Abstract
Medial arterial calcification (MAC) is a common outcome in diabetes and chronic kidney disease (CKD). It occurs as linear mineral deposits along the degraded elastin lamellae and is responsible for increased aortic stiffness and subsequent cardiovascular events. Current treatments for calcification, particularly in CKD, are predominantly focused on regulating the mineral disturbance and other risk factors. Ethylene diamine tetraacetic acid (EDTA), a chelating agent, can resorb mineral deposits, but the systemic delivery of EDTA may cause side effects such as hypocalcemia and bone resorption. We have developed elastin antibody conjugated albumin nanoparticles that target only degraded elastin in vasculature while sparing healthy tissues. In this study, we tested a targeted nanoparticle-based EDTA chelation therapy to reverse CKD-associated MAC. Renal failure was induced in Sprague-Dawley rats by a high adenine diet supplemented by high P and Ca for 28 days that led to MAC. Intravenous delivery of DiR dye-loaded nanoparticles confirmed targeting to vascular degraded elastin and calcification sites within 24 hours. Next, EDTA-loaded albumin nanoparticles conjugated with an anti-elastin antibody were intravenously injected twice a week for two weeks. The targeted nanoparticles delivered EDTA at the site of vascular calcification and reversed mineral deposits without any untoward effects. Systemic EDTA injections or blank nanoparticles were ineffective in reversing MAC. Reversal of calcification seems to be stable as it did not return after the treatment was stopped for an additional four weeks. Targeted EDTA chelation therapy successfully reversed calcification in this adenine rat model of CKD. We consider that targeted NP therapy will provide an attractive option to reverse calcification and has a high potential for clinical translation.
Highlights
Patients with chronic kidney disease (CKD) have an elevated burden of cardiovascular disease (CVD) and compared to age-matched individuals with normal renal function[1,2], are more likely to die due to CVD than to progress to renal failure
We demonstrated earlier that elastin antibody-conjugated nanoparticles (NPs) can be targeted to vascular calcification sites and that Ethylene diamine tetraacetic acid (EDTA) delivered by these NPs reverses elastin-specific medial arterial calcification (MAC) in a rat model of CaCl2 injury[12]
We used the adenine diet with high P and high Ca-induced CKD rat model to test if albumin NPs loaded with EDTA delivered systemically would target calcific sites and remove vascular mineral deposition without the side effects associated with systemic EDTA chelation
Summary
Patients with chronic kidney disease (CKD) have an elevated burden of cardiovascular disease (CVD) and compared to age-matched individuals with normal renal function[1,2], are more likely to die due to CVD than to progress to renal failure. Price et al introduced a variant to this model by lowering the amount of protein in the diet to 2.5% and higher amounts of P than in a standard rodent diet[16] Renal pathology of this model mimics the clinical situation with the development of hyperphosphatemia, hypocalcemia, severe secondary hyperparathyroidism, and other biochemical changes such as elevated serum creatinine and elevated blood urea nitrogen that lead to vascular calcification. This model is considered a useful tool to study complications of arterial calcification in CKD patients and to evaluate therapeutic agents in the prevention of uremia-related MAC17,18. We used the adenine diet with high P and high Ca-induced CKD rat model to test if albumin NPs loaded with EDTA delivered systemically would target calcific sites and remove vascular mineral deposition without the side effects associated with systemic EDTA chelation
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