Biodegradable Iodinated Polymeric Nanoparticle as a Computed Tomography Contrast Agent for Direct Imaging of Cerebral Thrombus.

Abstract

Polymer-based organic nanoparticles enabling direct imaging of cerebral thrombus were developed, distinguishing them from conventional methods that depend on vascular imaging to identify thrombus localization. The HEATI (bis(2-hydroxyethyl) 5-amino-2,4,6-triiodoisophthalate) monomer, synthesized from ATIPA (5-amino-2,4,6-triiodoisophthalic acid), was engineered to contain 58.9 wt % iodine for enhanced X-ray attenuation, confirmed by ¹H NMR spectroscopy. The polymerization of HEATI with oxalyl chloride resulted in a ROS-degradable iodinated polymer (IP-HEATI), as evidenced by the disappearance of the hydroxyl hydrogen peak in the NMR spectrum and a GPC-measured average molecular weight of 2800 g mol^-1. Fib-GC@IP-HEATI nanoparticles were formed through nanoprecipitation, yielding a hydrodynamic diameter of 197.2 ± 64.0 nm and a zeta potential of +24.8 mV. The conjugation of fibrin-targeting peptides increased the size to 255.9 ± 64.2 nm. <i>In vitro</i> assays revealed that Fib-GC@IP-HEATI had superior fibrin-binding affinity compared to GC@IP-HEATI, demonstrated by lower IP-HEATI concentrations in the supernatant. Furthermore, GPC analysis showed that IP-HEATI degraded rapidly in the presence of H₂O₂, with complete degradation within 24 h. <i>In vivo</i> imaging confirmed effective thrombus visualization volume with both GC@IP-HEATI and Fib-GC@IP-HEATI at 30 min after intravenous injection. The imaging-derived thrombus visualization volume decreased substantially within 48 h, consistent with nanoparticle degradation. In conclusion, Fib-GC@IP-HEATI enables imaging of both carotid and cerebral thrombi while undergoing time-dependent degradation, outperforming conventional iodine-based small molecule agents that are unable to visualize thrombi and provide a quantitative assessment of their burden.