Effect of kidney disease and vascular calcification on the circulation and distribution of tetracycline-functionalized polymer nanoparticles

Abstract

Cardiovascular disease is the leading cause of mortality in patients with chronic kidney disease (CKD), and it is exacerbated by vascular calcification (VC). This pathological deposition of hydroxyapatite in blood vessels leads to arterial and organ dysfunction, yet no effective treatment is currently available. Herein, we developed poly(ethylene glycol)-b-poly(lactic acid) (PEG-PLA) nanoparticles functionalized with tetracycline to target VC, given the antibiotic's strong affinity for hydroxyapatite. In rats with CKD, rats with CKD and VC, or healthy animals, we compared the circulation and biodistribution profiles of nanoparticles, as well as the urinary elimination of PEG. Blood and organ analyses revealed similar blood and tissue exposures, with no significant nanoparticle or PEG accumulation in the body. In the same model, we demonstrated that encapsulating vitamin K, a possible inhibitor of VC, alters the pharmacokinetics of the model drug and may enhance its systemic exposure. We employed various methodologies to assess the terminal distribution of nanoparticles in the calcified vascular wall. This work advances our understanding of how kidney disease and vascular calcification can alter the pharmacology of nanoparticles. However, further studies will be necessary to refine tetracycline-based targeting strategies and optimize nanomedicine approaches for VC treatment.