Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cells
Wei Hong,1 Hong Shi,2 Mingxi Qiao,3 Xiang Gao,1 Jie Yang,1 Chunlian Tian,1 Dexian Zhang,1 Shengli Niu,1 Mingchun Liu11Key Laboratory of Zoonosis of Liaoning, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenhe, Shenyang, Liaoning, 2Department of Pharmaceutics,...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2017-02-01
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| Series: | International Journal of Nanomedicine |
| Subjects: | |
| Online Access: | https://www.dovepress.com/rational-design-of-multifunctional-micelles-against-doxorubicin-sensit-peer-reviewed-article-IJN |
| _version_ | 1818992288905297920 |
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| author | Hong W Shi H Qiao M Gao X Yang J Tian C Zhang D Niu S Liu M |
| author_facet | Hong W Shi H Qiao M Gao X Yang J Tian C Zhang D Niu S Liu M |
| author_sort | Hong W |
| collection | DOAJ |
| description | Wei Hong,1 Hong Shi,2 Mingxi Qiao,3 Xiang Gao,1 Jie Yang,1 Chunlian Tian,1 Dexian Zhang,1 Shengli Niu,1 Mingchun Liu11Key Laboratory of Zoonosis of Liaoning, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenhe, Shenyang, Liaoning, 2Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Jiangning, Nanjing, 3Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, People’s Republic of China Abstract: Even though a tremendous number of multifunctional nanocarriers have been developed to tackle heterogeneous cancer cells, little attention has been paid to elucidate how to rationally design a multifunctional nanocarrier. In this study, three individual functions (active targeting, stimuli-triggered release and endo-lysosomal escape) were evaluated in doxorubicin (DOX)-sensitive MCF-7 cells and DOX-resistant MCF-7/ADR cells by constructing four kinds of micelles with active-targeting (AT-M), passive targeting, pH-triggered release (pHT-M) and endo-lysosomal escape (endoE-M) function, respectively. AT-M demonstrated the strongest cytotoxicity against MCF-7 cells and the highest cellular uptake of DOX due to the folate-mediated endocytosis. However, AT-M failed to exhibit the best efficacy against MCF-7/ADR cells, while endoE-M exhibited the strongest cytotoxicity against MCF-7/ADR cells and the highest cellular uptake of DOX due to the lowest elimination of DOX from the cells. This was attributed to the carrier-facilitated endo-lysosomal escape of DOX, which avoided exocytosis by lysosome secretion, resulting in an effective accumulation of DOX in the cytoplasm. The enhanced elimination of DOX from the MCF-7/ADR cells also accounted for the remarkable decrease in cytotoxicity against the cells of AT-M. Three micelles were further evaluated with MCF-7 cells and MCF-7/ADR-resistant cells xenografted mice model. In accordance with the in vitro results, AT-M and endoE-M demonstrated the strongest inhibition on the MCF-7 and MCF-7/ADR xenografted tumor, respectively. Active targeting and active targeting in combination with endo-lysosomal escape have been demonstrated to be the primary function for a nanocarrier against doxorubicin-sensitive and doxorubicin-resistant MCF-7 cells, respectively. These results indicate that the rational design of multifunctional nanocarriers for cancer therapy needs to consider the heterogeneous cancer cells and the primary function needs to be integrated to achieve effective payload delivery.Keywords: rational design, multidrug resistance, active targeting, pH-triggered release, endo-lysosomal escape |
| first_indexed | 2024-12-20T20:23:47Z |
| format | Article |
| id | doaj.art-745b1242217d41d8b13ef42109dfbfc9 |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-12-20T20:23:47Z |
| publishDate | 2017-02-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-745b1242217d41d8b13ef42109dfbfc92022-12-21T19:27:31ZengDove Medical PressInternational Journal of Nanomedicine1178-20132017-02-01Volume 12989100731244Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cellsHong WShi HQiao MGao XYang JTian CZhang DNiu SLiu MWei Hong,1 Hong Shi,2 Mingxi Qiao,3 Xiang Gao,1 Jie Yang,1 Chunlian Tian,1 Dexian Zhang,1 Shengli Niu,1 Mingchun Liu11Key Laboratory of Zoonosis of Liaoning, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenhe, Shenyang, Liaoning, 2Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Jiangning, Nanjing, 3Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, People’s Republic of China Abstract: Even though a tremendous number of multifunctional nanocarriers have been developed to tackle heterogeneous cancer cells, little attention has been paid to elucidate how to rationally design a multifunctional nanocarrier. In this study, three individual functions (active targeting, stimuli-triggered release and endo-lysosomal escape) were evaluated in doxorubicin (DOX)-sensitive MCF-7 cells and DOX-resistant MCF-7/ADR cells by constructing four kinds of micelles with active-targeting (AT-M), passive targeting, pH-triggered release (pHT-M) and endo-lysosomal escape (endoE-M) function, respectively. AT-M demonstrated the strongest cytotoxicity against MCF-7 cells and the highest cellular uptake of DOX due to the folate-mediated endocytosis. However, AT-M failed to exhibit the best efficacy against MCF-7/ADR cells, while endoE-M exhibited the strongest cytotoxicity against MCF-7/ADR cells and the highest cellular uptake of DOX due to the lowest elimination of DOX from the cells. This was attributed to the carrier-facilitated endo-lysosomal escape of DOX, which avoided exocytosis by lysosome secretion, resulting in an effective accumulation of DOX in the cytoplasm. The enhanced elimination of DOX from the MCF-7/ADR cells also accounted for the remarkable decrease in cytotoxicity against the cells of AT-M. Three micelles were further evaluated with MCF-7 cells and MCF-7/ADR-resistant cells xenografted mice model. In accordance with the in vitro results, AT-M and endoE-M demonstrated the strongest inhibition on the MCF-7 and MCF-7/ADR xenografted tumor, respectively. Active targeting and active targeting in combination with endo-lysosomal escape have been demonstrated to be the primary function for a nanocarrier against doxorubicin-sensitive and doxorubicin-resistant MCF-7 cells, respectively. These results indicate that the rational design of multifunctional nanocarriers for cancer therapy needs to consider the heterogeneous cancer cells and the primary function needs to be integrated to achieve effective payload delivery.Keywords: rational design, multidrug resistance, active targeting, pH-triggered release, endo-lysosomal escape https://www.dovepress.com/rational-design-of-multifunctional-micelles-against-doxorubicin-sensit-peer-reviewed-article-IJNmultifunctional micellesmultidrug resistanceactive targetingpH-triggered releaseendo-lysosomal escape. |
| spellingShingle | Hong W Shi H Qiao M Gao X Yang J Tian C Zhang D Niu S Liu M Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cells International Journal of Nanomedicine multifunctional micelles multidrug resistance active targeting pH-triggered release endo-lysosomal escape. |
| title | Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cells |
| title_full | Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cells |
| title_fullStr | Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cells |
| title_full_unstemmed | Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cells |
| title_short | Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cells |
| title_sort | rational design of multifunctional micelles against doxorubicin sensitive and doxorubicin resistant mcf 7 human breast cancer cells |
| topic | multifunctional micelles multidrug resistance active targeting pH-triggered release endo-lysosomal escape. |
| url | https://www.dovepress.com/rational-design-of-multifunctional-micelles-against-doxorubicin-sensit-peer-reviewed-article-IJN |
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