title: Novel prodrugs of SN38 using multiarm poly(ethylene glycol) linkers.
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.
authors: Enzon Pharmaceuticals, Inc., 20 Kingsbridge Road, Piscataway, New Jersey 08854, USA. hong.zhao@enzon.com
authors: Hong
authors: H
authors: Zhao
authors: Belen
authors: B
authors: Rubio
authors: Puja
authors: P
authors: Sapra
authors: Dechun
authors: D
authors: Wu
authors: Prasanna
authors: P
authors: Reddy
authors: Prakash
authors: P
authors: Sai
authors: Anthony
authors: A
authors: Martinez
authors: Ying
authors: Y
authors: Gao
authors: Yoany
authors: Y
authors: Lozanguiez
authors: Clifford
authors: C
authors: Longley
authors: Lee M
authors: LM
authors: Greenberger
authors: Ivan D
authors: ID
authors: Horak
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000077146:Irinotecan; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D012995:Solubility; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D011092:Polyethylene Glycols; D000077146:Irinotecan; D002166:Camptothecin