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

J Control Release. 2014 Dec 28;196:79-86. doi: 10.1016/j.jconrel.2014.09.029. Epub 2014 Oct 5.

Abstract

Background and aims: 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.

Methods and results: We optimized NP size, charge, and EDTA-loading efficiency (150-200 nm, zeta potential of -22.89--31.72 mV, loading efficiency for EDTA~20%) for in vivo targeting in rats. These NPs released EDTA slowly for up to 5 days. 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.

Conclusion: 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.

Keywords: Albumin nanoparticles; Arteriosclerosis; Elastin antibody; Medial calcification; Targeted EDTA chelation therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Albumins / chemistry
  • Animals
  • 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*
  • Female
  • Humans
  • In Vitro Techniques
  • Male
  • Middle Aged
  • Nanoparticles
  • Rats
  • Swine

Substances

  • Albumins
  • Chelating Agents
  • Edetic Acid