Camptothecin delivery systems: enhanced efficacy and tumor accumulation of camptothecin following its conjugation to polyethylene glycol via a glycine linker.
OBJECTIVE
This study was designed to assess the circulatory retention, antitumor activity and tissue biodistribution of polyethylene glycol (PEG)-conjugated camptothecin-20-O-glycinate, PEG-beta-camptothecin (PEG-beta-CPT). PEG-beta-CPT is a novel water-soluble transport form (macromolecular prodrug) of the naturally derived antitumor drug, 20-(S)-camptothecin (CPT).


METHODS
Circulatory retention studies were performed in nontumor-bearing mice injected intravenously (i.v.) with 875 mg/kg of PEG-beta-CPT. Antitumor activity was evaluated both intraperitoneally (i.p.) and i.v. in nude mouse xenograft models. Biodistribution studies were performed in nude mice bearing colorectal carcinoma xenografts with tritium-labelled PEG-beta-CPT and CPT injected i.v.


RESULTS
PEG-beta-CPT had a blood t1/2alpha of approximately 6 min and a t1/2beta of 10.2 h. Significant antitumor activity was seen in all treated xenograft models. Biodistribution studies demonstrated that PEG-beta-CPT in saline provided more available labelled CPT in the circulation than unconjugated CPT dissolved in intralipid. In addition, it appeared that more labelled CPT accumulated in solid tumors when delivered in the PEG-beta-CPT form, with greater preference for tumor tissue than normal tissue.


CONCLUSIONS
This soluble transport form of CPT and its underlying technology may have clinical application especially for the treatment of solid tumors.
Research and Development, Enzon Inc., Piscataway, NJ 08854-3998, USA.
C D
CD
Conover
R B
RB
Greenwald
A
A
Pendri
C W
CW
Gilbert
K L
KL
Shum
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004337:Drug Carriers; D005998:Glycine / Q000737:chemistry; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution; D014316:Tritium
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D011355:Prodrugs; D014316:Tritium; D011092:Polyethylene Glycols; C115093:pegamotecan; D005998:Glycine; D002166:Camptothecin