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体外微囊化肿瘤细胞模型的构建及其用于药物筛选的体外研究 被引量:2

Construction of in vitro multicellular tumor spheroid model with microencapsulation and its application in anticancer drug screening
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摘要 目的:利用静电液滴法制备三维生长的微囊化人乳腺癌细胞球并初步用于抗肿瘤药物筛选。方法:实验于2004-02/07在中国科学院大连化学物理研究所生物医学材料实验室完成。使用大功率高压脉冲微胶囊制备仪,制备微囊化人乳腺癌细胞(MCF-7),经体外培养5d可形成直径为125μm的微囊化多细胞肿瘤球并用于实验;在不同氧浓度下,抗癌药物丝裂霉素、阿霉素和5-氟尿嘧啶分别在0.1,1,10倍血浆峰值浓度下作用24,48,72h后测量微囊内细胞球的粒径、相差显微镜和苏木精-伊红染色观察细胞球形态并通过活/死染料定性细胞的活性、四甲基偶氮唑盐法定量测定微囊内细胞的活性以及溴脱氧尿嘧啶核苷掺入法检测细胞增殖状态。结果:①人乳腺癌细胞微囊化后可继续生长、增殖并聚集成团,同时消耗葡萄糖并产生乳酸。微囊化肿瘤细胞表现出较强的增殖活性,当微囊内的细胞团增大到一定程度时中心可出现坏死区,但分布于团块外层的细胞仍具有增殖活性。②抗癌药物作用后,随药物浓度的增加和作用时间延长,微囊内细胞球的粒径减小、细胞增殖活性代偿性增加。活细胞减少,死细胞增多,四甲基偶氮唑盐显示细胞活性降低,与平面培养细胞相比,抗癌药物对微囊化乳腺癌细胞球的抑制率降低。从药物效果看,丝裂霉素的抗肿瘤效果好于5-氟尿嘧啶和阿霉素。③随氧浓度增高,微囊化人乳腺癌细胞对抗癌药物的敏感性增强。结论:微囊化多细胞肿瘤球模拟了体内组织的三维生长方式,并有望成为一种快速、有效的体外药物筛选模型。 AIM: To prepare three-dimensional microencapsulated human breast cancer spheroid with electrostatic droplet generator and appl); it in the screening of anticancer drug. METHODS:The experiment was carried out at the Laboratory of Biomedical Materials, Institute of Chemical Physics, Chinese Academy of Science from February to July 2004. A method of microencapsulation with alginate and poly-L-lysine was developed to form APA human MCF-7 breast cancer muhicellular spheroid of 125 μm in diameter after 5-day cultivation. The MCF-7 MMTS was treated with mitomycin C (MC), adriamycin (ADM) and 5-fluorouracil (5-FU) at the concentrations of 0.1, 1 or 10 times of peak plasma concentration (ppc) for 24 hours,48 hours or 72 hours and in various oxygen concentrations of environment. Then the diameter of spheroid was measured. Cellular morphology was observed under phase contrast microscope after stained by haematoxylin and eosin and the cellular activity was determined. Cellular activity in the microencapsulation was determined by MTT and the cellular proliferation was detected with bromodeoxyuridine (BrdU). RESULTS: ①Microencapsulatod tumor cells could grow and proliferate into clump, in addition, consume glucose and produce lactic acid. Necrotic core appeared as the diameter of cell spheroid was enlarged. Proliferating cells were restricted to the outer two or three cellular layers in microencapoulated cells spheroid. ②The diameter of cell spheroid in microcapoule reduced and the proliferative ability of cell increased by treatment with anticancer drug along with time going and the increase of drug concentration. It was found that the cell viability of MMTS was decreased after treatment with anticancer drugs, which was similar to monolayer culture. However, the inhibition rate of cell viability in MMTS was much lower than that in monolayer cuhure.MC showed the strongest cytotoxicity in beth MMTS and monolayer; followed by 5-FU and ADM. ③ MMTS was more sensitive to anticancer drug with the increasing oxygen concentration of environment. CONCLUSION: It is concluded that the MMTS has the potential to be a rapid and valid in vitro model to screen chemotherapeutic drugs with a feature to mimic in vivo three-dimensional (3-D) cell growth pattern.
出处 《中国临床康复》 CSCD 北大核心 2006年第17期72-75,i0004,共5页 Chinese Journal of Clinical Rehabilitation
基金 科技部"九七三"项目(2002CB713804) 国家自然科学基金项目(20236040)~~
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