Effects of Nanoprobe Morphology on Cellular Binding and Inflammatory Responses: Hyaluronan-Conjugated Magnetic Nanoworms for Magnetic Resonance Imaging of Atherosclerotic Plaques

Abstract

Atherosclerosis is an inflammatory disease of arterial walls and the rupturing of atherosclerotic plaques is a major cause of heart attack and stroke. Imaging techniques that can enable the detection of atherosclerotic plaques before clinical manifestation are urgently needed. Magnetic resonance imaging (MRI) is a powerful technique to image the morphology of atherosclerotic plaques. In order to better analyze molecular processes in plaques, contrast agents that can selectively bind to plaque receptors will prove invaluable. CD44 is a cell surface protein overexpressed in plaque tissues, the level of which can be correlated with the risks of plaque rupture. Thus, targeting CD44 is an attractive strategy for detection of atherosclerotic plaques. Herein, we report the synthesis of hyaluronan-conjugated iron oxide nanoworms (HA-NWs). A new purification and gel electrophoresis protocol was developed to ensure the complete removal of free HA from HA-NWs. Compared to the more traditional spherical HA-bearing nanoparticles, HA-NWs had an elongated shape, which interacted much stronger with CD44-expressing cells in CD44- and HA-dependent manners. Furthermore, the HA-NWs did not induce much inflammatory response compared to the spherical HA nanoparticles. When assessed in vivo, HA-NWs enabled successful imaging of atherosclerotic plaques in a clinically relevant model of ApoE knockout transgenic mice for noninvasive plaque detection by MRI. Thus, nanoprobe shape engineering can be a useful strategy to significantly enhance their desired biological properties.