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Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity.

Liu Y, Piao H, Gao Y, Xu C, Tian Y, Wang L, Liu J, Tang B, Zou M, Cheng G - Int J Nanomedicine (2015)

Bottom Line: A larger AUC0-24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 (P<0.05).Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model.In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C20-OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People's Republic of China.

ABSTRACT
7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C10-OH)SN38 and chitosan-(C20-OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C10-OH)SN38 (CS-(10s)SN38) and chitosan-(C20-OH) SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC)0-24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P<0.01). A larger AUC0-24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 (P<0.05). Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg (P<0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C20-OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.

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Plasma concentrations of SN38 after intravenous administration of 10 mg/kg CS-(10s)SN38, CS-(20s)SN38, and CPT-11.Notes: All preparations were equivalent to SN38; data are shown as mean ± standard deviation; n=6.Abbreviations: CS-(10s)SN38, chitosan-(C10-OH)SN38; CS-(20s)SN38, chitosan-(C20-OH)SN38; SN38, 7-Ethyl-10-hydroxycamptothecin.
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f10-ijn-10-2295: Plasma concentrations of SN38 after intravenous administration of 10 mg/kg CS-(10s)SN38, CS-(20s)SN38, and CPT-11.Notes: All preparations were equivalent to SN38; data are shown as mean ± standard deviation; n=6.Abbreviations: CS-(10s)SN38, chitosan-(C10-OH)SN38; CS-(20s)SN38, chitosan-(C20-OH)SN38; SN38, 7-Ethyl-10-hydroxycamptothecin.

Mentions: The mean plasma concentration–time curves of SN38 after intravenous administration of the macromolecular prodrug micelles and CPT-11 are shown in Figure 10. The pharmacokinetic parameters of SN38 were calculated using noncompartmental analysis with DAS 2.0 software (Table 2). The area under the curve (AUC)0–24 values of free SN38 after intravenous administration of CS-(10s)SN38 and CS-(20s)SN38 were 7,011.18±969.76 μg·h/L and 8,925.92±1,907.46 μg·h/L respectively, which were statistically insignificant (P>0.05). However, when compared with CPT-11, both AUC0–24 values were much higher than that of CPT-11 (P<0.05). For CS-(10s)SN38 and CS-(20s)SN38, the half-life (T1/2) and mean residence time (MRT) of plasma SN38 were prolonged, while the renal clearance (CL) was reduced when compared with CPT-11 (P<0.05). The nonspecificity of hydrolysis could be an explanation for the higher conversion rate observed for SN38 of the prodrugs when compared with CPT-11. The AUC0–24 for free SN38 of CS-(10s)SN38 was slightly higher than that of CS-(20s)SN38, which might be due to the faster release of SN38 from CS-(10s)SN38 in plasma. The lactone form of SN38 is necessary for topoisomerase inhibition, and the determination of lactone form of SN38 is valuable for macromolecular prodrug study. We would like to discuss the percent of lactone form of SN38 in vivo in our future work.


Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity.

Liu Y, Piao H, Gao Y, Xu C, Tian Y, Wang L, Liu J, Tang B, Zou M, Cheng G - Int J Nanomedicine (2015)

Plasma concentrations of SN38 after intravenous administration of 10 mg/kg CS-(10s)SN38, CS-(20s)SN38, and CPT-11.Notes: All preparations were equivalent to SN38; data are shown as mean ± standard deviation; n=6.Abbreviations: CS-(10s)SN38, chitosan-(C10-OH)SN38; CS-(20s)SN38, chitosan-(C20-OH)SN38; SN38, 7-Ethyl-10-hydroxycamptothecin.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4376263&req=5

f10-ijn-10-2295: Plasma concentrations of SN38 after intravenous administration of 10 mg/kg CS-(10s)SN38, CS-(20s)SN38, and CPT-11.Notes: All preparations were equivalent to SN38; data are shown as mean ± standard deviation; n=6.Abbreviations: CS-(10s)SN38, chitosan-(C10-OH)SN38; CS-(20s)SN38, chitosan-(C20-OH)SN38; SN38, 7-Ethyl-10-hydroxycamptothecin.
Mentions: The mean plasma concentration–time curves of SN38 after intravenous administration of the macromolecular prodrug micelles and CPT-11 are shown in Figure 10. The pharmacokinetic parameters of SN38 were calculated using noncompartmental analysis with DAS 2.0 software (Table 2). The area under the curve (AUC)0–24 values of free SN38 after intravenous administration of CS-(10s)SN38 and CS-(20s)SN38 were 7,011.18±969.76 μg·h/L and 8,925.92±1,907.46 μg·h/L respectively, which were statistically insignificant (P>0.05). However, when compared with CPT-11, both AUC0–24 values were much higher than that of CPT-11 (P<0.05). For CS-(10s)SN38 and CS-(20s)SN38, the half-life (T1/2) and mean residence time (MRT) of plasma SN38 were prolonged, while the renal clearance (CL) was reduced when compared with CPT-11 (P<0.05). The nonspecificity of hydrolysis could be an explanation for the higher conversion rate observed for SN38 of the prodrugs when compared with CPT-11. The AUC0–24 for free SN38 of CS-(10s)SN38 was slightly higher than that of CS-(20s)SN38, which might be due to the faster release of SN38 from CS-(10s)SN38 in plasma. The lactone form of SN38 is necessary for topoisomerase inhibition, and the determination of lactone form of SN38 is valuable for macromolecular prodrug study. We would like to discuss the percent of lactone form of SN38 in vivo in our future work.

Bottom Line: A larger AUC0-24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 (P<0.05).Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model.In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C20-OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People's Republic of China.

ABSTRACT
7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C10-OH)SN38 and chitosan-(C20-OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C10-OH)SN38 (CS-(10s)SN38) and chitosan-(C20-OH) SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC)0-24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P<0.01). A larger AUC0-24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 (P<0.05). Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg (P<0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C20-OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.

No MeSH data available.


Related in: MedlinePlus