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 space rs in polyethylene glycol (PEG) conjugated camptothecin for their impact on the conjugates' antitumor activity, Secondly, an active member of this ser ies was used to assess the PEG-camptothecin conjugate's efficacy against a battery of solid tumor types, PEG-camptothecin is a novel water soluble tra nsport form (macromolecular prodrug) of the naturally derived antitumor dru g, 20-(S)-camptothecin (CPT), Rates of hydrolysis were studied in phosphate buffered saline (PBS) and the plasma of both rats and humans. In vivo effi cacy 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 va ried in both rat and human plasma according: to the amino acid spacer emplo yed. Not surprisingly, changing the amino acid also affected in vivo toxici ty and efficacy in the treatment of ascites and solid tumors, A representat ive of this amino acid series, PEG-alanine-CPT, which showed moderate activ ity in the solid tumor screen, was chosen for evaluation of efficacy across a wide range of solid tumor types and demonstrated significant antitumor a ctivity (%TIC < 30%) in all tested xenograft models (colon, ovarian, mammar y, lung, pancreatic and prostate). Therefore, this study showed that the us e of specific amino acid spacers affected both the PEG-camptothecin conjuga tes' breakdown and biological activity. We anticipate that using these insi ghts, this soluble macromolecular transport technology could be successfull y employed with a number of antitumor drugs.