Camptothecin delivery systems: enhanced efficacy and tumor accumulation of camptothecin following its conjugation to polyethylene glycol via a glycine linker

Purpose: 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 t(1/2 alpha) of approximately 6 min and a t(1/2 beta) 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. Conclusion: This soluble transport form of CPT and its underlying technology may have clinical application especially for the treatment of solid tumors.