Reversion of arterial calcification by elastin-targeted DTPA-HSA nanoparticles.

Abstract

Generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE) are characterized by pathologic calcifications in the media of large- and medium sized arteries. GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. Different treatment approaches including bisphosphonates and orally administered pyrophosphate (PPi) were investigated in recent years, but reversion of calcification could not be achieved. With this study, we pursued the idea of a combination of controlled drug delivery through nanoparticles and active targeting via antibody conjugation to develop a treatment for GACI and PXE. To establish a suitable drug delivery system, the chelating drug diethylenetriamine pentaacetic acid (DTPA) was conjugated to nanoparticles composed of human serum albumin (HSA) as biodegradable and non-toxic particle matrix. To accomplish an active targeting of the elastic fibers exposed through calcification of the affected areas, the nanoparticle surface was functionalized with an anti-elastin antibody. Cytotoxicity and cell interaction studies revealed favorable preconditions for the intended i.v. application. The chelating ability was evaluated in vitro and ex vivo on aortic ring culture isolated from two mouse models of GACI and PXE. The positive results led to the conclusion that the produced nanoparticles might be a promising therapy in the treatment of GACI and PXE.

• Authors: Jacqueline Keuth, Yvonne Nitschke, Dennis Mulac, Kristina Riehemann, Frank Rutsch, Klaus Langer
• Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 150 Pg. 108-119 (May 2020) ISSN: 1873-3441 [Electronic] Netherlands
• PMID: 32151731 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Abcc6 protein, mouse
• Antibodies
• Calcium Chelating Agents
• Drug Carriers
• Multidrug Resistance-Associated Proteins
• Pentetic Acid
• Elastin
• Serum Albumin, Human

Topics

• Animals
• Antibodies (chemistry, immunology)
• Aorta (drug effects, immunology, metabolism, pathology)
• Calcium Chelating Agents (chemistry, pharmacology)
• Cell Line
• Drug Carriers
• Drug Compounding
• Elastin (immunology)
• Female
• Humans
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Multidrug Resistance-Associated Proteins (deficiency, genetics)
• Nanoparticles
• Pentetic Acid (chemistry, pharmacology)
• Pseudoxanthoma Elasticum (drug therapy, immunology, metabolism, pathology)
• Serum Albumin, Human (chemistry, metabolism)
• Vascular Calcification (drug therapy, immunology, metabolism, pathology)