阿霉素长循环热敏脂质体的研制及其靶向治疗肿瘤作用的研究

The Preparation and the Anti-Tumor Targeting Therapy of Adriamycin Long Circulating Temperature-Sensitive Liposome

目的:研制阿霉素脂质体(AL)、阿霉素长循环脂质体(ALCL)和阿霉素长循环热敏脂质体(ALTSL)。研究不同类型脂质体对H22荷瘤小鼠肿瘤的抑制作用。方法:建立荷瘤小鼠模型,观察各实验组的抑瘤效果,计算抑瘤率和生命延长率;HPLC法研究静脉给药后各实验组阿霉素的药代动力学规律及组织学分布特征;制作病理切片,观察各实验组肿瘤和心脏等组织的病理变化。结果:ALCL和ALTSL对H22荷瘤小鼠肿瘤有显著的抑制作用,抑瘤率分别为57.8%和67.0%(P<0.01);尾静脉注射给药24h后,ALCL和ALTSL组荷瘤小鼠肿瘤组织和血液中的阿霉素含量明显上升,而在心、肺中的含量显著降低;ALTSL使肿瘤细胞大量坏死,而对心肌细胞无明显损伤。结论:ALCL和ALTSL均能提高化疗药阿霉素的抗肿瘤效果,降低阿霉素的心肺毒性,延长荷瘤小鼠的存活时间。

Objective: To develop adriamycin liposome (AL) , adriamycin long circulating liposome (ALCL) and adriamycin long circulating temprerature-sensitive liposome ( ALTSL) and to study their anti-tumor effects on tumor-bearing mice. Methods: The antitumor activity was observed using the tumor weight as index. The life prolongation rate of mice was calculated according to the tumor-bearing mice survival time. The tissue distribution of adriamycin was determined by HPLC method. Tumor, heart, liver and kidney tissue of the tumor-bearing mice, were sliced and prepared to observe the tissue pathology differences. Results: Compared with free adriamycin, the anti-tumor effects of ALCL and ALTSL were remarkably increased. Their tumor growth inhibitory rates were 57. 8% and 67. 0% respectively. The study of pharmacoki-netics indicated that the adriamycin concentrations were remarkably higher in tumor tissue and blood,lower in heart and lung tissue of ALCL and ALTSL groups when compared with the free ADM group; The pathology slices indicated that tumor cells in the ALTSL group with hyperthermia were mostly destroyed; the cardiac muscle cells in the ALTSL group were similar to the normal cardiac muscle. Conclusion: ALCL and ALTSL remarkably increased the adriamycin concentration on the tumor site, significantly enhanced the anti-tumor effects, decreased the side-effects (such as cytotoxicity) when compared with free ADM, they also significantly prolonged the survival time of the tumor-bearing mice.