Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
Biionix (Bionic Materials, Implants & Interfaces) Cluster, Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL 32827, USA.
Cells. 2020 Apr 10;9(4):937. doi: 10.3390/cells9040937.
Diseases of the kidney contribute a significant morbidity and mortality burden on society. Localized delivery of therapeutics directly into the kidney, via its arterial blood supply, has the potential to enhance their therapeutic efficacy while limiting side effects associated with conventional systemic delivery. Targeted delivery in humans is feasible given that we can access the renal arterial blood supply using minimally invasive endovascular techniques and imaging guidance. However, there is currently no described way to reproduce or mimic this approach in a small animal model. Here, we develop in mice a reproducible microsurgical technique for the delivery of therapeutics directly into each kidney, via its arterial blood supply. Using our technique, intra-arterially (IA) injected tattoo dye homogenously stained both kidneys, without staining any other organ. Survival studies showed no resulting mortality or iatrogenic kidney injury. We demonstrate the therapeutic potential of our technique in a mouse model of cisplatin-induced acute kidney injury (AKI). IA injection of mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) successfully reversed AKI, with reduced physiological and molecular markers of kidney injury, attenuated inflammation, and restoration of proliferation and regeneration markers. This reproducible delivery technique will allow for further pre-clinical translational studies investigating other therapies for the treatment of renal pathologies.
肾脏疾病会给社会带来重大的发病率和死亡率负担。通过其动脉血液供应将治疗剂直接递送到肾脏，具有提高其治疗效果的潜力，同时限制与常规全身递送相关的副作用。由于我们可以使用微创血管内技术和成像引导来访问肾动脉血液供应，因此在人类中进行靶向递送是可行的。然而，目前在小型动物模型中还没有描述如何复制或模拟这种方法。在这里，我们在小鼠中开发了一种可重复的显微外科技术，通过其动脉血液供应将治疗剂直接递送到每个肾脏。使用我们的技术，经动脉内（IA）注射的纹身染料均匀地染色了两个肾脏，而没有染色任何其他器官。生存研究表明，没有导致死亡或医源性肾损伤。我们在顺铂诱导的急性肾损伤（AKI）小鼠模型中证明了我们技术的治疗潜力。间质基质细胞（MSC）衍生的细胞外囊泡（EV）的 IA 注射成功地逆转了 AKI，降低了肾脏损伤的生理和分子标志物，减轻了炎症，并恢复了增殖和再生标志物。这种可重复的递药技术将允许进一步进行临床前转化研究，以研究其他治疗肾脏疾病的疗法。
