title: Synthesis of a macromolecular camptothecin conjugate with dual phase drug release.
abstract: A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t(1/2) = 2.2 +/- 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t(1/2) = 2.1 +/- 0.2 h, while the conjugate half-life was 14.2 +/- 1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.
authors: Laboratory of Molecular Bioengineering, Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: A V
authors: AV
authors: Yurkovetskiy
authors: A
authors: A
authors: Hiller
authors: S
authors: S
authors: Syed
authors: M
authors: M
authors: Yin
authors: X M
authors: XM
authors: Lu
authors: A J
authors: AJ
authors: Fischman
authors: M I
authors: MI
authors: Papisov
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000138:chemical synthesis / Q000627:therapeutic use; D004355:Drug Stability; D005998:Glycine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000627:therapeutic use; D006801:Humans; D046911:Macromolecular Substances / Q000138:chemical synthesis / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D046911:Macromolecular Substances; D005998:Glycine; D002166:Camptothecin