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目的:制备促黄体激素释放激素-甲氨蝶呤(LH-RH-MTX)并考察其对表达有促黄体激素释放激素(LH-RH)受体的肿瘤细胞的毒性作用。方法:以临床抗恶性肿瘤药物甲氨蝶呤(MTX)为模型药物,以促黄体激素释放激素[D-Lys6]LH-RH为导向物,通过共价键连接制备LH-RH-MTX。应用MTT法分别考察游离MTX和LH-RH-MTX对鼻咽癌HNE-1及前列腺癌PC-3细胞株的细胞毒性作用。结果:MTT法结果表明游离MTX和LH-RH-MTX对2种细胞株均有生长抑制作用,对前列腺癌PC-3细胞的抑制率大于鼻咽癌HNE-1细胞;给药12h后抑制率达到最大;当药物质量浓度为200.0μg.L-1,作用12h后:LH-RH-MTX对前列腺癌PC-3细胞的抑制率可高达97.73%,游离MTX为49.90%;LH-RH-MTX对鼻咽癌HNE-1细胞的抑制率为38.92%,游离MTX为7.41%;在同一种细胞株上,LH-RH-MTX的IC50值小于游离MTX。结论:经过短肽修饰的化合物LH-RH-MTX可与表达有LH-RH受体的肿瘤细胞特异性结合并发挥抑制作用,抗肿瘤活性高于游离MTX。提示用LH-RH作为TDDS的导向物,实现药物的靶向释放,提高药物生物利用度是可行的。
OBJECTIVE: To prepare luteinizing hormone-releasing hormone-methotrexate (LH-RH-MTX) and investigate its toxic effect on tumor cells expressing luteinizing hormone releasing hormone (LH-RH) receptor. Methods: Methotrexate (MTX) was used as a model drug and LH-RH-MTX was covalently linked with luteinizing hormone releasing hormone [D-Lys6] LH-RH. The cytotoxicity of free MTX and LH-RH-MTX on the HNE-1 NPC and PC-3 prostate cancer cell lines were investigated by MTT assay. Results: The results of MTT assay showed that both MTX and LH-RH-MTX had inhibitory effects on both cell lines and the inhibitory rate of prostate cancer PC-3 cells was higher than that of HNE-1 cells. After 12h administration, the inhibition rate The maximum inhibitory rate of LH-RH-MTX on prostate cancer PC-3 cells was 97.73% and the free MTX was 49.90% when the drug concentration was 200.0μg.L-1 for 12h. LH-RH-MTX The inhibitory rate of HNE-1 cells was 38.92% and the free MTX was 7.41%. The IC50 of LH-RH-MTX was less than that of free MTX on the same cell line. CONCLUSION: The short peptide-modified compound LH-RH-MTX can specifically bind to LH-RH receptor-expressing tumor cells and exert inhibitory effect, with higher antitumor activity than free MTX. It is feasible to use LH-RH as the guide of TDDS to achieve the targeted release of drugs and improve the bioavailability of drugs.