In vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice: repeated high-dose of glycol chitosan nanoparticles potentially induce cardiotoxicity
- 주제(키워드) Glycol chitosan nanoparticles , Nanotoxicology , Toxicity evaluation , Cardiotoxicity
- 주제(기타) Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology
- 설명문(일반) [Chang, Hyeyoun; Yhee, Ji Young; Jeon, Sangmin; Shim, Man Kyu; Yoon, Hong Yeol; Kim, Kwangmeyung] Korea Inst Sci & Technol, Med Mat Res Ctr, Biomed Res Div, Seoul 02792, South Korea; [Lee, Sangmin] Kyung Hee Univ, Coll Pharm, Dept Pharm, Seoul 02447, South Korea; [Kim, Kwangmeyung] Ewha Womans Univ, Coll Pharm, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 BMC
- 발행년도 2023
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000204289
- 본문언어 영어
- Published As https://doi.org/10.1186/s12951-023-01824-3
초록/요약
BackgroundGlycol 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.ResultsThe CNPs were prepared by conjugating hydrophilic glycol chitosan with hydrophobic 5 beta-cholanic acid and the amphiphilic glycol chitosan-5 beta-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.ConclusionsThis 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.
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