Maleimide-oligo(ethylene glycol) derivatives of camptothecin as albumin-binding prodrugs: synthesis and antitumor efficacy.
In situ binding of thiol-reactive prodrugs to the cysteine-34 position of circulating albumin is a new approach in drug delivery. Therefore, five maleimide-bearing derivatives of the anticancer drug camptothecin (CPT) were developed as albumin-binding prodrugs. These compounds were synthesized by reacting heterobifunctional cross-linkers based on oligo(ethylene glycols) [3-6 (O-CH(2)-CH(2)) units] bearing a maleimide group on one end and a carboxylic acid group on the other with camptothecin 20-O-glycinate. Incorporating oligo(ethylene glycol) chains into the prodrugs enhanced their water-solubility when compared to the parent compound (up to 27-fold). HPLC studies showed that the prodrugs react almost quantitatively with the cysteine-34 position of endogenous albumin within a few minutes after incubation of the CPT derivatives with human blood plasma. The therapeutic potential of two of the prodrugs was assessed in nude mice bearing a colon xenograft (HT-29). Both albumin-binding derivatives of camptothecin were well-tolerated and showed enhanced antitumor efficacy when compared to CPT.
Warnecke
André
A
Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany.
Kratz
Felix
F
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D003432:Cross-Linking Reagents; D005026:Ethylene Glycols / Q000737:chemistry*; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008301:Maleimides / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet; D014183:Transplantation, Heterologous
D000972:Antineoplastic Agents, Phytogenic; D003432:Cross-Linking Reagents; D005026:Ethylene Glycols; D007202:Indicators and Reagents; D008301:Maleimides; D011355:Prodrugs; D012709:Serum Albumin; D012997:Solvents; C478641:maleimide-oligo(ethylene glycol); D002166:Camptothecin