한빛사논문
- 조회227
Minseok Suh1,2,3†, Ji Yong Park1,2,4,5†, Guen Bae Ko4,6, Ji Yoon Kim1,7, Do Won Hwang8, Louis Rees9, Gillian E Conway9, Shareen H Doak9, Hyelim Kang10, Nohyun Lee10, Taeghwan Hyeon11,12, Yun-Sang Lee1,2* and Dong Soo Lee1,2,3,4,5,13*
1Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul, Korea
2Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Korea
3Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea
4Medical Research Center, College of Medicine, Seoul National University, Seoul, Korea
5Cancer Research Institute, Seoul National University, Seoul 03080, Republic of Korea
6Brightonix Imaging Inc, Seoul, Korea
7The Interdisciplinary Program of Cancer Biology, Seoul National University, Seoul, Korea
8Research and Development Center, THERABEST Co., Ltd., Seoul, South Korea
9In Vitro Toxicology Group, Institute of Life Science, Swansea University Medical School, Swansea, Wales, UK
10School of Advanced Materials Engineering, Kookmin University, Seoul, Korea
11Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Korea
12School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul, Korea
13Medical Science and Engineering, School of Convergence Science and Technology, Pohang University of Science and Technology (POSTECH), Pohang, Korea
†Minseok Suh and Ji Yong Park contributed to this paper evenly as co-first author.
*Correspondence: Yun-Sang Lee, Dong Soo Lee
Abstract
Background
Iron oxide nanoparticles (IONPs) have been cleared by the Food and Drug Administration (FDA) for various clinical applications, such as tumor-targeted imaging, hyperthermia therapy, drug delivery, and live-cell tracking. However, the application of IONPs as T1 contrast agents has been restricted due to their high r2 values and r2/r1 ratios, which limit their effectiveness in T1 contrast enhancement. Notably, IONPs with diameters smaller than 5 nm, referred to as extremely small-sized IONPs (ESIONs), have demonstrated potential in overcoming these limitations. To advance the clinical application of ESIONs as T1 contrast agents, we have refined a scale-up process for micelle encapsulation aimed at improving the hydrophilization of ESIONs, and have carried out comprehensive in vivo biodistribution and preclinical toxicity assessments.
Results
The optimization of the scale-up micelle-encapsulation process, specifically employing Tween60 at a concentration of 10% v/v, resulted in ESIONs that were uniformly hydrophilized, with an average size of 9.35 nm and a high purification yield. Stability tests showed that these ESIONs maintained consistent size over extended storage periods and dispersed effectively in blood and serum-mimicking environments. Relaxivity measurements indicated an r1 value of 3.43 mM− 1s− 1 and a favorable r2/r1 ratio of 5.36, suggesting their potential as T1 contrast agents. Biodistribution studies revealed that the ESIONs had extended circulation times in the bloodstream and were primarily cleared via the hepatobiliary route, with negligible renal excretion. We monitored blood clearance and organ distribution using positron emission tomography and magnetic resonance imaging (MRI). Additionally, MRI signal variations in a dose-dependent manner highlighted different behaviors at varying ESIONs concentrations, implying that optimal dosages might be specific to the intended imaging application. Preclinical safety evaluations indicated that ESIONs were tolerable in rats at doses up to 25 mg/kg.
Conclusions
This study effectively optimized a scale-up process for the micelle encapsulation of ESIONs, leading to the production of hydrophilic ESIONs at gram-scale levels. These optimized ESIONs showcased properties conducive to T1 contrast imaging, such as elevated r1 relaxivity and a reduced r2/r1 ratio. Biodistribution study underscored their prolonged bloodstream presence and efficient clearance through the liver and bile, without significant renal involvement. The preclinical toxicity tests affirmed the safety of the ESIONs, supporting their potential use as T1 contrast agent with versatile clinical application.
논문정보
- Research article
- 2024년 07월 (BRIC 등록일 2024-07-19)
- 국내(교신)+국외 연구진
- 바이오·의료융합 > 뇌인지과학
댓글 작성 로그인
팝업 닫기관련 링크
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
