CSIRO Materials Science and Engineering, 343 Royal Parade, Parkville, VIC 3052, Australia.
ChemMedChem. 2012 Feb 6;7(2):281-91. doi: 10.1002/cmdc.201100456. Epub 2011 Dec 5.
A series of well-defined polymer-drug conjugates were prepared in order to modify the physical properties of a known cytotoxic drug, 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan (CPT-11). Reversible addition-fragmentation chain transfer (RAFT) polymerisation was used to covalently and site-specifically append a defined N-(2-hydroxypropyl)methacrylamide (HPMA) polymer to SN-38 using a graft-from process. These poly-HPMA-SN-38 conjugates displayed excellent aqueous solubility and stability, whilst retaining the cytotoxic activity of the parent SN-38. In vitro co-culture assays containing both cancer and noncancer cell lines demonstrated the specificity of RAFT-derived poly-HPMA-SN-38 conjugates for cancerous cells. The concept of post-optimisation modification of small-molecule drugs through a graft-from polymer conjugation method is introduced.
为了修饰已知细胞毒性药物 7-乙基-10-羟基喜树碱（SN-38）的物理性质，即伊立替康（CPT-11）的活性代谢物，我们制备了一系列结构明确的聚合物-药物偶联物。采用可逆加成-断裂链转移（RAFT）聚合，通过“从枝到干”的过程，将特定数量的 N-（2-羟丙基）甲基丙烯酰胺（HPMA）聚合物共价且定点连接到 SN-38 上。这些聚 HPMA-SN-38 缀合物具有极好的水溶性和稳定性，同时保持了母体 SN-38 的细胞毒性活性。包含癌细胞和非癌细胞系的体外共培养试验表明，RAFT 衍生的聚 HPMA-SN-38 缀合物对癌细胞具有特异性。本文通过“从枝到干”的聚合物偶联方法，引入了对小分子药物进行后期优化修饰的概念。
