Toxicological Research

  • 제41권4호
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  • Pages.369-384
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  • 2025
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  • 1976-8257(pISSN)
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  • 2234-2753(eISSN)
한국독성학회 (Korean Society of Toxicology & Korea Environmental Mutagen Society)
권호 표지
DOI QR코드

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Systemic toxicity and toxicokinetics study of self‑assembled‑micelle inhibitory RNA‑targeting amphiregulin in cynomolgus monkeys following intravenous injection

  • Hyeon-Young Kim (Korea Occupational Safety and Health Agency) ;
  • Tae-Rim Kim (siRNAgen Therapeutics and Bioneer Corporation) ;
  • Sung-Hwan Kim (Jeonbuk Branch Institute, Korea Institute of Toxicology) ;
  • In-Hyeon Kim (College of Veterinary Medicine, Chonnam National University) ;
  • Woong-Il Kim (College of Veterinary Medicine, Chonnam National University) ;
  • Jun-Hong Park (siRNAgen Therapeutics and Bioneer Corporation) ;
  • Youngho Ko (siRNAgen Therapeutics and Bioneer Corporation) ;
  • Sungil Yun (siRNAgen Therapeutics and Bioneer Corporation) ;
  • Han-Oh Park (siRNAgen Therapeutics and Bioneer Corporation) ;
  • Jong-Choon Kim (College of Veterinary Medicine, Chonnam National University)
  • 투고 : 2024.08.06
  • 심사 : 2025.03.05
  • 발행 : 2025.07.15
⟨ 이전 논문 다음 논문 ⟩

초록

Self-assembled-micelle inhibitory RNA-targeting amphiregulin (SAMiRNA-AREG) is a novel RNA interference-based nanoparticle for treating fibrotic diseases. The present non-clinical study investigated the potential 4-week repeated intravenous dose toxicity and toxicokinetics of SAMiRNA-AREG at dose levels of 0, 25, 50, and 100 mg/kg/day in cynomolgus monkeys. During the test period, mortality, clinical observation, body and organ weights, food consumption, ophthalmology, electrocardiography, hematology, serum chemistry, urinalysis, and gross and microscopic pathology were examined. Serum samples were collected at various time points (0, 0.1, 0.5, 1, 3, 6, 10, 24, and 48 h) after dosing on days 1 and 29 for toxicokinetic analysis. The repeated intravenous dose toxicity study revealed no treatment-related significant changes or serious toxicity compared to the vehicle control group. SAMiRNA-AREG exhibited a non-linear toxicokinetic profile, with the t1/2 value ranging from 2.97 to 5.88 h in single dosing and from 2.44 to 4.01 h in repeated dosing. In conclusion, the no-observed-adverse-effect level for SAMiRNA-AREG was considered to be≥100 mg/kg/day with Cmax and AUClast values of 650,181.0-764,279.7 ㎍/mL and 539,728.0-606,033.5 h ng/mL, respectively, on day 29, and no target organs were identified.

키워드

과제정보

This research was supported by a grant funded by Civil and Military Dual-use Technology Program (14-CM-EB-09; NTIS 1695004819) and Korea Drug Development Fund (KDDF) funded by Ministry of Science, ICT, and Future Planning (MSIP); the Ministry of Trade, Industry, and Energy (MOTIE); the Ministry of Health and Welfare (MOHW) (Grant No KDDF-201706-03, Republic of Korea). This study was also supported by Chonnam National University (Grant number: 2020-1891).

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