Yan Ji-Jing, Kim Hyunjin, Kim Bomin, Piao Honglin, Jang Joon Young, Kang Tae Kyeom, Lee Wook-Bin, Kim Dohyeon, Jo Seunghyun, Shin Duckhyang, Abuzar Sharif Md, Kim Myung L, Yang Jaeseok, Jon Sangyong
Division of Nephrology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
Adv Healthc Mater. 2025 Mar;14(7):e2403846. doi: 10.1002/adhm.202403846. Epub 2025 Jan 23.
Renal ischemia/reperfusion injury (IRI) is a common form of acute kidney injury. The basic mechanism underlying renal IRI is acute inflammation, where oxidative stress plays an important role. Although bilirubin exhibits potent reactive oxygen species (ROS)-scavenging properties, its clinical application is hindered by problems associated with solubility, stability, and toxicity. In this study, BX-001N, a synthetic polyethylene glycol-conjugated bilirubin 3α nanoparticle is developed and assessed its renoprotective effects in renal IRI. Intravenous administration of BX-001N led to increase uptake in the kidneys with minimal migration to the brain after IRI. Peri-IRI BX-001N administration improves renal function and attenuates renal tissue injury and tubular apoptosis to a greater extent than free bilirubin on day 1 after IRI. BX-001N suppressed renal infiltration of inflammatory cells and reduced expression of TNF-α and MCP-1. Furthermore, BX-001N increases renal tubular regeneration on day 3 and suppresses renal fibrosis on day 28. BX-001N decreases the renal expressions of dihydroethidium, malondialdehyde, and nitrotyrosine after IRI. In conclusion, BX-001N, the first Good Manufacturing Practice-grade synthetic bilirubin-based nanomedicine attenuates acute renal injury and chronic fibrosis by suppressing ROS generation and inflammation after IRI. It shows adequate safety profiles and holds promise as a new therapy for renal IRI.
肾缺血/再灌注损伤（IRI）是急性肾损伤的一种常见形式。肾IRI的基本机制是急性炎症，氧化应激在其中起重要作用。尽管胆红素具有强大的活性氧（ROS）清除特性，但其临床应用因溶解度、稳定性和毒性等问题而受到阻碍。在本研究中，开发了一种合成的聚乙二醇共轭胆红素3α纳米颗粒BX-001N，并评估了其在肾IRI中的肾保护作用。静脉注射BX-001N可使肾脏摄取增加，而在IRI后迁移至脑的量最少。在IRI后第1天，围IRI期给予BX-001N比游离胆红素能更大程度地改善肾功能、减轻肾组织损伤和肾小管凋亡。BX-001N抑制炎症细胞向肾脏浸润，并降低TNF-α和MCP-1的表达。此外，BX-001N在第3天增加肾小管再生，并在第28天抑制肾纤维化。IRI后，BX-001N降低肾脏中二氢乙啶、丙二醛和硝基酪氨酸的表达。总之，BX-001N是首个符合药品生产质量管理规范（GMP）级别的基于合成胆红素的纳米药物，通过抑制IRI后的ROS生成和炎症反应减轻急性肾损伤和慢性纤维化。它显示出足够的安全性，有望成为肾IRI的一种新疗法。
