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Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression
Poor anti-metastasis effects and side-effects remain a challenge for the clinical application of camptothecin (CPT). Mitochondria can be a promising target for the treatment of metastatic tumors due to their vital roles in providing energy supply, upregulating pro-metastatic factors, and controlling...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331251/ https://www.ncbi.nlm.nih.gov/pubmed/35893790 http://dx.doi.org/10.3390/pharmaceutics14081534 |
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author | Yi, Xiaoli Yan, Yue Shen, Xinran Li, Lian Huang, Yuan |
author_facet | Yi, Xiaoli Yan, Yue Shen, Xinran Li, Lian Huang, Yuan |
author_sort | Yi, Xiaoli |
collection | PubMed |
description | Poor anti-metastasis effects and side-effects remain a challenge for the clinical application of camptothecin (CPT). Mitochondria can be a promising target for the treatment of metastatic tumors due to their vital roles in providing energy supply, upregulating pro-metastatic factors, and controlling cell-death signaling. Thus, selectively delivering CPT to mitochondria appears to be a feasible way of improving the anti-metastasis effect and reducing adverse effects. Here, we established a 2-(dimethylamino) ethyl methacrylate (DEA)-modified N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer–CPT conjugate (P-DEA-CPT) to mediate the mitochondrial accumulation of CPT. The mitochondria-targeted P-DEA-CPT could overcome multiple barriers by quickly internalizing into 4T1 cells, then escaping from lysosome, and sufficiently accumulating in mitochondria. Subsequently, P-DEA-CPT greatly damaged mitochondrial function, leading to the reactive oxide species (ROS) elevation, energy depletion, apoptosis amplification, and tumor metastasis suppression. Consequently, P-DEA-CPT successfully inhibited both primary tumor growth and distant metastasis in vivo. Furthermore, our studies revealed that the mechanism underlying the anti-metastasis capacity of P-DEA-CPT was partially via downregulation of various pro-metastatic proteins, such as hypoxia induction factor-1α (HIF-1α), matrix metalloproteinases-2 (MMP-2), and vascular endothelial growth factor (VEGF). This study provided the proof of concept that escorting CPT to mitochondria via a mitochondrial targeting strategy could be a promising approach for anti-metastasis treatment. |
format | Online Article Text |
id | pubmed-9331251 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93312512022-07-29 Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression Yi, Xiaoli Yan, Yue Shen, Xinran Li, Lian Huang, Yuan Pharmaceutics Article Poor anti-metastasis effects and side-effects remain a challenge for the clinical application of camptothecin (CPT). Mitochondria can be a promising target for the treatment of metastatic tumors due to their vital roles in providing energy supply, upregulating pro-metastatic factors, and controlling cell-death signaling. Thus, selectively delivering CPT to mitochondria appears to be a feasible way of improving the anti-metastasis effect and reducing adverse effects. Here, we established a 2-(dimethylamino) ethyl methacrylate (DEA)-modified N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer–CPT conjugate (P-DEA-CPT) to mediate the mitochondrial accumulation of CPT. The mitochondria-targeted P-DEA-CPT could overcome multiple barriers by quickly internalizing into 4T1 cells, then escaping from lysosome, and sufficiently accumulating in mitochondria. Subsequently, P-DEA-CPT greatly damaged mitochondrial function, leading to the reactive oxide species (ROS) elevation, energy depletion, apoptosis amplification, and tumor metastasis suppression. Consequently, P-DEA-CPT successfully inhibited both primary tumor growth and distant metastasis in vivo. Furthermore, our studies revealed that the mechanism underlying the anti-metastasis capacity of P-DEA-CPT was partially via downregulation of various pro-metastatic proteins, such as hypoxia induction factor-1α (HIF-1α), matrix metalloproteinases-2 (MMP-2), and vascular endothelial growth factor (VEGF). This study provided the proof of concept that escorting CPT to mitochondria via a mitochondrial targeting strategy could be a promising approach for anti-metastasis treatment. MDPI 2022-07-23 /pmc/articles/PMC9331251/ /pubmed/35893790 http://dx.doi.org/10.3390/pharmaceutics14081534 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Yi, Xiaoli Yan, Yue Shen, Xinran Li, Lian Huang, Yuan Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression |
title | Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression |
title_full | Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression |
title_fullStr | Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression |
title_full_unstemmed | Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression |
title_short | Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression |
title_sort | mitochondria-targeted delivery of camptothecin based on hpma copolymer for metastasis suppression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331251/ https://www.ncbi.nlm.nih.gov/pubmed/35893790 http://dx.doi.org/10.3390/pharmaceutics14081534 |
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