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

Citations Over TimeTop 10% of 2008 papers

Abstract

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.

Related Papers

• → Irinotecan and its active metabolite, SN‐38: review of bioanalytical methods and recent update from clinical pharmacology perspectives(2009)173 cited
• → 956 Pharmacokinetics and interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients(1995)6 cited
• → Passage of irinotecan and its active metabolite, SN-38, into human milk(2016)
• → Abstract 4042: N-121, a novel polypeptide conjugate of SN-38, demonstrated enhanced intratumoral accumulation and sustained release of free SN-38 with potent antitumor activity(2017)
• → Comparative Dft Studies of Cytotoxicity of Camptothecin, Irinotecan and Sn-38(2022)