Coulomb nanoradiator-mediated, site-specific thrombolytic proton treatment with a traversing pristine Bragg peak.

Jae-Kun Jeon,Kyuwook Ihm,Sung-Mi Han,Seung-Jun Seo,Won-Seok Chang,Jong-Ki Kim,Soon-Ki Min

doi:10.1038/srep37848

Abstract

Traversing proton beam-irradiated, mid/high-Z nanoparticles produce site-specific enhancement of X-ray photon-electron emission via the Coulomb nanoradiator (CNR) effect, resulting in a nano- to micro-scale therapeutic effect at the nanoparticle-uptake target site. Here, we demonstrate the uptake of iron oxide nanoparticles (IONs) and nanoradiator-mediated, site-specific thrombolysis without damaging the vascular endothelium in an arterial thrombosis mouse model. The enhancement of low-energy electron (LEE) emission and reactive oxygen species (ROS) production from traversing proton beam-irradiated IONs was examined. Flow recovery was only observed in CNR-treated mice, and greater than 50% removal of the thrombus was achieved. A 2.5-fold greater reduction in the thrombus-enabled flow recovery was observed in the CNR group compared with that observed in the untreated ION-only and proton-only control groups (p < 0.01). Enhancement of the X-ray photon-electron emission was evident from both the pronounced Shirley background in the electron yield and the 1.2- to 2.5-fold enhanced production of ROS by the proton-irradiated IONs, which suggests chemical degradation of the thrombus without potent emboli.

Highlights

The Coulomb nanoradiator (CNR) effect is defined as the production of burst emissions of fluorescent X-rays and low-energy electrons (LEEs) via Auger cascades and interatomic/intermolecular Coulomb decay (ICD) paths[13,14] from mid/high-Z nanoparticles under irradiation by a high-energy ion beam[15,16,17,18]
The chemical degradation and reduction of a thrombus by the ION-nanoradiator effect were achieved by CNR-mediated nanoscale energy deposition[19], which was indicated by enhancement of reactive oxygen species (ROS) production or the emission of low-energy ICD electrons
Thrombus formation and complete obstruction were indicated by the reduction or disappearance of the Doppler beat in the Doppler flow probe and confirmed by the flow void on MRI scans

Summary

Introduction

The CNR effect is defined as the production of burst emissions of fluorescent X-rays and low-energy electrons (LEEs) via Auger cascades and interatomic/intermolecular Coulomb decay (ICD) paths[13,14] from mid/high-Z nanoparticles under irradiation by a high-energy ion beam[15,16,17,18]. Instead of the conventional spread-out Bragg-peak (SOBP), which is not sufficiently precise to deliver conformal energy to the vascular target, a traversing proton beam (see Fig. 1) was applied to a mouse arterial thrombosis model dosed with IONs to induce the CNR effect. The chemical degradation and reduction of a thrombus by the ION-nanoradiator effect were achieved by CNR-mediated nanoscale energy deposition[19], which was indicated by enhancement of reactive oxygen species (ROS) production or the emission of low-energy ICD electrons

Methods

Results

Discussion

Conclusion