In vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice: repeated high-dose of glycol chitosan nanoparticles potentially induce cardiotoxicity
Abstract Background Glycol chitosan nanoparticles (CNPs) have emerged as an effective drug delivery system for cancer diagnosis and treatment. Although they have great biocompatibility owing to biodegradable chemical structure and low immunogenicity, sufficient information on in vivo toxicity to und...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-03-01
|
| Series: | Journal of Nanobiotechnology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12951-023-01824-3 |
| _version_ | 1797863671601299456 |
|---|---|
| author | Hyeyoun Chang Ji Young Yhee Sangmin Jeon Man Kyu Shim Hong Yeol Yoon Sangmin Lee Kwangmeyung Kim |
| author_facet | Hyeyoun Chang Ji Young Yhee Sangmin Jeon Man Kyu Shim Hong Yeol Yoon Sangmin Lee Kwangmeyung Kim |
| author_sort | Hyeyoun Chang |
| collection | DOAJ |
| description | Abstract Background Glycol chitosan nanoparticles (CNPs) have emerged as an effective drug delivery system for cancer diagnosis and treatment. Although they have great biocompatibility owing to biodegradable chemical structure and low immunogenicity, sufficient information on in vivo toxicity to understand the potential risks depending on the repeated high-dose have not been adequately studied. Herein, we report the results of in vivo toxicity evaluation for CNPs focused on the number and dose of administration in healthy mice to provide a toxicological guideline for a better clinical application of CNPs. Results The CNPs were prepared by conjugating hydrophilic glycol chitosan with hydrophobic 5β-cholanic acid and the amphiphilic glycol chitosan-5β-cholanic acid formed self-assembled nanoparticles with its concentration-dependent homogeneous size distributions (265.36–288.3 nm) in aqueous condition. In cell cultured system, they showed significantly high cellular uptake in breast cancer cells (4T1) and cardiomyocytes (H9C2) than in fibroblasts (L929) and macrophages (Raw264.7) in a dose- and time-dependent manners, resulting in severe necrotic cell death in H9C2 at a clinically relevant highly concentrated condition. In particular, when the high-dose (90 mg/kg) of CNPs were intravenously injected into the healthy mice, considerable amount was non-specifically accumulated in major organs (liver, lung, spleen, kidney and heart) after 6 h of injection and sustainably retained for 72 h. Finally, repeated high-dose of CNPs (90 mg/kg, three times) induced severe cardiotoxicity accompanying inflammatory responses, tissue damages, fibrotic changes and organ dysfunction. Conclusions This study demonstrates that repeated high-dose CNPs induce severe cardiotoxicity in vivo. Through the series of toxicological assessments in the healthy mice, this study provides a toxicological guideline that may expedite the application of CNPs in the clinical settings. |
| first_indexed | 2024-04-09T22:39:15Z |
| format | Article |
| id | doaj.art-560183bd7ecd4f038878a94bde70572b |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-09T22:39:15Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-560183bd7ecd4f038878a94bde70572b2023-03-22T12:16:25ZengBMCJournal of Nanobiotechnology1477-31552023-03-0121111410.1186/s12951-023-01824-3In vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice: repeated high-dose of glycol chitosan nanoparticles potentially induce cardiotoxicityHyeyoun Chang0Ji Young Yhee1Sangmin Jeon2Man Kyu Shim3Hong Yeol Yoon4Sangmin Lee5Kwangmeyung Kim6Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and TechnologyMedicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and TechnologyMedicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and TechnologyMedicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and TechnologyMedicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and TechnologyDepartment of Pharmacy, College of Pharmacy, Kyung Hee UniversityMedicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and TechnologyAbstract Background Glycol chitosan nanoparticles (CNPs) have emerged as an effective drug delivery system for cancer diagnosis and treatment. Although they have great biocompatibility owing to biodegradable chemical structure and low immunogenicity, sufficient information on in vivo toxicity to understand the potential risks depending on the repeated high-dose have not been adequately studied. Herein, we report the results of in vivo toxicity evaluation for CNPs focused on the number and dose of administration in healthy mice to provide a toxicological guideline for a better clinical application of CNPs. Results The CNPs were prepared by conjugating hydrophilic glycol chitosan with hydrophobic 5β-cholanic acid and the amphiphilic glycol chitosan-5β-cholanic acid formed self-assembled nanoparticles with its concentration-dependent homogeneous size distributions (265.36–288.3 nm) in aqueous condition. In cell cultured system, they showed significantly high cellular uptake in breast cancer cells (4T1) and cardiomyocytes (H9C2) than in fibroblasts (L929) and macrophages (Raw264.7) in a dose- and time-dependent manners, resulting in severe necrotic cell death in H9C2 at a clinically relevant highly concentrated condition. In particular, when the high-dose (90 mg/kg) of CNPs were intravenously injected into the healthy mice, considerable amount was non-specifically accumulated in major organs (liver, lung, spleen, kidney and heart) after 6 h of injection and sustainably retained for 72 h. Finally, repeated high-dose of CNPs (90 mg/kg, three times) induced severe cardiotoxicity accompanying inflammatory responses, tissue damages, fibrotic changes and organ dysfunction. Conclusions This study demonstrates that repeated high-dose CNPs induce severe cardiotoxicity in vivo. Through the series of toxicological assessments in the healthy mice, this study provides a toxicological guideline that may expedite the application of CNPs in the clinical settings.https://doi.org/10.1186/s12951-023-01824-3Glycol chitosan nanoparticlesNanotoxicologyToxicity evaluationCardiotoxicity |
| spellingShingle | Hyeyoun Chang Ji Young Yhee Sangmin Jeon Man Kyu Shim Hong Yeol Yoon Sangmin Lee Kwangmeyung Kim In vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice: repeated high-dose of glycol chitosan nanoparticles potentially induce cardiotoxicity Journal of Nanobiotechnology Glycol chitosan nanoparticles Nanotoxicology Toxicity evaluation Cardiotoxicity |
| title | In vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice: repeated high-dose of glycol chitosan nanoparticles potentially induce cardiotoxicity |
| title_full | In vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice: repeated high-dose of glycol chitosan nanoparticles potentially induce cardiotoxicity |
| title_fullStr | In vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice: repeated high-dose of glycol chitosan nanoparticles potentially induce cardiotoxicity |
| title_full_unstemmed | In vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice: repeated high-dose of glycol chitosan nanoparticles potentially induce cardiotoxicity |
| title_short | In vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice: repeated high-dose of glycol chitosan nanoparticles potentially induce cardiotoxicity |
| title_sort | in vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice repeated high dose of glycol chitosan nanoparticles potentially induce cardiotoxicity |
| topic | Glycol chitosan nanoparticles Nanotoxicology Toxicity evaluation Cardiotoxicity |
| url | https://doi.org/10.1186/s12951-023-01824-3 |
| work_keys_str_mv | AT hyeyounchang invivotoxicityevaluationoftumortargetedglycolchitosannanoparticlesinhealthymicerepeatedhighdoseofglycolchitosannanoparticlespotentiallyinducecardiotoxicity AT jiyoungyhee invivotoxicityevaluationoftumortargetedglycolchitosannanoparticlesinhealthymicerepeatedhighdoseofglycolchitosannanoparticlespotentiallyinducecardiotoxicity AT sangminjeon invivotoxicityevaluationoftumortargetedglycolchitosannanoparticlesinhealthymicerepeatedhighdoseofglycolchitosannanoparticlespotentiallyinducecardiotoxicity AT mankyushim invivotoxicityevaluationoftumortargetedglycolchitosannanoparticlesinhealthymicerepeatedhighdoseofglycolchitosannanoparticlespotentiallyinducecardiotoxicity AT hongyeolyoon invivotoxicityevaluationoftumortargetedglycolchitosannanoparticlesinhealthymicerepeatedhighdoseofglycolchitosannanoparticlespotentiallyinducecardiotoxicity AT sangminlee invivotoxicityevaluationoftumortargetedglycolchitosannanoparticlesinhealthymicerepeatedhighdoseofglycolchitosannanoparticlespotentiallyinducecardiotoxicity AT kwangmeyungkim invivotoxicityevaluationoftumortargetedglycolchitosannanoparticlesinhealthymicerepeatedhighdoseofglycolchitosannanoparticlespotentiallyinducecardiotoxicity |