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Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells
Reactive oxygen species (ROS)-sensitive polymer nanoparticles were synthesized for tumor targeting of an anticancer drug, doxorubicin (DOX). For this purpose, chitosan-methoxy poly(ethylene glycol) (mPEG) (ChitoPEG)-graft copolymer was synthesized and then DOX was conjugated to the backbone of chito...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10531032/ https://www.ncbi.nlm.nih.gov/pubmed/37762003 http://dx.doi.org/10.3390/ijms241813704 |
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author | Yoon, Kaengwon Jung, Seunggon Ryu, Jaeyoung Park, Hong-Ju Oh, Hee-Kyun Kook, Min-Suk |
author_facet | Yoon, Kaengwon Jung, Seunggon Ryu, Jaeyoung Park, Hong-Ju Oh, Hee-Kyun Kook, Min-Suk |
author_sort | Yoon, Kaengwon |
collection | PubMed |
description | Reactive oxygen species (ROS)-sensitive polymer nanoparticles were synthesized for tumor targeting of an anticancer drug, doxorubicin (DOX). For this purpose, chitosan-methoxy poly(ethylene glycol) (mPEG) (ChitoPEG)-graft copolymer was synthesized and then DOX was conjugated to the backbone of chitosan using a thioketal linker. Subsequently, the chemical structure of the DOX-conjugated ChitoPEG copolymer (ChitoPEGthDOX) was confirmed via (1)H nuclear magnetic resonance (NMR) spectra. Nanoparticles of the ChitoPEGthDOX conjugates have spherical shapes and a size of approximately 100 nm. Transmission electron microscopy (TEM) has shown that ChitoPEGthDOX nanoparticles disintegrate in the presence of hydrogen peroxide and the particle size distribution also changes from a monomodal/narrow distribution pattern to a multi-modal/wide distribution pattern. Furthermore, DOX is released faster in the presence of hydrogen peroxide. These results indicated that ChitoPEGthDOX nanoparticles have ROS sensitivity. The anticancer activity of the nanoparticles was evaluated using AT84 oral squamous carcinoma cells. Moreover, DOX-resistant AT84 cells were prepared in vitro. DOX and its nanoparticles showed dose-dependent cytotoxicity in both DOX-sensitive and DOX-resistant AT84 cells in vitro. However, DOX itself showed reduced cytotoxicity against DOX-resistant AT84 cells, while the nanoparticles showed almost similar cytotoxicity to DOX-sensitive and DOX-resistant AT84 cells. This result may be due to the inhibition of intracellular delivery of free DOX, while nanoparticles were efficiently internalized in DOX-resistant cells. The in vivo study of a DOX-resistant AT84 cell-bearing tumor xenograft model showed that nanoparticles have higher antitumor efficacy than those found in free DOX treatment. These results may be related to the efficient accumulation of nanoparticles in the tumor tissue, i.e., the fluorescence intensity in the tumor tissue was stronger than that of any other organs. Our findings suggest that ChitoPEGthDOX nanoparticles may be a promising candidate for ROS-sensitive anticancer delivery against DOX-resistant oral cancer cells. |
format | Online Article Text |
id | pubmed-10531032 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-105310322023-09-28 Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells Yoon, Kaengwon Jung, Seunggon Ryu, Jaeyoung Park, Hong-Ju Oh, Hee-Kyun Kook, Min-Suk Int J Mol Sci Article Reactive oxygen species (ROS)-sensitive polymer nanoparticles were synthesized for tumor targeting of an anticancer drug, doxorubicin (DOX). For this purpose, chitosan-methoxy poly(ethylene glycol) (mPEG) (ChitoPEG)-graft copolymer was synthesized and then DOX was conjugated to the backbone of chitosan using a thioketal linker. Subsequently, the chemical structure of the DOX-conjugated ChitoPEG copolymer (ChitoPEGthDOX) was confirmed via (1)H nuclear magnetic resonance (NMR) spectra. Nanoparticles of the ChitoPEGthDOX conjugates have spherical shapes and a size of approximately 100 nm. Transmission electron microscopy (TEM) has shown that ChitoPEGthDOX nanoparticles disintegrate in the presence of hydrogen peroxide and the particle size distribution also changes from a monomodal/narrow distribution pattern to a multi-modal/wide distribution pattern. Furthermore, DOX is released faster in the presence of hydrogen peroxide. These results indicated that ChitoPEGthDOX nanoparticles have ROS sensitivity. The anticancer activity of the nanoparticles was evaluated using AT84 oral squamous carcinoma cells. Moreover, DOX-resistant AT84 cells were prepared in vitro. DOX and its nanoparticles showed dose-dependent cytotoxicity in both DOX-sensitive and DOX-resistant AT84 cells in vitro. However, DOX itself showed reduced cytotoxicity against DOX-resistant AT84 cells, while the nanoparticles showed almost similar cytotoxicity to DOX-sensitive and DOX-resistant AT84 cells. This result may be due to the inhibition of intracellular delivery of free DOX, while nanoparticles were efficiently internalized in DOX-resistant cells. The in vivo study of a DOX-resistant AT84 cell-bearing tumor xenograft model showed that nanoparticles have higher antitumor efficacy than those found in free DOX treatment. These results may be related to the efficient accumulation of nanoparticles in the tumor tissue, i.e., the fluorescence intensity in the tumor tissue was stronger than that of any other organs. Our findings suggest that ChitoPEGthDOX nanoparticles may be a promising candidate for ROS-sensitive anticancer delivery against DOX-resistant oral cancer cells. MDPI 2023-09-05 /pmc/articles/PMC10531032/ /pubmed/37762003 http://dx.doi.org/10.3390/ijms241813704 Text en © 2023 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 Yoon, Kaengwon Jung, Seunggon Ryu, Jaeyoung Park, Hong-Ju Oh, Hee-Kyun Kook, Min-Suk Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells |
title | Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells |
title_full | Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells |
title_fullStr | Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells |
title_full_unstemmed | Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells |
title_short | Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells |
title_sort | redox-sensitive delivery of doxorubicin from nanoparticles of poly(ethylene glycol)-chitosan copolymer for treatment of drug-resistant oral cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10531032/ https://www.ncbi.nlm.nih.gov/pubmed/37762003 http://dx.doi.org/10.3390/ijms241813704 |
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