在制药工业和学术界已经有许多尝试通过与大分子缀合来改善抗肿瘤小分子药物的药代动力学特征,如单克隆抗体,叫做ADC。在这种情况下,白蛋白,血液中最丰富的蛋白质之一,还提出了作为与抗癌小分子药物缀合的大分子。人体内白蛋白的半衰期为3周,其在肿瘤中的分布高于正常组织。然而,对体内制备的白蛋白-药物缀合物进行了很少的研究,可能是由于缺乏强大的生物分析方法,这对于评估体内制备的白蛋白-药物缀合物的ADME/PK性质至关重要。在这项研究中,我们开发了白蛋白结合的MAC葡糖苷酸苯酚连接的SN-38的生物分析方法((2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]吲哚并[1,2-b]喹啉-9-基)氧基)甲基)(2-(2(甲基磺酰基)乙基)氨基甲酰基)氧基)甲基)-2-(2-(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-N-甲基丙酰胺基)乙酰氨基)-苯氧基-3,5-三羟基该方法基于使用磁珠的免疫沉淀和使用小鼠血浆中的LC-qTOF/MS的白蛋白缀合的药物浓度的定量。最后,所开发的方法适用于MAC葡糖苷酸苯酚连接的SN-38的体内静脉(IV)小鼠药代动力学研究。
There have been many attempts in pharmaceutical industries and academia to improve the pharmacokinetic characteristics of anti-tumor small-molecule drugs by conjugating them with large molecules, such as monoclonal antibodies, called ADCs. In this context, albumin, one of the most abundant proteins in the blood, has also been proposed as a large molecule to be conjugated with anti-cancer small-molecule drugs. The half-life of albumin is 3 weeks in humans, and its distribution to tumors is higher than in normal tissues. However, few studies have been conducted for the in vivo prepared albumin-drug conjugates, possibly due to the lack of robust bioanalytical methods, which are critical for evaluating the ADME/PK properties of in vivo prepared albumin-drug conjugates. In this
study, we developed a bioanalytical method of the albumin-conjugated MAC glucuronide phenol linked SN-38 ((2S,3S,4S,5R,6S)-6-(4-(((((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano [3\',4\':6,7] indolizino [1,2-b] quinolin-9-yl)oxy)methyl)(2 (methylsulfonyl)ethyl)carbamoyl)oxy)methyl)-2-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methylpropanamido)acetamido)phenoxy)-3,4,5-trihydroxytetra-hydro-2H-pyran-2-carboxylic acid) as a proof-of-concept. This method is based on
immunoprecipitation using magnetic beads and the quantification of albumin-conjugated drug concentration using LC-qTOF/MS in mouse plasma. Finally, the developed method was applied to the in vivo intravenous (IV) mouse pharmacokinetic
study of MAC glucuronide phenol-linked SN-38.