology 1987; 162: 849-52
[53]Abramas H L.The response of neoplastic ranal vessels to epinephrine in man. Radiology 1964; 82: 217
[54]Iwai K, Maeda H, Konno T.Use of oily contrast medium for selective drag targeting to tumor: enhanced therapeutic effect and X-ray image. Cancer Research 1984; 44(5): 2115-2121.
[55]Nakakuma K, et al. An attempt for increasing effects of hepatic artery ligation for advanced hepatoma. Jap-Deutsche Med Berichte 1979; 24: 672
[56]Konno T, Maeda H, Iwai K, Maki S, Tashiro S, Uchida M, Miyauchi Y. Selective targeting of anti-cancer drag and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium. Cancer1984; 54: 2367-74.
[57]Senger DR, Galli S J, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrets a vascular permeability factor that promotes accumulation of Ascites fluid. Science 1983; 219: 983-985.
[58]李麟菘主编，临床介入治疗学．1994；58．
[59]李天晓，樊青霞，王瑞林主编，恶性肿瘤介入治疗学。2000年第一版，79：80．
[60]殷恭宽．物理药学(第一版)[M]．北京：北京医科大学出版社，1993：393-398．
[61]刘恒戈，张辉文，古拉扎提·木哈买提哈里．阿霉素在常用输液中的稳定性考察．新疆医科大学学报．2001Dec，24(4)：357—358．
[62]王立非，韩长春，杨立，徐风华，吕晓川，威景春．碘化油．阿霉素混悬剂物理稳定性的实验研究．中国药业．1999：8(12)：15—16
[63]施海彬、李麟荪、谈恒山．碘油抗癌药物乳剂与混悬剂的基础实验研究．介入放射学杂志，1994，3(1)：33—35．
[64]Katagiri Y, Mabuchi K, Itakura T, Naora K, Iwamoto K, Nozu Y, Hirai S, Ikeda N, Kawai T. Adriamycin-Lipiodol suspension for i.a. chemotherapy of hepatocellular carcinoma. Cancer Chemother Pharmacol 1989;23: 238-242.
[65]周步良，李萍，谈恒山．碘油抗癌药造影栓塞乳剂配制比例的实验研究．苏州医学院学报2000；20(6)：534—540．
[66]Heresbach D, Raoul JL, Bentue-Ferrer D, Bretagne JF, Van den Driessche J, Gastard J. Chemotherapy combined with Lipiodol. In vitro study of the kinetics of release of adriamycin. Gastroenterol Clin Biol 1989 Oct; 13(10): 775-8.
[67]许海燕，孔桦，杨子彬．纳米材料及其在生物医学工程中的应用．国外医学生物医学工程分册．1998；21(5)262—266
[68]张志荣，魏振平．载药毫微粒制备方法及药物靶向性．华西药学杂志．1996，11：123—126．
[69]K.reuter J. Nanoparticles and microparticles for drug and advance delivery. J.A.nat, 1996, 189(3): 503-505.
[70]彭冬先，何援利．纳米技术在临床医学中的应用研究进展及前景．医学综述．20017(11)：698—700．
[71]Gulyaev AE, Gelperina SE, Skidan IN, Antropov AS, Kivman GY, Kreuter J. Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticle. [J]. Pharm Res, 1999, 16(10): 1564-9.
[72]Soma CE, Dubernet C, Bentolila D, Benita S, Couvreur P. Reversion of multidrug resistance by co-encapsulation of doxorubcin and cyclosporin A in polyalkylcyanoacrylate nanoparticles. [J]. Biomaterials, 2000, 21(1): 1-7.
[73]高学云；张劲松；张立德；汪思应．纳米红色元素硒对C57小鼠Lewis肺癌移植瘤形成与转移的影响．中国公共卫生．2000．02．10；16(2)：109-110．
[74]吴道澄，陈江浩，王执民．多柔比星纳米微粒—碘油乳剂肝动脉栓塞治疗大鼠肝癌的药效学研究．中国医药工业杂志，1999；30(4)：162—165
[75]吴道澄，席晓莉，陈江浩等．阿霉素纳米微粒碘油乳剂肝动脉栓塞治疗肝癌[A]．第三届全国“超微颗粒制备与应用”研讨会论文集[C]．兰州：中国化学会物理化学专业委员会，1998：58-59．
[76]王浩，赵文宽，方佑龄．二氧化钛光催化杀灭肿瘤细胞的研究[J]．催化学报，1999，20(3)：373 374．
[77]陈克正，王丽平，刘兴斌．纳米微粒在生物医药领域中的应用研究．药学进展．2000，24(4)：193—196．
[78]张洪新；王执民；任炜；刘振堂；刘燕；郭卫平；刘毅勇；曹玮；王义清；李文献；倪代会；韩瑞炀．介入性热化疗与介入性化疗治疗中晚期肝癌的疗效对比[J]．实用放射学杂志，2003，19(4)：339-342
[79]Hino T., Kawashima Y., Shimabayashi S. Basic study for stabilization of w/o/w emulsion and its application to transcatheter arterial embolization therapy [J]. Advanced Drug Delivery Reviews, 2000, 45: 27-45.
[80]程洪艳，李素文，李艳平，张鸿卿，薛绍白．抗癌药物阿霉素的荧光发射光谱分析[J]，1999．6，35(2)：262-265．
[81]王立非；韩长春；杨立；徐风华；吕晓川；威景春．碘化油-阿霉素混悬剂物理稳定性的实验研究．药物研究[J]，1999，8(12)：15-16．
[82]刘福全；岳振东；李阳；石晓露；李炎秋；殷其谭．碘油乳剂的制作及其对肝脏增强的实验研究[J]，1998，5(1)：3-5．
[83]晁明；蒋定尧；任志达；方兵．微导管在肝癌介入治疗上的应用．实用放射学杂志[J]，2001，17(4)：247-249．
[84]李常青；徐道振；许东海；李秀兰；张伟；刘悦德．高温碘油热栓塞治疗原发性肝癌患者．中华肝脏病杂志，2002，10(3)：174-177．
[85]周步良，李萍，谈恒山．碘油抗癌药造影栓塞乳剂配制比例的实验研究．苏州医学院学报2000；20(6)：534-540．
[86]陆彬主编．药剂学．中国医药科技出版社2003年1月(第一版)
[87] 曹玮，王执民，张洪新，王义清，郭卫平，李文献，倪代会，梁志会，齐连君．兔Vx2肝癌改良模型的建立及其DSA影像分析．
[88] 曹晓明，王执民，张洪新，曹玮，刘毅勇．经肝动脉热疗对兔肝VX2肿瘤血管渗透性的影响．第四军医大学学报，2002．09．15；23(17)：1587-1589．
[89] MugitaniT, Taniguchi H, TakadaA, YamaguchiA, MasuyamaM, Hoshima M, Takahashi T. TNP-470 inhibits collateralization to complement the anti-tumor effect of hepatic artery ligation [J]. Br J Cancer. 1998; 77(4): 638-642.
[90] Fety R, Lucas C, Solere P, et al. Hepatic intra-arterial infusion of fotemustine: pharmacokinetics. Cancer Chemother Pharmacol. 1992; 31: 118-122.