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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Autores principales:	Enping Chen, Ting Wang, Junmei Zhang, Xiang Zhou, Yafan Niu, Fu Liu, Yinan Zhong, Dechun Huang, Wei Chen
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	multidrug resistance reversal mitochondrial targeting pH responsive nanogel combination therapy Biotechnology TP248.13-248.65
Acceso en línea:	https://doaj.org/article/d9b241e559a34da69d057c009856dbc9
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spelling	oai:doaj.org-article:d9b241e559a34da69d057c009856dbc92021-12-01T13:48:58ZMitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance2296-418510.3389/fbioe.2021.787320https://doaj.org/article/d9b241e559a34da69d057c009856dbc92021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fbioe.2021.787320/fullhttps://doaj.org/toc/2296-4185Multidrug 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.Enping ChenTing WangJunmei ZhangXiang ZhouYafan NiuFu LiuYinan ZhongDechun HuangDechun HuangWei ChenWei ChenFrontiers Media S.A.articlemultidrug resistance reversalmitochondrial targetingpH responsivenanogelcombination therapyBiotechnologyTP248.13-248.65ENFrontiers in Bioengineering and Biotechnology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	multidrug resistance reversal mitochondrial targeting pH responsive nanogel combination therapy Biotechnology TP248.13-248.65
spellingShingle	multidrug resistance reversal mitochondrial targeting pH responsive nanogel combination therapy Biotechnology TP248.13-248.65 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
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.
format	article
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
title	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_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_sort	mitochondrial targeting and ph-responsive nanogels for co-delivery of lonidamine and paclitaxel to conquer drug resistance
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/d9b241e559a34da69d057c009856dbc9
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Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance

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