한빛사논문
- 조회454
Hyeyoun Chang1†, Ji Young Yhee1†, Sangmin Jeon1, Man Kyu Shim1, Hong Yeol Yoon1, Sangmin Lee2* and Kwangmeyung Kim1,3*
1Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
2Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
3College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
†Hyeyoun Chang and Ji Young Yhee have contributed equally to this work.
*Correspondence: Sangmin Lee, Kwangmeyung Kim
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.
논문정보
- Research article
- 2023년 03월 (BRIC 등록일 2023-03-24)
- 국내 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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