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研究磁性吉西他滨隐形纳米脂质体(magnetic gemcitabine stealth nano-liposomes,MGSL)的体内磁响应性及对MCF-7细胞生物学特性的影响。对小鼠头颅部施加磁场,并静脉注射MGSL,通过对脑组织药物含量的分析,研究MGSL在体内的磁响应性;然后在有磁场和无磁场的不同情况下,静脉给予小鼠MGSL,通过对小鼠脑、心、肝、脾、肺及肾等组织的药物含量分析,考察吉西他滨在体内的分布差异,比较磁性靶向作用和单纯给药在组织分布的不同。在体外,观察了MGSL诱导的MCF-7细胞凋亡过程中的细胞形态学改变、MTT法获得MGSL作用乳腺癌细胞生长抑制率、流式细胞仪分析MGSL引起的细胞凋亡率和细胞周期分布。最后制成裸鼠乳腺癌皮下移植瘤模型,通过在移植瘤表面定时给予三维立体梯度磁场作用,观察MGSL靶向治疗裸鼠乳腺癌的效果。低强度磁场组的吉西他滨血药浓度显著高于无磁场组(P<0.01),而高强度磁场组吉西他滨的含量较低强度磁场组显著升高(P<0.01),且当磁场强度达到5000高斯时,吉西他滨含量可达无磁场组的8.5倍。另外应用外加磁场,吉西他滨可以有效聚集到靶部位,显著提高病灶部位吉西他滨的浓度,降低心脏、肾脏等器官的药物浓度。MGSL对人乳腺癌细胞在体外有明显的杀伤作用,其杀伤作用随浓度升高有上升趋势;结果还显示MGSL是主要作用于S期的细胞周期药物;采用流式细胞术证实了MGSL还有促乳腺癌细胞凋亡的作用,其诱导凋亡率达到51.62%。MGSL可以显著抑制裸鼠皮下移植瘤的生长,与其他组别相比均有显著差异(P<0.05)。本法制备的MGSL符合作为纳米磁靶向给药系统的条件,同时它具备较好的磁响应性,在外磁场的作用下可以有效增加肿瘤组织内的药物浓度,而降低正常组织的药物含量,达到靶向化疗的目的,且在体内外显示了较好的抑瘤效应,可望成为一种有效的抗肿瘤制剂。
To investigate the in vivo magnetic responsiveness of magnetic gemcitabine stealth nano-liposomes (MGSL) and its effect on the biological characteristics of MCF-7 cells. The magnetic field was applied to the skull of mice and MGSL was injected intravenously to study the magnetic responsiveness of MGSL in vivo by analyzing the content of the drug in brain tissue. Then MGSL was administered intravenously to mice by MGSL in different situations with or without magnetic field The content of gemcitabine in the brain, heart, liver, spleen, lung, kidney and other tissues was analyzed. The distribution of gemcitabine in vivo was analyzed. The differences between the magnetic targeting and the simple administration in tissue distribution were compared. The morphological changes of MCSL-7 cells induced by MGSL were observed in vitro. The growth inhibition rate of MGSL cells was determined by MTT method. The apoptosis rate and cell cycle distribution induced by MGSL were analyzed by flow cytometry . Finally, a subcutaneous xenograft model of nude mice with breast cancer was established, and the effect of MGSL targeted therapy on breast cancer in nude mice was observed by timed three-dimensional gradient magnetic field on the surface of the xenografted tumor. The plasma concentration of gemcitabine in the low-intensity magnetic field group was significantly higher than that in the non-magnetic field group (P <0.01), while that in the high-intensity magnetic field group was significantly higher than that in the lower-intensity magnetic field group (P <0.01) , Gemcitabine content up to 8.5 times the field-free group. In addition, applying an applied magnetic field, gemcitabine can effectively aggregate to the target site, significantly increase the concentration of gemcitabine in the lesion site, and reduce the drug concentration in the heart, kidney and other organs. MGSL on human breast cancer cells in vitro significant killing effect, its killing effect increased with increasing concentration; results also showed that MGSL is a major role in the S phase of the cell cycle drugs; using flow cytometry confirmed MGSL also Promote breast cancer cell apoptosis, the rate of apoptosis induced 51.62%. MGSL could significantly inhibit the growth of subcutaneous xenografts in nude mice, which was significantly different from other groups (P <0.05). The MGSL prepared by the method is suitable for the condition of the nano-magnetic target drug delivery system, and at the same time, it has good magnetic responsiveness. Under the action of an external magnetic field, MGSL can effectively increase the drug concentration in the tumor tissue and reduce the drug content in the normal tissue, Achieve the purpose of targeting chemotherapy, and show good anti-tumor effect both in vivo and in vitro, which is expected to become an effective antitumor agent.