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Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite, SN-38. Unfortunately, the limited utility of irinotecan is attributed to its pH-dependent stability, short half-life and dose-limiting toxicity. To address this problem, a novel trivalent PEGylated prodrug (PEG-[Irinotecan]3) has been synthesized and its full-profile pharmacokinetics, antitumor activity and toxicity compared with those of irinotecan. The results show that after intravenous administration to rats, PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3‒x (x = 1,2) and PEG-[linker] during which time the released irinotecan undergoes conversion to SN-38. As compared with conventional irinotecan, PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life. In a colorectal cancer-bearing model in nude mice, the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan. In summary, PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan. This supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phase II trial stage.
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Accurate tumor targeting, deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine. To achieve these requirements, a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer (d-SN38)-loaded nanoparticles (d-SN38@NPs/iRGD). Upon intravenous injection, d-SN38@NPs with high drug loading efficiency (33.92 ± 1.33%) could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD. The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy. The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm, which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor.
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Objective To develop an HPLC method for the simultaneous determination of 7-ethyl-10-hydroxycamptothecin-10-palmitic acid ester(SN38-PA)and its active metabolite 7-ethyl-10-hydroxycamptothecin(SN38)in rat plasma. Methods The inter standard was 10-hydroxycamptothecin. The protein in plasma was precipitated with methanol after acidification with formic acid. SN38-PA and SN38 were separated on Agilent C18 column(4.6 mm×250 mm,5μm) with gradient elution by using the mobile phase of methanol-0.2% formic acid solution. The flow rate was 1 ml/min. The detection wavelength was set at 372 nm. The column temperature was maintained at 30℃. Results The linear ranges for SN38-PA and SN38 were 0.25-62.5(r=0.9998) and 0.05-12.5 μg/ml (r=0.9997) respectively. The limits of quantification were 0.18 and 0.04 μg/ml, respectively. The average relative recovery of SN38-PA and SN38 were 95.89% and 97.03%. The average absolutely recovery of SN38-PA and SN38 were 99.54% and 99.84%. The RSD for intra-day and inter-day were both less than 3%. Conclusion The method is fast, convenient, accurate and sensitive, so it can be used for determination of SN38-PA and SN38 in vivo.
RESUMEN
Objective To develop an HPLC method for the simultaneous determination of 7-ethyl-10-hydroxycamptothecin- 10-palmitic acid ester(SN38-PA)and its active metabolite 7-ethyl-10-hydroxycamptothecin(SN38 Min rat plasma. Methods The inter standard was 10-hydroxycamptothecin. The protein in plasma was precipitated with methanol after acidification with formic acid. SN38-PA and SN38 were separated on Agilent C18 column (4.6 mmx250 mm, 5 µm) with gradient elution by using the mobile phase of methanol-0.2% formic acid solution. The flow rate was l µg/min. The detection wavelength was set at 372 nm. The column temperature was maintained at 30°C. Results The linear ranges for SN38-PA and SN38 were 0.25-62.5(r=0.9998) and 0.05- 12.5 µg/ml (r =0.9997) respectively. The limits of quantification were 0.18 and 0.04 µg/ml, respectively. The average relative recovery of SN38-PA and SN38 were 95.89% and 97.03%. The average absolutely recovery of SN38-PA and SN38 were 99.54% and 99.84%. The RSD for intra-day and inter-day were both less than 3%. Conclusion The method is fast, convenient, accurate and sensitive, so it can be used for determination of SN38-PA and SN38 in vivo.
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OBJECTIVE: To develop an LC-MS/MS method for determination of irinotecanin nanoparticles and its metabolite SN-38 in rats whole blood. METHODS: The drugs were using liquid-liquid extraction method in rats of whole blood, with diazepam as an internal standard. The Shim-pack XR-ODS (2.0 mm×100 mm, 2.2 μm) column was used. The gradient mobile phase consisted of 5 mmol·mL-1 ammonium formates solution (A) and Acetonitrile (B) at the flow rate of 0.3 mL·mL-1, the injection volume was 10 μL and the column temperature was 35°C. The total time of the analysis was 4.2 min. Electrospray ionization sourceand selective ion monitoringwere employed. RESULTS: The linear ranges of irinotecan and SN-38 were 1-2000 and 0.5-100 ng·mL-1, respectively; lower limit of quantification (LLOQ) was 1 and 0.5 ng·mL-1, respectively; the intra-batch RSD were less than 9.43% and 11.39%, respectively, the inter-batch RSD were less than 9.73% and 11.79%, respectively. The extraction recoveries were 73.7%-117.4% and 61.7%-75.5%, respectively. CONCLUSION: The method had less interference and is sensitive, accurate for the determination of irinotecan and its metabolite SN-38 in the whole blood of rats.
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OBJECTIVE: To study pharmacokinetics of irinotecan and its metabolite SN-38 in rats after administration of irinotecan and thalidomide.METHODS: Healthy male SD rats were randomized to given 10 mg?kg-1 irinotecan and 20 mg?kg-1 irinotecan (control group) or irinotecan combined with 20 mg?kg-1 thalidomide (trial group).Blood samples were collected at 0.083 h,0.5 h,1.0 h,2.0 h,4.0 h,6.0 h,8.0 h,10 h and 12 h after medication.The plasma concentrations of irinotecan and SN-38 were determined and pharmacokinetic parameters were calculated using DASver2.0 software.RESULTS: As compared with control group,AUC0～t and Cmax of irinotecan in 10 mg?kg-1 irinotecan trial group were increased significantly (P