Camptothecin delivery systems: the utility of amino acid spacers for the conjugation of camptothecin with polyethylene glycol to create prodrugs

The primary purpose of this study was to screen individual amino acid spacers in polyethylene glycol (PEG) conjugated camptothecin for their impact on the conjugates' antitumor activity. Secondly, an active member of this series was used to assess the PEG-camptothecin conjugate's efficacy against a battery of solid tumor types. PEG-camptothecin is a novel water soluble transport form (macromolecular prodrug) of the naturally derived antitumor drug, 20-(S)-camptothecin (CPT). Rates of hydrolysis were studied in phosphate buffered saline (PBS) and the plasma of both rats and humans. In vivo efficacy screens were performed against P388/0 murine leukemia and LS174T human colon solid tumor xenograft models. The results showed that while all the derivatives had considerable stability in PBS, their rates of hydrolysis varied in both rat and human plasma according to the amino acid spacer employed. Not surprisingly, changing the amino acid also affected in vivo toxicity and efficacy in the treatment of ascites and solid tumors. A representative of this amino acid series, PEG-alanine-CPT, which showed moderate activity in the solid tumor screen, was chosen for evaluation of efficacy across a wide range of solid tumor types and demonstrated significant antitumor activity (% T/C < 30%) in all tested xenograft models (colon, ovarian, mammary, lung, pancreatic and prostate). Therefore, this study showed that the use of specific amino acid spacers affected both the PEG-camptothecin conjugates' breakdown and biological activity. We anticipate that using these insights, this soluble macromolecular transport technology could be successfully employed with a number of antitumor drugs.