Poly(vinyl alcohol) reduced and capped gold nanoparticles as contrast enhancers to target and improve detection of medial calcification

Medial calcification is the pathological deposition of calcium phosphate (CaP) minerals in the elastin-rich medial layers of arteries, leading to vessel stiffening and increased risk of heart failure. There are no drugs to treat medial calcification, and thus it would be important to detect the disease as early as possible to enable adequate prevention. In the clinic, X-ray based computed tomography (CT) is used to diagnose medial calcification, but the few and small CaP minerals present in early stages of medial calcification do not provide enough X-ray contrast to be detectable by CT. Herein, we propose poly(vinyl alcohol) (PVA) reduced and capped gold nanoparticles (PVA@AuNPs) to target medial calcification and improve its detection in early stages. AuNPs can greatly absorb X-rays and thus work as contrast enhancers for CT. Results show that PVA@AuNPs can bind to CaP minerals containing hydroxyl ions on their surface, most likely via hydrogen-bond interactions with PVA capping polymers; indeed, mineral binding efficiency depends on the hydrolysis degree of PVA. AuNPs prepared from 99 %+ hydrolyzed PVA (PVA99@AuNPs) bind selectively to calcified vs. non-calcified elastin in vitro, and in vivo they improve the contrast of medial calcification in 4-week-old matrix Gla-protein deficient mice imaged through micro-CT. STATEMENT OF SIGNIFICANCE: The few and small calcium phosphate (CaP) minerals present in early stages of medial calcification do not provide enough contrast for clinical detection via computed tomography (CT). Herein, we show that 99 %+ hydrolyzed poly(vinyl alcohol) reduced and capped gold nanoparticles (PVA99@AuNPs) selectively bind CaP minerals in medial calcification, thus improving their contrast and (micro)CT detection. Unlike previously proposed targeting agents, PVA99@AuNPs bind to CaP mineral phases present in early-stage medial calcification but not to the extracellular matrix onto which minerals are deposited, thus enabling accurate and specific targeting. Their straightforward synthesis and biocompatibility significantly enhance their potential for clinical translation. Earlier detection of medial calcification would greatly improve disease management, particularly important since no treatments are available for the disease.