Site-specific chelation therapy with EDTA-loaded albumin nanoparticles reverses arterial calcification in a rat model of chronic kidney disease

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.

Nanoparticle-based targeted delivery of pentagalloyl glucose reverses elastase-induced abdominal aortic aneurysm and restores aorta to the healthy state in mice

“…We used our novel nanoparticles coated with elastin antibody that only targets degraded elastin while sparing healthy elastin to deliver PGG to the AAA site 3,6,13,26 . We chose albumin-based NPs as they are proven to be non-toxic 27 and are used to deliver paclitaxel in patients (Abraxane).…”

Nanoparticle-based targeted delivery of pentagalloyl glucose reverses elastase-induced abdominal aortic aneurysm and restores aorta to the healthy state in mice

“…DiR (1, 1-dioctadecyl-3, 3, 3, 3-tetramethylindotricarbocyanine iodide) (PromoCell GmbH, Heidelberg, Germany) loaded BSA (Seracare, Milford, MA) nanoparticles were prepared by a similar method as described previously [3,6]. Briefly, bovine serum albumin, BSA (250 mg) was dissolved in DI water (4 mL) and then DiR dye (25 mg suspended in acetone) was added to BSA solution and stirred for one hour following the addition of glutaraldehyde (EM grade 70%, EMS, PA, USA) at a concentration of 42 μg/mg BSA.…”

“…We used our novel nanoparticles coated with elastin antibody that only targets degraded elastin while sparing healthy elastin to deliver PGG to the AAA site [3,6,13,26]. We chose albumin-based NPs as they are proven to be non-toxic [27] and are used to deliver paclitaxel in patients (Abraxane).…”

Preparation, characterization and preliminary pharmacokinetic study of pH-sensitive Hydroxyapatite/Zein nano-drug delivery system for doxorubicin hydrochloride

“…Currently, anticancer drugs are limited by weak selectivity towards tumour cells and severe side effects on normal tissues . Nano‐drug delivery systems, such as polymeric micelles, liposomes and nanoparticles (NPs), have been used to increase tumour targeting . NPs are known to enter tumour cells through the enhanced permeability and retention (EPR) effect due to their small size and large surface area …”

“…[1][2][3][4] Nano-drug delivery systems, such as polymeric micelles, liposomes and nanoparticles (NPs), have been used to increase tumour targeting. [5][6][7][8][9] NPs are known to enter tumour cells through the enhanced permeability and retention (EPR) effect due to their small size and large surface area. [9][10][11] Doxorubicin hydrochloride (DOX) is one of the most commonly used anticancer drugs in chemotherapy and is widely used by many researchers in different drug delivery systems.…”