聚乙二醇-达沙替尼结合物的合成及初步药效研究

Synthesis and Preliminary Pharmacological Efficacy Study of PEG-dasatinib Conjugates

关键词:  达沙替尼  聚乙二醇-达沙替尼结合物  合成  药效

Key words:  dasatinib  PEG-dasatinib conjugate  synthesis  pharmacological efficacy

摘要:

目的 合成2种聚乙二醇-达沙替尼结合物（JK120303和JK120304），并评价结合物JK120303和JK120304在K562人慢性髓系白血病皮下瘤模型中的抗肿瘤作用。方法 将达沙替尼用缬氨酸衍生后分别和mPEG-二肽酸和4arm-PEG-乙酸反应得到聚乙二醇-达沙替尼结合物，于NOD/SCID小鼠右侧背部皮下接种K562细胞，建立人慢性髓系白血病异种移植动物皮下模型，根据相对肿瘤增殖率进行疗效评价。结果 合成得到2个聚乙二醇-达沙替尼结合物。结合物JK120303（2.5 mg·kg^-1和5 mg·kg^-1）的药效优于达沙替尼（5 mg·kg^-1），结合物JK120304（2.5 mg·kg^-1和5 mg·kg^-1）的药效与达沙替尼（5 mg·kg^-1）相当。结论 聚乙二醇-达沙替尼结合物JK120303药效优于达沙替尼，值得进一步研究。

Abstract:

OBJECTIVE To synthesis two PEG-dasatinib conjugates (JK120303 and JK120304) and get preliminary antitumor effect of these compounds in the K562 subcutaneous tumor model of human chronic myeloid leukemia. METHODS Dasatinib was derived with valine, then react with mPEG-dipeptide acid and 4arm-PEG-acetic acid to obtain PEG-dasatinib conjugates, K562 cells were inoculated subcutaneously in the right back of NOD/SCID mice to establish human chronic myeloid leukemia xenograft animal subcutaneous model, the curative effect was evaluated according to the relative tumor proliferation rate (T/C%). RESULTS Two PEG-dasatinib conjugates were synthesized, the efficacy of JK120303 (2.5 mg·kg^-1 and 5 mg·kg^-1) was better than that of dasatinib (5 mg·kg^-1) and the efficacy of JK120304 (2.5 mg·kg^-1 and 5 mg·kg^-1) was almost the same as that of dasatinib (5 mg·kg^-1). CONCLUSION The efficacy of PEG-dasatinib conjugate JK120303 is better than that of dasatinib and worth further study.