Targeted chelation therapy with EDTA-loaded albumin nanoparticles regresses arterial calcification without causing systemic side effects

• Published in: Journal of controlled release Vol. 196; pp. 79 - 86
• Main Authors: Lei, Yang, Nosoudi, Nasim, Vyavahare, Naren
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28.12.2014
• Subjects: Aged; Albumin nanoparticles; Albumins - chemistry; Animals; Arteriosclerosis; Calcinosis - drug therapy; Calcinosis - pathology; Chelating Agents - administration & dosage; Chelating Agents - adverse effects; Chelating Agents - therapeutic use; Chelation Therapy - adverse effects; Chelation Therapy - methods; Drug Delivery Systems; Edetic Acid - administration & dosage; Edetic Acid - adverse effects; Edetic Acid - therapeutic use; Elastin antibody; Female; Humans; In Vitro Techniques; Male; Medial calcification; Middle Aged; Nanoparticles; Rats; Swine; Targeted EDTA chelation therapy; Albumin nanoparticles; Elastin antibody; Arteriosclerosis; Targeted EDTA chelation therapy; Medial calcification
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2014.09.029

Elastin-specific medial arterial calcification (MAC) is an arterial disease commonly referred as Monckeberg's sclerosis. It causes significant arterial stiffness, and as yet, no clinical therapy exists to prevent or reverse it. We developed albumin nanoparticles (NPs) loaded with disodium ethylene diaminetetraacetic acid (EDTA) that were designed to target calcified elastic lamina when administrated by intravenous injection. We optimized NP size, charge, and EDTA-loading efficiency (150–200nm, zeta potential of −22.89 – −31.72mV, loading efficiency for EDTA ~20%) for in vivo targeting in rats. These NPs released EDTA slowly for up to 5days. In both ex-vivo study and in vivo study with injury-induced local abdominal aortic calcification, we showed that elastin antibody-coated and EDTA-loaded albumin NPs targeted the damaged elastic lamina while sparing healthy artery. Intravenous NP injections reversed elastin-specific MAC in rats after four injections over a 2-week period. EDTA-loaded albumin NPs did not cause the side effects observed in EDTA injection alone, such as decrease in serum calcium (Ca), increase in urine Ca, or toxicity to kidney. There was no bone loss in any treated groups. We demonstrate that elastin antibody-coated and EDTA-loaded albumin NPs might be a promising nanoparticle therapy to reverse elastin-specific MAC and circumvent side effects associated with systemic EDTA chelation therapy. [Display omitted]