Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles

Dazhong Chen,1–3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. Keywords: combined therapy, cancer stem cells, liver cancer, doxorubicin, elacridar, nanoparticles Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Chen D [verfasserIn] Pan X [verfasserIn] Xie F [verfasserIn] Lu Y [verfasserIn] Zou H [verfasserIn] Yin C [verfasserIn] Zhang Y [verfasserIn] Gao J [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	combined therapy cancer stem cells liver cancer doxorubicin elacridar nanoparticles

Übergeordnetes Werk:	In: International Journal of Nanomedicine - Dove Medical Press, 2018, (2018), Seite 6855-6870
Übergeordnetes Werk:	year:2018 ; pages:6855-6870

Links:	Link aufrufen Link aufrufen Journal toc

Katalog-ID:	DOAJ075608839

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520			\|a Dazhong Chen,1–3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. Keywords: combined therapy, cancer stem cells, liver cancer, doxorubicin, elacridar, nanoparticles
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allfields	(DE-627)DOAJ075608839 (DE-599)DOAJ83b0153cf49548d5b7061f6c440a26e9 DE-627 ger DE-627 rakwb eng R5-920 Chen D verfasserin aut Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Dazhong Chen,1–3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. Keywords: combined therapy, cancer stem cells, liver cancer, doxorubicin, elacridar, nanoparticles combined therapy cancer stem cells liver cancer doxorubicin elacridar nanoparticles Medicine (General) Pan X verfasserin aut Xie F verfasserin aut Lu Y verfasserin aut Zou H verfasserin aut Yin C verfasserin aut Zhang Y verfasserin aut Gao J verfasserin aut In International Journal of Nanomedicine Dove Medical Press, 2018 (2018), Seite 6855-6870 (DE-627)537879560 (DE-600)2377464-2 11782013 nnns year:2018 pages:6855-6870 https://doaj.org/article/83b0153cf49548d5b7061f6c440a26e9 kostenfrei https://www.dovepress.com/codelivery-of-doxorubicin-and-elacridar-to-target-both-liver-cancer-ce-peer-reviewed-article-IJN kostenfrei https://doaj.org/toc/1178-2013 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 2018 6855-6870
spelling	(DE-627)DOAJ075608839 (DE-599)DOAJ83b0153cf49548d5b7061f6c440a26e9 DE-627 ger DE-627 rakwb eng R5-920 Chen D verfasserin aut Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Dazhong Chen,1–3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. Keywords: combined therapy, cancer stem cells, liver cancer, doxorubicin, elacridar, nanoparticles combined therapy cancer stem cells liver cancer doxorubicin elacridar nanoparticles Medicine (General) Pan X verfasserin aut Xie F verfasserin aut Lu Y verfasserin aut Zou H verfasserin aut Yin C verfasserin aut Zhang Y verfasserin aut Gao J verfasserin aut In International Journal of Nanomedicine Dove Medical Press, 2018 (2018), Seite 6855-6870 (DE-627)537879560 (DE-600)2377464-2 11782013 nnns year:2018 pages:6855-6870 https://doaj.org/article/83b0153cf49548d5b7061f6c440a26e9 kostenfrei https://www.dovepress.com/codelivery-of-doxorubicin-and-elacridar-to-target-both-liver-cancer-ce-peer-reviewed-article-IJN kostenfrei https://doaj.org/toc/1178-2013 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 2018 6855-6870
allfields_unstemmed	(DE-627)DOAJ075608839 (DE-599)DOAJ83b0153cf49548d5b7061f6c440a26e9 DE-627 ger DE-627 rakwb eng R5-920 Chen D verfasserin aut Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Dazhong Chen,1–3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. Keywords: combined therapy, cancer stem cells, liver cancer, doxorubicin, elacridar, nanoparticles combined therapy cancer stem cells liver cancer doxorubicin elacridar nanoparticles Medicine (General) Pan X verfasserin aut Xie F verfasserin aut Lu Y verfasserin aut Zou H verfasserin aut Yin C verfasserin aut Zhang Y verfasserin aut Gao J verfasserin aut In International Journal of Nanomedicine Dove Medical Press, 2018 (2018), Seite 6855-6870 (DE-627)537879560 (DE-600)2377464-2 11782013 nnns year:2018 pages:6855-6870 https://doaj.org/article/83b0153cf49548d5b7061f6c440a26e9 kostenfrei https://www.dovepress.com/codelivery-of-doxorubicin-and-elacridar-to-target-both-liver-cancer-ce-peer-reviewed-article-IJN kostenfrei https://doaj.org/toc/1178-2013 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 2018 6855-6870
allfieldsGer	(DE-627)DOAJ075608839 (DE-599)DOAJ83b0153cf49548d5b7061f6c440a26e9 DE-627 ger DE-627 rakwb eng R5-920 Chen D verfasserin aut Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Dazhong Chen,1–3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. Keywords: combined therapy, cancer stem cells, liver cancer, doxorubicin, elacridar, nanoparticles combined therapy cancer stem cells liver cancer doxorubicin elacridar nanoparticles Medicine (General) Pan X verfasserin aut Xie F verfasserin aut Lu Y verfasserin aut Zou H verfasserin aut Yin C verfasserin aut Zhang Y verfasserin aut Gao J verfasserin aut In International Journal of Nanomedicine Dove Medical Press, 2018 (2018), Seite 6855-6870 (DE-627)537879560 (DE-600)2377464-2 11782013 nnns year:2018 pages:6855-6870 https://doaj.org/article/83b0153cf49548d5b7061f6c440a26e9 kostenfrei https://www.dovepress.com/codelivery-of-doxorubicin-and-elacridar-to-target-both-liver-cancer-ce-peer-reviewed-article-IJN kostenfrei https://doaj.org/toc/1178-2013 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 2018 6855-6870
allfieldsSound	(DE-627)DOAJ075608839 (DE-599)DOAJ83b0153cf49548d5b7061f6c440a26e9 DE-627 ger DE-627 rakwb eng R5-920 Chen D verfasserin aut Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Dazhong Chen,1–3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. Keywords: combined therapy, cancer stem cells, liver cancer, doxorubicin, elacridar, nanoparticles combined therapy cancer stem cells liver cancer doxorubicin elacridar nanoparticles Medicine (General) Pan X verfasserin aut Xie F verfasserin aut Lu Y verfasserin aut Zou H verfasserin aut Yin C verfasserin aut Zhang Y verfasserin aut Gao J verfasserin aut In International Journal of Nanomedicine Dove Medical Press, 2018 (2018), Seite 6855-6870 (DE-627)537879560 (DE-600)2377464-2 11782013 nnns year:2018 pages:6855-6870 https://doaj.org/article/83b0153cf49548d5b7061f6c440a26e9 kostenfrei https://www.dovepress.com/codelivery-of-doxorubicin-and-elacridar-to-target-both-liver-cancer-ce-peer-reviewed-article-IJN kostenfrei https://doaj.org/toc/1178-2013 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 2018 6855-6870
language	English
source	In International Journal of Nanomedicine (2018), Seite 6855-6870 year:2018 pages:6855-6870
sourceStr	In International Journal of Nanomedicine (2018), Seite 6855-6870 year:2018 pages:6855-6870
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	combined therapy cancer stem cells liver cancer doxorubicin elacridar nanoparticles Medicine (General)
isfreeaccess_bool	true
container_title	International Journal of Nanomedicine
authorswithroles_txt_mv	Chen D @@aut@@ Pan X @@aut@@ Xie F @@aut@@ Lu Y @@aut@@ Zou H @@aut@@ Yin C @@aut@@ Zhang Y @@aut@@ Gao J @@aut@@
publishDateDaySort_date	2018-01-01T00:00:00Z
hierarchy_top_id	537879560
id	DOAJ075608839
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ075608839</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230501181736.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230228s2018 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ075608839</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ83b0153cf49548d5b7061f6c440a26e9</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">R5-920</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Chen D</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2018</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Dazhong Chen,1&ndash;3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. 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callnumber-first	R - Medicine
author	Chen D
spellingShingle	Chen D misc R5-920 misc combined therapy misc cancer stem cells misc liver cancer misc doxorubicin misc elacridar misc nanoparticles misc Medicine (General) Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles
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topic_title	R5-920 Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles combined therapy cancer stem cells liver cancer doxorubicin elacridar nanoparticles
topic	misc R5-920 misc combined therapy misc cancer stem cells misc liver cancer misc doxorubicin misc elacridar misc nanoparticles misc Medicine (General)
topic_unstemmed	misc R5-920 misc combined therapy misc cancer stem cells misc liver cancer misc doxorubicin misc elacridar misc nanoparticles misc Medicine (General)
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title	Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles
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title_full	Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles
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title_sort	codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles
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title_auth	Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles
abstract	Dazhong Chen,1–3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. Keywords: combined therapy, cancer stem cells, liver cancer, doxorubicin, elacridar, nanoparticles
abstractGer	Dazhong Chen,1–3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. Keywords: combined therapy, cancer stem cells, liver cancer, doxorubicin, elacridar, nanoparticles
abstract_unstemmed	Dazhong Chen,1–3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. Keywords: combined therapy, cancer stem cells, liver cancer, doxorubicin, elacridar, nanoparticles
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title_short	Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles
url	https://doaj.org/article/83b0153cf49548d5b7061f6c440a26e9 https://www.dovepress.com/codelivery-of-doxorubicin-and-elacridar-to-target-both-liver-cancer-ce-peer-reviewed-article-IJN https://doaj.org/toc/1178-2013
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Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. 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Codelivery of doxorubicin and elacridar to target both liver cancer cells and stem cells by polylactide-co-glycolide/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles

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