Novel SN38 conjugate-forming nanoparticles as anticancer prodrug: In vitro and in vivo studies

The clinical utility of CPT-11 is restricted by factors such as the low conversion rate to SN38, high interpatient variability and dose-limiting toxicity. SN38 is significantly more potent than CPT-11, but parental administration of SN38 is impossible due to its poor solubility and low stability. This study aimed to develop a novel SN38 prodrug (OEG-SN38) that may overcome the various drawbacks of CPT-11 and SN38 and be useful for clinics. We attached a very low molecular weight oligo (ethylene glycol) (OEG) chain selected as the hydrophilic part to hydrophobic SN38 via ester bond at the C20 position to form the amphiphilic OEG-SN38. In aqueous solution OEG-SN38 formed micelles with diameter of 28.74 +/- 2.51 nm, and showed greatly improved drug loading, solubility and stability, with drug loading as high as 36% (wt.%). Moreover, these micelles were stable in PBS with only 4.71% SN38 released from the prodrug even after 35 h incubation, but released SN38 promptly by esterase hydrolysis. Most importantly, OEG-SN38 exhibited potent antitumor activity against a panel of human tumor cell lines, as well as favorable antitumor activity and high safety in human xenograft models. These encouraging data merit further preclinical and clinical investigation on this novel SN38 delivery system. (C) 2012 Elsevier B.V. All rights reserved.