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

Yi Liu,1 Hongyu Piao,1 Ying Gao,1 Caihong Xu,2 Ye Tian,1 Lihong Wang,1 Jinwen Liu,1 Bo Tang,1 Meijuan Zou,1 Gang Cheng1 1Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People’s Republic of China; 2Department of Food Science, Shenyang Normal...

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Autores principales:	Liu Y, Piao HY, Gao Y, Xu CH, Tian Y, Wang LH, Liu JW, Tang B, Zou MJ, Cheng G
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2015
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/118bc3a84f5549d28a9a563378cbf723
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spelling	oai:doaj.org-article:118bc3a84f5549d28a9a563378cbf7232021-12-02T00:53:28ZComparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity1178-2013https://doaj.org/article/118bc3a84f5549d28a9a563378cbf7232015-03-01T00:00:00Zhttp://www.dovepress.com/comparison-of-two-self-assembled-macromolecular-prodrug-micelles-with--peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013 Yi Liu,1 Hongyu Piao,1 Ying Gao,1 Caihong Xu,2 Ye Tian,1 Lihong Wang,1 Jinwen Liu,1 Bo Tang,1 Meijuan Zou,1 Gang Cheng1 1Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People’s Republic of China; 2Department of Food Science, Shenyang Normal 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. Keywords: self-assembled prodrug micelles, in vitro cytotoxicity, pharmacokinetics, in vivo antitumor activity Liu YPiao HYGao YXu CHTian YWang LHLiu JWTang BZou MJCheng GDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2015, Iss default, Pp 2295-2311 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Liu Y Piao HY Gao Y Xu CH Tian Y Wang LH Liu JW Tang B Zou MJ Cheng G Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity
description	Yi Liu,1 Hongyu Piao,1 Ying Gao,1 Caihong Xu,2 Ye Tian,1 Lihong Wang,1 Jinwen Liu,1 Bo Tang,1 Meijuan Zou,1 Gang Cheng1 1Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People’s Republic of China; 2Department of Food Science, Shenyang Normal 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. Keywords: self-assembled prodrug micelles, in vitro cytotoxicity, pharmacokinetics, in vivo antitumor activity
format	article
author	Liu Y Piao HY Gao Y Xu CH Tian Y Wang LH Liu JW Tang B Zou MJ Cheng G
author_facet	Liu Y Piao HY Gao Y Xu CH Tian Y Wang LH Liu JW Tang B Zou MJ Cheng G
author_sort	Liu Y
title	Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity
title_short	Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity
title_full	Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity
title_fullStr	Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity
title_full_unstemmed	Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity
title_sort	comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of sn38 for enhancing antitumor activity
publisher	Dove Medical Press
publishDate	2015
url	https://doaj.org/article/118bc3a84f5549d28a9a563378cbf723
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Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

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