抗体导向药物的研究——Ⅰ.以多聚谷氨酸为中介载体的抗体药物偶合物的制备

RESEARCH ON ANTIBODY TARGETED DRUGSⅠ. SYNTHESIS OF ANTIBODY-DRUG CONJUGATES WITH POLY-L-GLUTAMIC ACID AS AN INTERMEDIATE CARRIER

本文以多聚-L-谷氨酸(PLGA)为中介载体,将抗肿瘤药物丝裂霉素C、柔红霉素及阿霉素分别与抗胃癌单克隆抗体MGb_2偶联,研制抗体导向偶合物。为了避免多聚物的形成,我们采用了一种反应选择性的交联策略。首先于PLGA分子中引入一定数目的保护性巯基,制备PLGA衍生物(Ⅰ);在碳二亚胺作用下,丝裂霉素C、柔红霉素或阿霉素与(Ⅰ)缩合,得药物-PLGA缩合物(Ⅱ);然后以二硫苏糖醇还原脱保护,即得巯基化的药物-PLGA缩合物(Ⅲ);相应地,制备马来酰亚胺取代的抗体衍生物(Ⅳ);最后,(Ⅲ)分子中的巯基与(Ⅳ)分子中的马来酰亚胺基的双键进行反应,形成以硫醚键交联的抗体导向偶合物R-NH-PLGA-S-MGb_2(Ⅴ_(1～3))。

The antitumor agents mitomycin C,daunomycin and adriamycin were conjugated with a monoclonal antigastric cancer antibody,poly-L-glutamic acid(PLGA)being used as an intermediate carrier. Three antibody targeted conjugates were prepared. In order to avoid the polymerization of macromolecules,a reaction-selective-conjugating strategy was developed. With this strategy we first introduced a number of protected thiol grorps into PLGA. After coupling of the derivatized PLGA-drug conjugates were reacted with the maleimido group having being introduced into the antibody previously. Thus the antibody targeted conjugates R-NH-PLGA-S-MGb_2 (v_(1～3)were obtained.