Novel prodrugs of SN38 using multiarm poly(ethylene glycol) linkers
Novel prodrugs of SN38 using multiarm poly(ethylene glycol) linkers
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DOI：
10.1021/bc700333s
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发表时间：
2008-04-01
影响因子：
4.7
通讯作者：
Horak, Ivan D.
中科院分区：
文献类型：
--
作者：
Zhao, Hong;Rubio, Belen;Horak, Ivan D.
CPT-11，也称为伊立替康，是一种被批准用于治疗晚期结直肠癌的前药。CPT-11的活性代谢产物SN 38（7-乙基-10-羟基-喜树碱）在组织细胞培养中的细胞毒活性是CPT-11的100- 1000倍。然而，SN 38的肠胃外给药是不可能的，因为其固有的水溶性差。据报道，已成功制备了与四个SN 38分子连接的多臂聚乙二醇（PEG）骨架（PEG-SN 38），具有高载药量和显着改善的水溶性（增加400至1000倍）。已经开发了三种不同的保护策略，以选择性地酰化SN 38的20-OH，从而在仍然连接PEG的同时以内酯形式（具有细胞毒性活性的SN 38的活性形式）保留其E-环。已经优化了一种化学方法，以高产率制备大量的PEG-SN 38缀合物，其可以容易地适用于放大生产。PEG-SN 38缀合物在一组癌细胞系中显示出优异的体外抗癌活性，其效力与天然SN 38的效力相似。与CPT-11相比，PEG-SN 38缀合物在MX-1异种移植小鼠模型中也显示出上级抗癌活性。在四种缀合物中，已选择PEG-Gly-（20）-SN 38（23）作为进一步临床前开发的主要候选物。
CPT-11, also known as irinotecan, is a prodrug that is approved for the treatment of advanced colorectal cancer. The active metabolite of CPT-11, SN38 (7-ethyl-10-hydroxy-camptothecin), has 100- to 1000-fold more potent cytotoxic activity in tissue cell culture compared with CPT-11. However, parental administration of SN38 is not possible because of its inherently poor water solubility. It is reported here that a multiarm poly(ethylene glycol) (PEG) backbone linked to four SN38 molecules (PEG-SN38) has been successfully prepared with high drug loading and significantly improved water solubility (400-to 1000-fold increase). Three different protecting strategies have been developed in order to selectively acylate the 20-OH of SN38 to preserve its E-ring in the lactone form (the active form of SN38 with cytotoxic activities) while PEG is still attached. One chemical process has been optimized to make a large quantity of the PEG-SN38 conjugate with a high yield that can be readily adapted for scale-up production. The PEG-SN38 conjugates have shown excellent in vitro anticancer activity, with potency similar to that of native SN38, in a panel of cancer cell lines. The PEG-SN38 conjugates also have demonstrated superior anticancer activity in the MX-1 xenograft mice model compared with CPT-11. Among the four conjugates, PEG-Gly-(20)-SN38 (23) has been selected as the lead candidate for further preclinical development.