Senadheera Sanjeewa N, Zhang Ti, Groer Chad E, Forrest M Laird
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA.
HylaPharm LLC, Lawrence, KS 66047, USA.
Eur J Med Chem. 2017 Aug 18;136:452-456. doi: 10.1016/j.ejmech.2017.05.020. Epub 2017 May 6.
A new pH-activated polymer chelate of cisplatin was synthesized using a scalable and green aqueous technique. Synthesis of the chelate was based on formation of a 6-member ring of platinum(II) with acetyl-homo-Lysine (Ac-homo-Lys), which was accomplished under completely aqueous conditions using a traceless photocleavable protection chemistry. Synthesis preceded by, first, amidation of a photocaged homo-Ac-Lys with hyaluronic acid (HA) in water using a p-hydroxyphenacyl (pHP) group as the photoremovable protecting group, followed by reaction of cisplatin (diaqua form) in water to form the reversible chelate. Platinum drug release was pH rate controlled, with more rapid release (t 20 h) at acidic pH similar to the tumor microenvironment yet slower release (t 35 h) at normal physiological pH.
采用可扩展的绿色水相技术合成了一种新的顺铂pH活化聚合物螯合物。该螯合物的合成基于铂（II）与乙酰高赖氨酸（Ac-高赖氨酸）形成六元环，这是在完全水相条件下使用无痕光可裂解保护化学方法完成的。合成过程如下：首先，在水中使用对羟基苯甲酰基（pHP）作为光可去除保护基团，将光笼化的高乙酰赖氨酸与透明质酸（HA）进行酰胺化反应，然后在水中使顺铂（二水合物形式）反应形成可逆螯合物。铂类药物的释放受pH速率控制，在类似于肿瘤微环境的酸性pH下释放更快（t 20小时），而在正常生理pH下释放较慢（t 35小时）。
