Zhang J Allen, Xuan Tong, Parmar Manjeet, Ma Lan, Ugwu Sydney, Ali Shahid, Ahmad Imran
Research & Development, NeoPharm, Inc., Waukegan, IL 60085, USA.
Int J Pharm. 2004 Feb 11;270(1-2):93-107. doi: 10.1016/j.ijpharm.2003.10.015.
SN-38, 7-ethyl-10-hydroxycamptothecin, is the active metabolite of Irinotecan (CPT-11), a topoisomerase I inhibitor commercially available as Camptosar. SN-38 is approximately 200-2000-fold more cytotoxic than CPT-11. Despite its promising anticancer potential, SN-38 thus far has not been used as an anticancer drug due to its poor solubility in any pharmaceutically acceptable solvents. In addition, SN-38 has low affinity to lipid membranes; it tends to precipitate in aqueous phase resulting in a very low drug-to-liposome entrapment. SN-38 also reversibly converts to an inactive open lactone ring structure at physiological pH. We have developed a novel, liposome-based SN-38 formulation (LE-SN-38). The formulation contains liposomes of uniform size distribution (<200nm), and it is easy-to-use. Drug entrapment efficiency of the formulation is >95%. Long-term stability studies indicate that the lyophilized LE-SN-38 is physically and chemically stable for at least 6 months at 2-8 degrees C. In preclinical studies, LE-SN38 has shown promising results in terms of increased cytotoxicity against various tumor cell lines and better therapeutic efficacy towards xenograft mouse models compared to CPT-11.
SN-38，即7-乙基-10-羟基喜树碱，是伊立替康（CPT-11）的活性代谢产物，伊立替康是一种拓扑异构酶I抑制剂，商品名为开普拓。SN-38的细胞毒性比CPT-11高约200-2000倍。尽管SN-38具有潜在的抗癌前景，但由于其在任何药学可接受溶剂中的溶解度较差，迄今为止尚未用作抗癌药物。此外，SN-38对脂质膜的亲和力较低；它倾向于在水相中沉淀，导致药物与脂质体的包封率非常低。SN-38在生理pH值下也会可逆地转化为无活性的开环内酯结构。我们开发了一种新型的基于脂质体的SN-38制剂（LE-SN-38）。该制剂包含尺寸分布均匀（<200nm）的脂质体，且易于使用。该制剂的药物包封效率>95%。长期稳定性研究表明，冻干的LE-SN-38在2-8℃下至少6个月在物理和化学上是稳定的。在临床前研究中，与CPT-11相比，LE-SN38在对各种肿瘤细胞系的细胞毒性增加以及对异种移植小鼠模型的治疗效果更好方面显示出有希望的结果。
