Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance
Multidrug resistance (MDR) is one of the leading causes of the failure of cancer chemotherapy and mainly attributed to the overexpression of drug efflux transporters in cancer cells, which is dependent on adenosine triphosphate (ATP). To overcome this phenomenon, herein, a mitochondrial-directed pH-...
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Bioengineering and Biotechnology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fbioe.2021.787320/full |
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| author | Enping Chen Ting Wang Junmei Zhang Xiang Zhou Yafan Niu Fu Liu Yinan Zhong Dechun Huang Dechun Huang Wei Chen Wei Chen |
| author_facet | Enping Chen Ting Wang Junmei Zhang Xiang Zhou Yafan Niu Fu Liu Yinan Zhong Dechun Huang Dechun Huang Wei Chen Wei Chen |
| author_sort | Enping Chen |
| collection | DOAJ |
| description | Multidrug resistance (MDR) is one of the leading causes of the failure of cancer chemotherapy and mainly attributed to the overexpression of drug efflux transporters in cancer cells, which is dependent on adenosine triphosphate (ATP). To overcome this phenomenon, herein, a mitochondrial-directed pH-sensitive polyvinyl alcohol (PVA) nanogel incorporating the hexokinase inhibitor lonidamine (LND) and the chemotherapeutic drug paclitaxel (PTX) was developed to restore the activity of PTX and synergistically treat drug-resistant tumors. The introduction of 2-dimethylaminoethanethiol (DMA) moiety into the nanogels not only promoted the drug loading capacity but also enabled the lysosomal escape of the nanogels. The subsequent mitochondrial targeting facilitated the accumulation and acid-triggered payload release in the mitochondria. The released LND can destroy the mitochondria by exhausting the mitochondrial membrane potential (MMP), generating reactive oxygen species (ROS) and restraining the energy supply, resulting in apoptosis and susceptibility of the MCF-7/MDR cells to PTX. Hence, the nanogel-enabled combination regimen of LND and PTX showed a boosted anti-tumor efficacy in MCF-7/MDR cells. These mitochondrial-directed pH-sensitive PVA nanogels incorporating both PTX and LND represent a new nanoplatform for MDR reversal and enhanced therapeutic efficacy. |
| first_indexed | 2024-12-21T04:25:53Z |
| format | Article |
| id | doaj.art-d9b241e559a34da69d057c009856dbc9 |
| institution | Directory Open Access Journal |
| issn | 2296-4185 |
| language | English |
| last_indexed | 2024-12-21T04:25:53Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Bioengineering and Biotechnology |
| spelling | doaj.art-d9b241e559a34da69d057c009856dbc92022-12-21T19:16:03ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852021-11-01910.3389/fbioe.2021.787320787320Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug ResistanceEnping Chen0Ting Wang1Junmei Zhang2Xiang Zhou3Yafan Niu4Fu Liu5Yinan Zhong6Dechun Huang7Dechun Huang8Wei Chen9Wei Chen10Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, ChinaEngineering Research Center for Smart Pharmaceutical Manufacturing Technologies, Ministry of Education, School of Engineering, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, ChinaEngineering Research Center for Smart Pharmaceutical Manufacturing Technologies, Ministry of Education, School of Engineering, China Pharmaceutical University, Nanjing, ChinaMultidrug resistance (MDR) is one of the leading causes of the failure of cancer chemotherapy and mainly attributed to the overexpression of drug efflux transporters in cancer cells, which is dependent on adenosine triphosphate (ATP). To overcome this phenomenon, herein, a mitochondrial-directed pH-sensitive polyvinyl alcohol (PVA) nanogel incorporating the hexokinase inhibitor lonidamine (LND) and the chemotherapeutic drug paclitaxel (PTX) was developed to restore the activity of PTX and synergistically treat drug-resistant tumors. The introduction of 2-dimethylaminoethanethiol (DMA) moiety into the nanogels not only promoted the drug loading capacity but also enabled the lysosomal escape of the nanogels. The subsequent mitochondrial targeting facilitated the accumulation and acid-triggered payload release in the mitochondria. The released LND can destroy the mitochondria by exhausting the mitochondrial membrane potential (MMP), generating reactive oxygen species (ROS) and restraining the energy supply, resulting in apoptosis and susceptibility of the MCF-7/MDR cells to PTX. Hence, the nanogel-enabled combination regimen of LND and PTX showed a boosted anti-tumor efficacy in MCF-7/MDR cells. These mitochondrial-directed pH-sensitive PVA nanogels incorporating both PTX and LND represent a new nanoplatform for MDR reversal and enhanced therapeutic efficacy.https://www.frontiersin.org/articles/10.3389/fbioe.2021.787320/fullmultidrug resistance reversalmitochondrial targetingpH responsivenanogelcombination therapy |
| spellingShingle | Enping Chen Ting Wang Junmei Zhang Xiang Zhou Yafan Niu Fu Liu Yinan Zhong Dechun Huang Dechun Huang Wei Chen Wei Chen Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance Frontiers in Bioengineering and Biotechnology multidrug resistance reversal mitochondrial targeting pH responsive nanogel combination therapy |
| title | Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance |
| title_full | Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance |
| title_fullStr | Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance |
| title_full_unstemmed | Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance |
| title_short | Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance |
| title_sort | mitochondrial targeting and ph responsive nanogels for co delivery of lonidamine and paclitaxel to conquer drug resistance |
| topic | multidrug resistance reversal mitochondrial targeting pH responsive nanogel combination therapy |
| url | https://www.frontiersin.org/articles/10.3389/fbioe.2021.787320/full |
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