Synthesis, characterization, and antitumor evaluation of the albumin-SN38 conjugate
Synthesis, characterization, and antitumor evaluation of the albumin-SN38 conjugate
复制标题
白蛋白-SN38 缀合物的合成、表征和抗肿瘤评价
DOI：
10.1097/cad.0b013e32835c3543
复制
发表时间：
2013-03-01
影响因子：
2.3
通讯作者：
Yang, Jinliang
中科院分区：
文献类型：
--
作者：
Yao, Yuqin;Su, Xiaolan;Yang, Jinliang
7-乙基-10-羟基喜树碱 (SN38) 是伊立替康的活性代谢物，对多种肿瘤细胞系的作用比伊立替康本身高 100 倍至 1000 倍。然而SN38的水不溶性阻碍了其作为抗肿瘤药物直接应用于临床。为了提高水溶性和抗肿瘤功效，SN38 通过硫醇结合接头特异性地共价连接到 BSA 位点上半胱氨酸 34 上唯一的游离巯基，形成前药 BSA-SN38 缀合物（BSA : SN38 = 1 : 1）。使用当前方法，该缀合物的水溶性与白蛋白相似。此外，该缀合物中的 SN38 负载变得可控。对SDS-PAGE电泳产物进行尺寸排阻色谱纯化和UV表征。然后，通过MTT法测试该缀合物对5种结肠癌细胞系的体外抗肿瘤作用。 BSA-SN38 缀合物的 72h IC50 值范围为 1.5 至 6.1 mumol/l。建立小鼠结直肠腹膜癌模型以确定BSA-SN38缀合物的腹腔化疗效果。每 4 天施用 10 mg/kg/天的 SN38 等效剂量的 BSA-SN38 缀合物。操作后十八天，将小鼠安乐死，收集腹腔内的肿瘤并称重。 BSA-SN38缀合物治疗组中的肿瘤（m=0.21+/-0.15g）被发现明显（P=5）轻于NS对照组中的肿瘤（m=4.74+/-0.73g）。结果表明，这种水溶性BSA-SN38结合物对结直肠癌具有很强的抗肿瘤作用。抗癌药物 24:270-277 (C) 2013 Wolters Kluwer Health 垂直栏 Lippincott Williams & Wilkins。
7-Ethyl-10-hydroxycamptothecin (SN38), the active metabolite of irinotecan, exerts a 100-fold to 1000-fold higher effect than irinotecan itself against several tumor cell lines. However, the water insolubility of SN38 has prevented its direct use as an antitumor drug in the clinic. To improve the water solubility and antitumor efficacy, SN38 was covalently attached to the only free sulfhydryl at cysteine-34 on the BSA site specifically through a thiol-binding linker to form a prodrug BSA-SN38 conjugate (BSA : SN38 = 1 : 1). The water solubility of this conjugate was similar to albumin using the current method. Also, SN38 loading in this conjugate became controllable. Size-exclusion chromatography purification and UV characterization of the SDS-PAGE electrophoresis product were carried out. Then, an MTT assay was carried out to test the antitumor effect of this conjugate on five colon cancer cell lines in vitro. The 72h IC50 values of the BSA-SN38 conjugate ranged from 1.5 to 6.1 mu mol/l. A colorectal peritoneal carcinomatosis model in mice was established to determine the intraperitoneal chemotherapy effect of the BSA-SN38 conjugate. The BSA-SN38 conjugate at an SN38 equivalent dose of 10 mg/kg/day was administrated every 4 days. Eighteen days after manipulation, the mice were euthanized and the tumors in the abdominal cavity were collected and weighed. Tumors in the BSA-SN38 conjugate treatment group (m=0.21+/-0.15 g) were found to be significantly (P = 5) lighter than those in the NS control group (m=4.74+/-0.73 g). The results indicated that this water-soluble BSA-SN38 conjugate exerted a strong antitumor effect on colorectal carcinoma. Anti-Cancer Drugs 24:270-277 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.