Overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancer
Doxorubicin (DOX) is limited to use in clinical practice because of poor targeting, serious side effects and multidrug resistance (MDR). Vitamin E and its derivatives are currently considered as hydrophobic material that can reverse tumor MDR by suppressing the action of p-glycoprotein (p-gp). There...
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doaj-039a32603e4940529509faac9057aaeb2021-06-11T05:11:52ZengElsevierBiomedicine & Pharmacotherapy0753-33222021-02-01134111108Overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancerJing Mao0Lipeng Qiu1Lu Ge2Juan Zhou3Qian Ji4Yang Yang5Miaomiao Long6Danhui Wang7Liping Teng8Jinghua Chen9School of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, Jiangsu, ChinaSchool of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, Jiangsu, China; Sunhover Industry Group Company Limited, Linyi, 276000, Shandong, ChinaSchool of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, Jiangsu, ChinaSchool of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, Jiangsu, ChinaSchool of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, Jiangsu, ChinaSchool of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, Jiangsu, ChinaDepartment of Pharmacy, Wuxi Higher Health Vocational Technology School, Wuxi, 214028, Jiangsu, China; Corresponding authors.Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, ChinaWuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, China; Corresponding authors.School of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, Jiangsu, ChinaDoxorubicin (DOX) is limited to use in clinical practice because of poor targeting, serious side effects and multidrug resistance (MDR). Vitamin E and its derivatives are currently considered as hydrophobic material that can reverse tumor MDR by suppressing the action of p-glycoprotein (p-gp). Therefore, reduction-sensitive amphiphilic heparosan polysaccharide-cystamine-vitamin E succinate (KSV) copolymers were designed to reverse breast cancer MDR cells. The spherical micelles (DOX/KSV) micelles which had suitable particle size presented redox-sensitive release character. Simultaneously, DOX-loaded reduction insensitive heparosan-adipic dihydrazide-vitamin E succinate (KV) micellar system was designed as a control. DOX/KSV and DOX/KV micelles had the higher capability to overcome tumor MDR than that free DOX. However, DOX/KSV had the highest amount of cellular uptake which might be caused by the synergistic intracellular drug release and inhibition of p-gp expression. The mechanism experiments revealed that DOX/KSV could be fast disassembled to release DOX after internalization into tumor cells. Moreover, DOX/KSV produced more ROS than free DOX and DOX/KV resulting in enhanced anticancer effect. In vivo tumor-bearing mice study suggested that DOX/KSV micelles could efficiently enhance antitumor effect by overcoming tumor MDR and reduce toxicity of DOX. The DOX/KSV micelles could synergistically increase the therapeutic effect of chemotherapeutic drug on tumor MDR cells.http://www.sciencedirect.com/science/article/pii/S0753332220313019Reduction-sensitive micelleHeparosan polysaccharideVitamin E succinateDoxorubicinTumor multidrug resistance |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jing Mao Lipeng Qiu Lu Ge Juan Zhou Qian Ji Yang Yang Miaomiao Long Danhui Wang Liping Teng Jinghua Chen |
spellingShingle |
Jing Mao Lipeng Qiu Lu Ge Juan Zhou Qian Ji Yang Yang Miaomiao Long Danhui Wang Liping Teng Jinghua Chen Overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancer Biomedicine & Pharmacotherapy Reduction-sensitive micelle Heparosan polysaccharide Vitamin E succinate Doxorubicin Tumor multidrug resistance |
author_facet |
Jing Mao Lipeng Qiu Lu Ge Juan Zhou Qian Ji Yang Yang Miaomiao Long Danhui Wang Liping Teng Jinghua Chen |
author_sort |
Jing Mao |
title |
Overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancer |
title_short |
Overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancer |
title_full |
Overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancer |
title_fullStr |
Overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancer |
title_full_unstemmed |
Overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancer |
title_sort |
overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancer |
publisher |
Elsevier |
series |
Biomedicine & Pharmacotherapy |
issn |
0753-3322 |
publishDate |
2021-02-01 |
description |
Doxorubicin (DOX) is limited to use in clinical practice because of poor targeting, serious side effects and multidrug resistance (MDR). Vitamin E and its derivatives are currently considered as hydrophobic material that can reverse tumor MDR by suppressing the action of p-glycoprotein (p-gp). Therefore, reduction-sensitive amphiphilic heparosan polysaccharide-cystamine-vitamin E succinate (KSV) copolymers were designed to reverse breast cancer MDR cells. The spherical micelles (DOX/KSV) micelles which had suitable particle size presented redox-sensitive release character. Simultaneously, DOX-loaded reduction insensitive heparosan-adipic dihydrazide-vitamin E succinate (KV) micellar system was designed as a control. DOX/KSV and DOX/KV micelles had the higher capability to overcome tumor MDR than that free DOX. However, DOX/KSV had the highest amount of cellular uptake which might be caused by the synergistic intracellular drug release and inhibition of p-gp expression. The mechanism experiments revealed that DOX/KSV could be fast disassembled to release DOX after internalization into tumor cells. Moreover, DOX/KSV produced more ROS than free DOX and DOX/KV resulting in enhanced anticancer effect. In vivo tumor-bearing mice study suggested that DOX/KSV micelles could efficiently enhance antitumor effect by overcoming tumor MDR and reduce toxicity of DOX. The DOX/KSV micelles could synergistically increase the therapeutic effect of chemotherapeutic drug on tumor MDR cells. |
topic |
Reduction-sensitive micelle Heparosan polysaccharide Vitamin E succinate Doxorubicin Tumor multidrug resistance |
url |
http://www.sciencedirect.com/science/article/pii/S0753332220313019 |
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