한빛사논문
- 조회246
Yoshio Funahashi1, Seung Hun Park2, Jessica Hebert1, Mahaba B. Eiwaz1, Adam C. Munhall1, Tahnee Groat1, Lingxue Zeng3, Jonghan Kim3∗, Hak Soo Choi2∗, Michael P. Hutchens1,4∗
1Department of Anesthesiology & Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239
2Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
3Department of Biomedical & Nutritional Sciences, University of Massachusetts Lowell, Lowell, MA
4Operative Care Division, Portland Veterans Administration Medical Center, Portland, OR 97239
Corresponding authors : Jonghan Kim, Hak Soo Choi, Michael P. Hutchens
∗shared corresponding authorship
Abstract
Acute kidney injury (AKI) increases the risk of in-hospital death, adds to expense of care, and risk of early chronic kidney disease. AKI often follows an acute event such that timely treatment could ameliorate AKI and potentially reduce the risk of additional disease. Despite therapeutic success of dexamethasone in animal models, clinical trials have not demonstrated broad success. To improve the safety and efficacy of dexamethasone for AKI, we developed and characterized a novel, kidney-specific nanoparticle enabling specific within-kidney targeting to proximal tubular epithelial cells provided by the megalin ligand cilastatin. Cilastatin and dexamethasone were complexed to H-Dot nanoparticles, which were constructed from generally recognized as safe components. Cilastatin/Dexamethasone/H-Dot nanotherapeutics were found to be stable at plasma pH and demonstrated salutary release kinetics at urine pH. In vivo, they were specifically biodistributed to the kidney and bladder, with 75% recovery in the urine and with reduced systemic toxicity compared to native dexamethasone. Cilastatin complexation conferred proximal tubular epithelial cell specificity within the kidney in vivo, and enabled dexamethasone delivery to the proximal tubular epithelial cell nucleus in vitro. The Cilastatin/Dexamethasone/H-Dot nanotherapeutic improved kidney function and reduced kidney cellular injury when administered to male C57BL/6 mice in two translational models of AKI (rhabdomyolysis and bilateral ischemia reperfusion). Thus, our design-based targeting and therapeutic loading of a kidney-specific nanoparticle resulted in preservation of the efficacy of dexamethasone, combined with reduced off-target disposition and toxic effects. Hence, our study illustrates a potential strategy to target AKI and other diseases of the kidney.
논문정보
- Research article
- 2024년 07월 (BRIC 등록일 2024-07-29)
- 국외 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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