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聚（乙二醇）-壳聚糖共聚物纳米粒对阿霉素的氧化还原敏感递送用于治疗耐药口腔癌细胞

Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells.

作者信息

Yoon Kaengwon, Jung Seunggon, Ryu Jaeyoung, Park Hong-Ju, Oh Hee-Kyun, Kook Min-Suk

机构信息

El-Dental Clinic, Seomun Daero Street 625, Namgu, Gwangju 61737, Republic of Korea.

Department of Maxillofacial Oral Surgery, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea.

出版信息

Int J Mol Sci. 2023 Sep 5;24(18):13704. doi: 10.3390/ijms241813704.

DOI:10.3390/ijms241813704
PMID:37762003
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10531032/
Abstract

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 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.

摘要

合成了对活性氧（ROS）敏感的聚合物纳米颗粒，用于抗癌药物阿霉素（DOX）的肿瘤靶向。为此，合成了壳聚糖-甲氧基聚（乙二醇）（mPEG）（ChitoPEG）接枝共聚物，然后使用硫缩酮连接子将DOX连接到壳聚糖主链上。随后，通过氢核磁共振（NMR）光谱确认了DOX共轭ChitoPEG共聚物（ChitoPEGthDOX）的化学结构。ChitoPEGthDOX共轭物的纳米颗粒呈球形，大小约为100 nm。透射电子显微镜（TEM）显示，ChitoPEGthDOX纳米颗粒在过氧化氢存在下会分解，并且粒径分布也从单峰/窄分布模式变为多峰/宽分布模式。此外，在过氧化氢存在下，DOX释放得更快。这些结果表明ChitoPEGthDOX纳米颗粒具有ROS敏感性。使用AT84口腔鳞状癌细胞评估了纳米颗粒的抗癌活性。此外，在体外制备了耐DOX的AT84细胞。DOX及其纳米颗粒在体外对DOX敏感和耐DOX的AT84细胞均显示出剂量依赖性细胞毒性。然而，DOX本身对耐DOX的AT84细胞的细胞毒性降低，而纳米颗粒对DOX敏感和耐DOX的AT84细胞显示出几乎相似的细胞毒性。该结果可能是由于游离DOX的细胞内递送受到抑制，而纳米颗粒在耐DOX的细胞中被有效内化。对携带耐DOX的AT84细胞的肿瘤异种移植模型的体内研究表明，纳米颗粒比游离DOX治疗具有更高的抗肿瘤功效。这些结果可能与纳米颗粒在肿瘤组织中的有效积累有关，即肿瘤组织中的荧光强度比任何其他器官都强。我们的研究结果表明，ChitoPEGthDOX纳米颗粒可能是针对耐DOX的口腔癌细胞进行ROS敏感型抗癌递送的有前途的候选物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/582d4b5ee155/ijms-24-13704-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/02cc3550e3fb/ijms-24-13704-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/5b0ccc92b9d5/ijms-24-13704-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/8294ec5a2d06/ijms-24-13704-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/45d5e07189a6/ijms-24-13704-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/4f15f38e7338/ijms-24-13704-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/e4d0b971a10c/ijms-24-13704-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/013943624ef9/ijms-24-13704-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/147b2d23ea8b/ijms-24-13704-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/582d4b5ee155/ijms-24-13704-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/02cc3550e3fb/ijms-24-13704-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/5b0ccc92b9d5/ijms-24-13704-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/8294ec5a2d06/ijms-24-13704-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/45d5e07189a6/ijms-24-13704-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/4f15f38e7338/ijms-24-13704-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/e4d0b971a10c/ijms-24-13704-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/013943624ef9/ijms-24-13704-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/147b2d23ea8b/ijms-24-13704-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60c5/10531032/582d4b5ee155/ijms-24-13704-g009.jpg

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本文引用的文献

[1]
CD44 Receptor-Mediated/Reactive Oxygen Species-Sensitive Delivery of Nanophotosensitizers against Cervical Cancer Cells.

Int J Mol Sci. 2022-3-25

[2]
Nanocarrier cancer therapeutics with functional stimuli-responsive mechanisms.

J Nanobiotechnology. 2022-3-24

[3]
Reactive Oxygen Species-Sensitive Nanophotosensitizers of Methoxy Poly(ethylene glycol)-Chlorin e6/Phenyl Boronic Acid Pinacol Ester Conjugates Having Diselenide Linkages for Photodynamic Therapy of Cervical Cancer Cells.

Materials (Basel). 2021-12-25

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The role of tumor acidification in aggressiveness, cell dissemination and treatment resistance of oral squamous cell carcinoma.

Life Sci. 2022-1-1

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Caffeic Acid Phenethyl Ester-Incorporated Radio-Sensitive Nanoparticles of Phenylboronic Acid Pinacol Ester-Conjugated Hyaluronic Acid for Application in Radioprotection.

Int J Mol Sci. 2021-6-14

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Impact of delay in diagnosis and treatment-initiation on disease stage and survival in oral cavity cancer: a systematic review.

Acta Oncol. 2021-9

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Antioxidants (Basel). 2021-3-25

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Drug Resistance in Glioblastoma: The Two Faces of Oxidative Stress.

Front Mol Biosci. 2021-1-27

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Int J Mol Sci. 2020-5-2

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