Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitor
Multi-drug resistance (MDR) in advanced breast cancer (ABC) is triggered by the high expression of P-glycoprotein (P-gp), which reduces intracellular concentration of anti-tumor drugs, in turn preventing oxidative stress damage to cytoplasmic and mitochondrial membranes. It is therefore of clinical...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-06-01
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| Series: | Materials Today Bio |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590006424000887 |
| _version_ | 1797249063013318656 |
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| author | Sifeng Zhu Chao Sun Zimin Cai Yunyan Li Wendian Liu Yun Luan Cheng Wang |
| author_facet | Sifeng Zhu Chao Sun Zimin Cai Yunyan Li Wendian Liu Yun Luan Cheng Wang |
| author_sort | Sifeng Zhu |
| collection | DOAJ |
| description | Multi-drug resistance (MDR) in advanced breast cancer (ABC) is triggered by the high expression of P-glycoprotein (P-gp), which reduces intracellular concentration of anti-tumor drugs, in turn preventing oxidative stress damage to cytoplasmic and mitochondrial membranes. It is therefore of clinical relevance to develop P-gp-specific targeted nanocarriers for the treatment of drug resistant ABC. Herein, a drug carrier targeting CD44 and mitochondria was synthesised for the delivery of encequidar (ER, P-gp inhibitor) and paclitaxel (PTX). HT@ER/PTX nanoparticles (ER:PTX molar ratio 1:1) had excellent P-gp inhibition ability and targeted mitochondria to induce apoptosis in MCF-7/PTX cells in vitro. Furthermore, HT@ER/PTX nanocarriers showed more anti-tumor efficacy than PTX (Taxol®) in a xenograft mouse model of MCF-7/PTX cells; the tumor inhibitory rates of HT@ER/PTX nanoparticles and Taxol® were 72.64% ± 4.41% and 32.36% ± 4.09%, respectively. The survival of tumor-bearing mice administered HT@ER/PTX nanoparticles was prolonged compared to that of the mice treated with Taxol®. In addition, HT@ER/PTX not only inhibited P-gp-mediated removal of toxic lipid peroxidation byproducts resulting from anti-tumor drugs but also upregulated the expression of mitochondrial dynamics-related protein, fostering oxidative stress damage, which induced activation of the Caspase-3 apoptosis pathway. Our findings indicate that mitochondria targeted co-delivery of anti-tumor drugs and P-gp inhibitors could be a practical approach in treating multi-drug resistance in ABC. |
| first_indexed | 2024-04-24T20:24:31Z |
| format | Article |
| id | doaj.art-1c78e2cd82124585938708e00d8f2afa |
| institution | Directory Open Access Journal |
| issn | 2590-0064 |
| language | English |
| last_indexed | 2024-04-24T20:24:31Z |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Materials Today Bio |
| spelling | doaj.art-1c78e2cd82124585938708e00d8f2afa2024-03-22T05:40:31ZengElsevierMaterials Today Bio2590-00642024-06-0126101029Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitorSifeng Zhu0Chao Sun1Zimin Cai2Yunyan Li3Wendian Liu4Yun Luan5Cheng Wang6Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, ChinaInstitute of Medical Science, Central Research Laboratory, the Second Hospital of Shandong University, 250033, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, ChinaInstitute of Medical Science, Central Research Laboratory, the Second Hospital of Shandong University, 250033, China; Department of Cardiology, the Second Hospital of Shandong University, Ji'nan, 250033, China; Corresponding author. Institute of Medical Science, Central Research Laboratory, the Second Hospital of Shandong University, 250033, China.Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Corresponding author. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.Multi-drug resistance (MDR) in advanced breast cancer (ABC) is triggered by the high expression of P-glycoprotein (P-gp), which reduces intracellular concentration of anti-tumor drugs, in turn preventing oxidative stress damage to cytoplasmic and mitochondrial membranes. It is therefore of clinical relevance to develop P-gp-specific targeted nanocarriers for the treatment of drug resistant ABC. Herein, a drug carrier targeting CD44 and mitochondria was synthesised for the delivery of encequidar (ER, P-gp inhibitor) and paclitaxel (PTX). HT@ER/PTX nanoparticles (ER:PTX molar ratio 1:1) had excellent P-gp inhibition ability and targeted mitochondria to induce apoptosis in MCF-7/PTX cells in vitro. Furthermore, HT@ER/PTX nanocarriers showed more anti-tumor efficacy than PTX (Taxol®) in a xenograft mouse model of MCF-7/PTX cells; the tumor inhibitory rates of HT@ER/PTX nanoparticles and Taxol® were 72.64% ± 4.41% and 32.36% ± 4.09%, respectively. The survival of tumor-bearing mice administered HT@ER/PTX nanoparticles was prolonged compared to that of the mice treated with Taxol®. In addition, HT@ER/PTX not only inhibited P-gp-mediated removal of toxic lipid peroxidation byproducts resulting from anti-tumor drugs but also upregulated the expression of mitochondrial dynamics-related protein, fostering oxidative stress damage, which induced activation of the Caspase-3 apoptosis pathway. Our findings indicate that mitochondria targeted co-delivery of anti-tumor drugs and P-gp inhibitors could be a practical approach in treating multi-drug resistance in ABC.http://www.sciencedirect.com/science/article/pii/S2590006424000887Multi-drug resistanceMitochondria-targetingP-glycoproteinAdvanced breast cancerCo-deliverySynergistic effect |
| spellingShingle | Sifeng Zhu Chao Sun Zimin Cai Yunyan Li Wendian Liu Yun Luan Cheng Wang Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitor Materials Today Bio Multi-drug resistance Mitochondria-targeting P-glycoprotein Advanced breast cancer Co-delivery Synergistic effect |
| title | Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitor |
| title_full | Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitor |
| title_fullStr | Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitor |
| title_full_unstemmed | Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitor |
| title_short | Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitor |
| title_sort | effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and p glycoprotein inhibitor |
| topic | Multi-drug resistance Mitochondria-targeting P-glycoprotein Advanced breast cancer Co-delivery Synergistic effect |
| url | http://www.sciencedirect.com/science/article/pii/S2590006424000887 |
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