Renal-Accumulating Selenium-Doped Carbon Quantum Dots Treat Acute Kidney Injury in Mice.

411 Objectives: Acute kidney injury (AKI) often complicates treatment outcomes of hospitalized patients, which manifests as decreased kidney glomerular filtration and results in toxic chemicals accumulating in blood. The pathogenesis of many AKI conditions has implicated reactive oxygen species (ROS) as a major factor. Ongoing research has shown that nanomaterials are superior to their small molecule counterparts due to the ability to control their biodistribution and intrinsic scavenging abilities. We found that selenium-doped carbon quantum dots localize in the kidneys of mice and eliminate ROS to treat and prevent AKI. Methods: Carbon quantum dots with high antioxidant capacity were prepared by doping selenium (SeCQDs) through a hydrothermal treatment. PET imaging of SeCQDs was preformed to evaluate biodistribution using Zr-89 (half life: 78.4 h) after functionalizing with deferoxamine (DFO; 89Zr-DFO-SeCQDs). AKI was induced by intramuscular injection of 50% glycerol into the hindlimbs (8 mL/kg) as well as by intraperitoneal injection of cisplatin (20 mg/kg) in mice. An equivalent dose of amifostine, an FDA approved drug that acts through a similar mechanism for AKI treatment, was used to demonstrate the superiority of SeCQDs for AKI therapy. Results: SeCQDs were found to rapidly and exclusively accumulate in kidneys as the uptake was 25.37±4.51 %ID/g at 4 h post-injection (p.i.) following intravenous administration and up to 72 h p.i. (20.47 %ID/g) using PET imaging (n=3). Blood serum creatinine (CRE) and blood urea nitrogen (BUN) as well as H&E staining of kidney tissue were used to validate therapeutic effects in the AKI models. Therapeutic doses of SeCQDs were found to be 1 µg per mouse for AKI induced using 50% glycerol. Serum CRE and BUN were markedly lower for SeCQDs (0.38±0.08 and 44.2±11.7 mg/dL, respectively) compared to PBS negative controls (1.76±0.42 and 169.2±55.1 mg/dL, respectively) (n=5 for all groups). Moreover, cisplatin-induced AKI was prevented by administering 50 µg of SeCQDs per mouse as determined by serum CRE and BUN for SeCQDs (0.5±0.07 and 93.4±53.3 mg/dL, respectively) compared to PBS negative controls (2.24±0.4 and 199.2±36.4 mg/dL, respectively) (n=5 for all groups). Amifostine at an equivalent dose in each AKI model (based on selenium and sulfur composition) was ineffective to treat either glycerol- (BUN: 129.4±45 mg/dL, CRE: 1.06±0.4 mg/dL) or cisplatin-induced AKI (BUN: 174±24.3 mg/dL, CRE: 2±0.59 mg/dL) (n=5 for all groups). Conclusion: PET imaging elucidated that SeCQDs predominately accumulate in kidneys for as long as 72 h. The high renal accumulation of SeCQDs proved a highly effective therapy for the treatment of AKI induced using 50% glycerol and prevention of AKI from cisplatin due to its antioxidant properties. In the same animal models, amifostine was unsuccessful in AKI treatment and demonstrates the promise of utilizing nanomaterials over small molecule drugs to treat kidney diseases.