Novel Prodrugs of SN38 Using Multiarm Poly(ethylene glycol) Linkers

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• 作者：Hong Zhao ; Belen Rubio ; Puja Sapra ; Dechun Wu ; Prasanna Reddy ; Prakash Sai ; Anthony Martinez ; Ying Gao ; Yoany Lozanguiez ; Clifford Longley ; Lee M. Greenberger ; Ivan D. Horak
• 刊名：Bioconjugate Chemistry
• 出版年：2008
• 出版时间：April 2008
• 年：2008
• 卷：19
• 期：4
• 页码：849 - 859
• 全文大小：522K
• 年卷期：v.19,no.4(April 2008)
• ISSN：1520-4812

文摘

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.