Multi-Modulation of Doxorubicin Resistance in Breast Cancer Cells by Poly(<span style="font-variant: small-caps">l</span>-histidine)-Based Multifunctional Micelles
Even though the reversal of multi-drug resistance (MDR) by numerous nanoparticles has been extensively studied, limited success has been achieved. To overcome this barrier, we report a rationally-designed pH-sensitive micelle, in which doxorubicin (Dox) and resveratrol (Res) were co-loaded. The mice...
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| Format: | Article |
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MDPI AG
2019-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/11/8/385 |
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| author | Li Jia Nan Jia Yan Gao Haiyang Hu Xiuli Zhao Dawei Chen Mingxi Qiao |
| author_facet | Li Jia Nan Jia Yan Gao Haiyang Hu Xiuli Zhao Dawei Chen Mingxi Qiao |
| author_sort | Li Jia |
| collection | DOAJ |
| description | Even though the reversal of multi-drug resistance (MDR) by numerous nanoparticles has been extensively studied, limited success has been achieved. To overcome this barrier, we report a rationally-designed pH-sensitive micelle, in which doxorubicin (Dox) and resveratrol (Res) were co-loaded. The micelle was based on methoxy <i>poly</i> (ethylene glycol)-poly(<span style="font-variant: small-caps;">d</span>,<span style="font-variant: small-caps;">l</span>-lactide)-poly(<span style="font-variant: small-caps;">l</span>-histidine) (mPEG-PLA-PHis), which integrated passive targeting, endo-lysosomal escape and pH-responsive payloads release. At a physiological pH of 7.4 (slightly alkali), Dox and Res were incorporated into the micelles core using the thin-film hydration method (pH-endoSM/Dox/Res). After cellular uptake, the micelles exhibited an enhanced dissociation in response to the acidic endosomes, triggering the release of Res and Dox. Furthermore, Res was observed to synergistically improve the cytotoxicity of Dox by down-regulating the P-glycoprotein (P-gp) expression, decreasing the membrane potential of the mitochondrial and ATP level, as well as inducing cell apoptosis mediated by mitochondria. The pH-endoSM/Dox/Res showed a prominent ability to decrease the IC<sub>50</sub> of Dox by a factor of 17.38 in cell cytotoxicity against the MCF-7/ADR cell line. In vivo distribution demonstrated the excellent tumor-targeting ability of the pH-endoSM/Dox/Res. All results indicated that pH-endoSM/Dox/Res held great potential for the treatment of Dox-resistance breast cancer cells. |
| first_indexed | 2024-04-13T06:46:53Z |
| format | Article |
| id | doaj.art-d795372fb453458fac2a5d1f366b5dbb |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-13T06:46:53Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-d795372fb453458fac2a5d1f366b5dbb2022-12-22T02:57:32ZengMDPI AGPharmaceutics1999-49232019-08-0111838510.3390/pharmaceutics11080385pharmaceutics11080385Multi-Modulation of Doxorubicin Resistance in Breast Cancer Cells by Poly(<span style="font-variant: small-caps">l</span>-histidine)-Based Multifunctional MicellesLi Jia0Nan Jia1Yan Gao2Haiyang Hu3Xiuli Zhao4Dawei Chen5Mingxi Qiao6School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, P.O. Box 42, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, P.O. Box 42, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, P.O. Box 42, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, P.O. Box 42, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, P.O. Box 42, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, P.O. Box 42, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, P.O. Box 42, Shenyang 110016, ChinaEven though the reversal of multi-drug resistance (MDR) by numerous nanoparticles has been extensively studied, limited success has been achieved. To overcome this barrier, we report a rationally-designed pH-sensitive micelle, in which doxorubicin (Dox) and resveratrol (Res) were co-loaded. The micelle was based on methoxy <i>poly</i> (ethylene glycol)-poly(<span style="font-variant: small-caps;">d</span>,<span style="font-variant: small-caps;">l</span>-lactide)-poly(<span style="font-variant: small-caps;">l</span>-histidine) (mPEG-PLA-PHis), which integrated passive targeting, endo-lysosomal escape and pH-responsive payloads release. At a physiological pH of 7.4 (slightly alkali), Dox and Res were incorporated into the micelles core using the thin-film hydration method (pH-endoSM/Dox/Res). After cellular uptake, the micelles exhibited an enhanced dissociation in response to the acidic endosomes, triggering the release of Res and Dox. Furthermore, Res was observed to synergistically improve the cytotoxicity of Dox by down-regulating the P-glycoprotein (P-gp) expression, decreasing the membrane potential of the mitochondrial and ATP level, as well as inducing cell apoptosis mediated by mitochondria. The pH-endoSM/Dox/Res showed a prominent ability to decrease the IC<sub>50</sub> of Dox by a factor of 17.38 in cell cytotoxicity against the MCF-7/ADR cell line. In vivo distribution demonstrated the excellent tumor-targeting ability of the pH-endoSM/Dox/Res. All results indicated that pH-endoSM/Dox/Res held great potential for the treatment of Dox-resistance breast cancer cells.https://www.mdpi.com/1999-4923/11/8/385poly(<span style="font-variant: small-caps">l</span>-histidine)pH sensitive micelleMDR |
| spellingShingle | Li Jia Nan Jia Yan Gao Haiyang Hu Xiuli Zhao Dawei Chen Mingxi Qiao Multi-Modulation of Doxorubicin Resistance in Breast Cancer Cells by Poly(<span style="font-variant: small-caps">l</span>-histidine)-Based Multifunctional Micelles Pharmaceutics poly(<span style="font-variant: small-caps">l</span>-histidine) pH sensitive micelle MDR |
| title | Multi-Modulation of Doxorubicin Resistance in Breast Cancer Cells by Poly(<span style="font-variant: small-caps">l</span>-histidine)-Based Multifunctional Micelles |
| title_full | Multi-Modulation of Doxorubicin Resistance in Breast Cancer Cells by Poly(<span style="font-variant: small-caps">l</span>-histidine)-Based Multifunctional Micelles |
| title_fullStr | Multi-Modulation of Doxorubicin Resistance in Breast Cancer Cells by Poly(<span style="font-variant: small-caps">l</span>-histidine)-Based Multifunctional Micelles |
| title_full_unstemmed | Multi-Modulation of Doxorubicin Resistance in Breast Cancer Cells by Poly(<span style="font-variant: small-caps">l</span>-histidine)-Based Multifunctional Micelles |
| title_short | Multi-Modulation of Doxorubicin Resistance in Breast Cancer Cells by Poly(<span style="font-variant: small-caps">l</span>-histidine)-Based Multifunctional Micelles |
| title_sort | multi modulation of doxorubicin resistance in breast cancer cells by poly span style font variant small caps l span histidine based multifunctional micelles |
| topic | poly(<span style="font-variant: small-caps">l</span>-histidine) pH sensitive micelle MDR |
| url | https://www.mdpi.com/1999-4923/11/8/385 |
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