Unambiguous detection of atherosclerosis using bioorthogonal nanomaterials

Abstract

The importance of atherosclerosis is driving research to create improved diagnostic tools based on molecular imaging. Pretargeted imaging is the use of bioorthogonal probes that selectively accumulate upon reaction with a pre-modified biomolecule in vivo. To date, this very promising approach has not been applied to atherosclerosis. Neither has been the use of a single nano-radiomaterial for PET / T 1-MR imaging of atherosclerosis. Here, we synthesized bioorthogonal nano-radiomaterials for in vivo pretargeted molecular imaging in a mouse model of atherosclerosis. Based on tetrazineligation, these functionalized 68 Ga iron oxide nano-radiomaterials provide simultaneous PET and T 1-MRI signals and selectively accumulate in atherosclerotic plaques in mice sequentially injected with trans-cyclooctene-modified antibodies against oxidized LDL followed by the hybrid nano-radiomaterial. Our results demonstrate the ability of this approach to unambiguously detect atherosclerosis. Furthermore, we show the first example of how hybrid imaging can be used for pretargeted bioorthogonal molecular imaging with nanomaterials.

Iron Oxide Nanoparticles: An Alternative for Positive Contrast in Magnetic Resonance Imaging

“…Moreover, they showed a high r1 value of 7.1 mM −1 s −1 at 1.5 T and a low r2/r1 ratio of 2.5, making them useful as contrast agents for T1-weighted MRI. Ex vivo T1-MRI of the aorta of an atherosclerotic mouse model showed a brighter signal on the atherosclerotic plaque [117].…”

Iron Oxide Nanoparticles as Imaging and Therapeutic Agents for Atherosclerosis

“…51,52 PET complements MRI by enabling in vivo real-time and quantifiable imaging of processes at the molecular level 53 however, PET as a sole imaging technique has a hard time differentiating whether the biological process being imaged is disease specific or is occurring within healthy tissue due to the use of nonspecific radionuclide markers. 54 MRI can differentiate between atherosclerotic and normal tissue and therefore complements PET by establishing a specific disease location in which to look at these molecular processes. Pellico et al achieved bi-modal PET/MRI imaging by formulating a pretargeted imaging probe without the use of a chelator intermediate, thereby simplifying and improving the synthesis procedure.…”

Small Dimension—Big Impact! Nanoparticle-Enhanced Non-Invasive and Intravascular Molecular Imaging of Atherosclerosis In Vivo

“…Specific accumulation due to the biorthogonal reaction and selective recognition of oxidized phospholipids was confirmed by a control group of C57BL/6 mice and ApoE −/− mice on a normal diet, as well as control particles (Ga-NRM without tetrazine) and a blocking experiment with the oxLDL antibody injected prior to the full experiment in order to block most of the recognition sites. Ex vivo MRI of the aorta specimen of ApoE -/mice injected with Ga-NRM and Ga-NRM-TZ allowed researchers not involved in the previous experiments to distinguish between control and experimental specimens, due to hyperintense areas representing atherosclerotic lesion sites [34].…”

“…Mainly two considerations mark the difference between scientific curiosity and clinical need with regard to these technologies. [34] (THI0567-lipid NP) liposomal NP bearing gadolinium, selective integrin α4β1 antagonist THI0567 and rhodamine [28] (NAP9-lipid NP) paramagnetic micellar NP conjugated with gadolinium, rhodamine and EMMPRIN-specific binding peptide NAP9 [30] (A5-mNP) micellar NP bearing Cy5.5 and rhodamine, gadolinium and polymers, covalently coupled to phosphatidylserine ligand annexin A5 [36] ( 64 Cu-CANF-comb) NPR-C-targeting polymeric positron-emitting nanoparticle (TAP-SiO2@AuNP) gold NP coated with silicon dioxide linked to a thrombin-activatable fluorescent peptide [39] (DDNP) NP based on paramagnetic iron oxide and Indian ink linked to cRGD-and GA-EWVDV-ligands targeting glycoprotein IIb/IIIa and P-selectin on activated platelets [40].…”