摘要
目的 制备羟基喜树碱微粉（nHCPT）并考察其毒性和抗肿瘤活性。方法 本实验采用超临界流体抗溶剂法制备nHCPT，扫描电子显微镜（SEM）观察形态、原子力显微镜（AFM）检测其粒径。红外光谱（FTIR）和高效液相色谱确认nHCPT化学性质。气相色谱法测定nHCPT中残留DMSO含量。以HCPT和拓朴替原（TPT）为阳性对照，四甲基偶氮唑蓝（MTT）法检测nHCPT对PC-3、MCF-7和HCT-8细胞的生长抑制作用。显微操作系统观察HCT-8细胞对于nHCPT吸收。采用S180实体瘤模型，考察了nHCPT的抗肿瘤活性和对器官的毒性。结果 超临界处理后的nHCPT以无定型形态存在，粒径为（150±40）nm，形态为不规则球状结构，化学性质没有改变。nHCPT中残留DMSO含量符合ICH要求。样品在4 ℃、避光干燥条件下储存一个月后性质稳定。nHCPT对3种细胞株的抑制率略优于HCPT和TPT， nHCPT的细胞膜渗透能力较HCPT明显增强。nHCPT的体内抑瘤活性较HCPT明显提高，与TPT抑瘤活性相近，且对器官毒副作用明显低于TPT和HCPT。结论 nHCPT具有独特的优越性，可以作为进一步新制剂开发的原料药。
Abstract
OBJECTIVE To prepare micronized hydroxycamptothecin (nHCPT), and to investigate the antitumor activities and toxicity of nHCPT. METHODS Micronized hydroxycamptothecin was prepared using Supercritical Anti-Solvent Processis method (SAS). The morphology and the particle size of nHCPT were detected by SEM and AFM， respectively. The chemical properties of nHCPT were confirmed by FTIR and HPLC. The content of the residual DMSO was determined by GC analysis. The cytotoxicity on nHCPT on PC-3， MCF-7 and HCT-8 was evaluated by MTT method using HCPT and TPT as positive control， and the nHCPT uptakes by cultured HCT-8 cells were investigated by Micromanipulator System. The inhibition effect against tumors and the toxicity on organs of nHCPT were determined in sarcoma-180(S-180) bearing mice. RESULTS The particle size of nHCPT was (150±40) nm， and the morphology was irregularly spherical. nHCPT showed amorphous form， and the chemical properties was not changed. The residual DMSO content in nHCPT was less than the ICH limit. The samples were stable during storage at 4 ℃ and drying condition for a month in the dark. The inhibition rate of nHCPT was higher than HCPT and TPT on three kinds of tumor cells， and the ability of penetration into cell membrane was improved obviously compared with HCPT. nHCPT also exhibited superior antitumor activities compared with HCPT， which was similar to TPT. However， nHCPT had less toxicity than TPT and HCPT. CONCLUSION nHCPT had potential to become the drug material of new drug formulations due to it′s special characterization.
关键词
羟基喜树碱微粉 /
超临界抗溶剂法 /
抑瘤活性 /
毒性 /
拓朴替原
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Key words
micronized hydroxycamptothecin /
supercritical anti-solvent processes method /
antitumor activities /
toxicity /
topotecan
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李庆勇 刘晨 姚丽萍 赵修华 苏琳 高洋 祖元刚.
羟基喜树碱微粉的制备及抗肿瘤活性[J]. 中国药学杂志, 2010, 45(23): 1831-1836
LI Qing-yong;LIU Chen;YO Li-ping;ZHO Xiu-hu;SU Lin;GO Yng;ZU Yun-gng.
Preparation and Antitumor Activities of Micronized Hydroxycamptothecin[J]. Chinese Pharmaceutical Journal, 2010, 45(23): 1831-1836
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