Novel SN38Conjugate-forming Nanoparticles As Anticancer Prodrug:Synthesis, Characterization And Anticancer Studies

Purpose:CPT-11(irinotecan or7-ethyl-10[4-(1-piperidino)-1-piperidino]-carbonyloxy camptothecin) is a commonly used chemotherapeutic drug, which acts primarily by inhibiting the nuclear enzyme topoisomerase I. However, the clinical utility of CPT-11is significantly restricted by factors such as the low conversion rate (mainly2-8%) to SN38by human carboxylesterase (hCE), high interpatient variability, and severe dose-limiting toxicities (e.g. diarrhea, myelosupression) etc. SN38, the active metabolite of CPT-11, is several hundreds to1,000-fold more potent in vitro compared with CPT-11, but direct use of SN38in clinic is impossible due to its extremely low water solubility in any physiologically compatible and pharmaceutically acceptable solvents. This study aimed to develop a novel SN38prodrug with high therapeutic efficacy but low side toxicity that may overcome the various drawbacks of CPT-11and reported SN38-incorporating nanodrugs and may have the potential for clinical applicaton.Experimental Design:A very low molecular weight Oligo (ethylene glycol)(OEG) chain selected as the hydrophilic part was attached to SN38via ester bond at the C20position of SN38to form the amphiphilic OEG-SN38. This molecular is expected to form micelle spontaneously in aqueous solution. Besides, sulfer atom was introduced onto the linker between SN38and OEG to utilize the oxidant response to liberate SN38in addition to esterase-promoted release. The physiochemical properties, cellular uptake, preclinical antitumor activity and acute toxicity of OEG-SN38were all carefully investigated.Results:OEG-SN38formed micelle in aqueous solution with diameter around37nm, and had greatly improved solubility and stability of SN38, with drug loading so high as36%, which is significantly higher than all other reported SN-38-containing drug delivery systems. Besides, OEG-SN38was quite stable in physiological conditions (PBS, pH=7.4), but released SN38promptly in an oxidant-responsive manner. OEG-SN38showed significantly potent antitumor activity in vitro, comparable to free SN38but far better than CPT-11, against a large panel of human tumor cell lines, and exhibited favorable antitumor activity and high safety in animal models.Conclusions:We have successfully prepared a novel OEG-SN38conjugate with high purity as a promising SN38prodrug, which has extremely high and stable drug loading, releases SN38in a controlled manner, and exhibits excellent antitumor activities and high safety in vivo. This novel SN38-conjugate would overcome the various drawbacks of free SN38, such as low water solubility, low bioavailability and poor stability, etc. It may also overcome the various disadvantages of CPT-11in drug activation, metabolism and elimination in vivo. In brief, OEG-SN38is a novel and promising antitumor agent, deserves further studies and may have the potential for clinical application.