Bioinspired, Multi-Antioxidant Nanomedicine for Improved Treatment of Acute Kidney Injury

About This Grant

PROJECT SUMMARY Acute kidney injury (AKI) is marked by a rapid loss of kidney function and is associated with high mortality, particularly in critical care settings. Despite advances in early biomarkers and standardized definitions, current clinical management remains largely supportive, aiming only to mitigate secondary complications. A key driver of AKI pathogenesis is the overproduction of reactive oxygen species (ROS), prompting interest in antioxidant- based therapies. However, conventional small-molecule antioxidants suffer from limited bioavailability and nonspecific distribution, necessitating frequent high-dose administrations that reduce the therapeutic impact. Chalcogens (or the oxygen family), known for their redox properties, can form stable colloidal nanoparticles when combined with phenolic compounds, which are natural antioxidants found in plants and foodstuffs. This combination enhances ROS scavenging capacity and provides metal-chelating abilities. I previously demonstrated that sub-5 nm silver chalcogenide nanoparticles are concentrated in the kidneys and undergo predominant renal clearance. Therefore, I hypothesize that ultrasmall chalcogen-phenolic nanoparticles (CPNP) can more effectively neutralize ROS and accumulate in the kidneys compared to small-molecule antioxidants, thus improving treatment efficacy while reducing dosage and cost. My preliminary investigation shows that a CPNP formulation composed of tellurium and caffeic acid (TeCA-NP) exhibits potent antioxidant activity, kidney-specific delivery, and therapeutic benefit in a murine model of glycerol-induced AKI. Leveraging my expertise in nanomaterial design, I will synthesize a library of sub-5 nm CPNP formulations and evaluate their antioxidant activity in vitro (Aim 1). This approach is expected to yield at least one additional candidate with performance comparable to or exceeding that of TeCA-NP, thereby strengthening the feasibility and robustness of the proposed work. I will then assess the therapeutic efficacy of both formulations in a clinically relevant model of ischemia-reperfusion-induced AKI at the histological, molecular, and functional levels (Aim 2). Finally, I will examine the biodistribution, pharmacokinetics, and in vivo safety of radiolabeled CPNP through positron emission tomography imaging (Aim 3). These comparative studies will identify an optimized lead and provide preclinical data to support the translational potential of this novel nanotherapeutic platform for AKI and other oxidative stress-related diseases. This K01 application will also provide valuable educational and training opportunities to refine my skills in nanomaterial synthesis while broadening my expertise in nuclear medicine imaging, drug delivery, and organ injury treatment. I have assembled a multidisciplinary team of experienced mentors across two institutions to guide me in this undertaking. These efforts will generate data for future R01 applications and position me to achieve my long-term goal of establishing an independent research program at the interface of nanomedicine and molecular imaging to improve disease diagnosis and treatment.