Paramagnetic, Silicon Quantum Dots for Magnetic Resonance and Two-Photon Imaging of Macrophages

Quantum dots (QDs) are an attractive platform for building multimodality imaging probes, but the toxicity for typical cadmium QDs limits enthusiasm for their clinical use. Nontoxic, silicon QDs are more promising but tend to require short-wavelength excitations which are subject to tissue scattering and autofluorescence artifacts. Herein, we report the synthesis of paramagnetic, manganese-doped, silicon QDs (Si_(Mn) QDs) and demonstrate that they are detectable by both MRI and near-infrared excited, two-photon imaging. The Si_(Mn) QDs are coated with dextran sulfate to target them to scavenger receptors on macrophages, a biomarker of vulnerable plaques. TEM images show that isolated QDs have an average core diameter of 4.3 ± 1.0 nm and the hydrodynamic diameters of coated nanoparticles range from 8.3 to 43 nm measured by dynamic light scattering (DLS). The Si_(Mn) QDs have an r_1 relaxivity of 25.50 ± 1.44 mM^(−1) s^(−1) and an r_2 relaxivity of 89.01 ± 3.26 mM^(−1) s^(−1 )(37 °C, 1.4 T). They emit strong fluorescence at 441 nm with a quantum yield of 8.1% in water. Cell studies show that the probes specifically accumulate in macrophages by a receptor-mediated process, are nontoxic to mammalian cells, and produce distinct contrast in both T_1-weighted magnetic resonance and single- or two-photon excitation fluorescence images. These QDs have promising diagnostic potential as high macrophage density is associated with atherosclerotic plaques vulnerable to rupture

Activatable T1 and T2 Magnetic Resonance Imaging Contrast Agents

Magnetic resonance imaging (MRI) has become one of the most important diagnosis tools available in medicine. Typically MRI is not capable of sensing biochemical activities. However, recently emerged activatable MRI contrast agents (CAs), whose relaxivity is variable in response to a specific parameter change in the surrounding physiological microenvironment, potentially allow for MRI to indicate biological processes. Among the various factors influencing the relaxivity of a CA, the number of inner-sphere water molecules (q) directly coordinated to the metal center, the residence time of the coordinated water molecule (τm), and the rotational correlation time representing the molecular tumbling time of a complex (τR) contribute strongly to the relaxivity of an activatable CA. Tuning the ligand structure and properties has been the subject of intensive research for activatable MR CA designs. This review summarizes a variety of activatable MRI CAs sensitive to common variables in microenvironment in vivo, i.e., pH, luminescence, metal ions, redox, and enzymes, etc., with emphasis on the influence of ligand design on parameters q, τm, and τR

Reversible low-light induced photoswitching of crowned spiropyran-DO3A complexed with gadolinium(III) ions.

Photoswitchable spiropyran has been conjugated to the crowned ring system DO3A, which improves its solubility in dipolar and polar media and stabilizes the merocyanine isomer. Adding the lanthanide ion gadolinium(III) to the macrocyclic ring system leads to a photoresponsive magnetic resonance imaging contrast agent that displays an increased spin-lattice relaxation time (T₁) upon visible light stimulation. In this work, the photoresponse of this photochromic molecule to weak light illumination using blue and green light emitting diodes was investigated, simulating the emission spectra from bioluminescent enzymes. Photon emission rate of the light emitting diodes was changed, from 1.75 × 10¹⁶ photons·s⁻¹ to 2.37 × 10¹² photons·s⁻¹. We observed a consistent visible light-induced isomerization of the merocyanine to the spiropyran form with photon fluxes as low as 2.37 × 10¹² photons·s⁻¹ resulting in a relaxivity change of the compound. This demonstrates the potential for use of the described imaging probes in low light level applications such as sensing bioluminescence enzyme activity. The isomerization behavior of gadolinium(III)-ion complexed and non-complexed spiropyran-DO3A was analyzed in water and ethanol solution in response to low light illumination and compared to the emitted photon emission rate from over-expressed Gaussia princeps luciferase

Multimodality PET/MRI agents targeted to activated macrophages

The recent emergence of multimodality imaging, particularly the combination of PET and MRI, has led to excitement over the prospect of improving detection of disease. Iron oxide nanoparticles have become a popular platform for the fabrication of PET/MRI probes owing to their advantages of high MRI detection sensitivity, biocompatibility, and biodegradability. In this article, we report the synthesis of dextran-coated iron oxide nanoparticles (DIO) labeled with the positron emitter ^(64)Cu to generate a PET/MRI probe, and modified with maleic anhydride to increase the negative surface charge. The modified nanoparticulate PET/MRI probe (MDIO-^(64)Cu-DOTA) bears repetitive anionic charges on the surface that facilitate recognition by scavenger receptor type A (SR-A), a ligand receptor found on activated macrophages but not on normal vessel walls. MDIO-^(64)Cu-DOTA has an average iron oxide core size of 7–8 nm, an average hydrodynamic diameter of 62.7 nm, an r_1 relaxivity of 16.8 mM^(−1) s^(−1), and an r_2 relaxivity of 83.9 mM^(−1) s^(−1) (37 °C, 1.4 T). Cell studies confirmed that the probe was nontoxic and was specifically taken up by macrophages via SR-A. In comparison with the nonmodified analog, the accumulation of MDIO in macrophages was substantially improved. These characteristics demonstrate the promise of MDIO-^(64)Cu-DOTA for identification of vulnerable atherosclerotic plaques via the targeting of macrophages

Receptor-targeted iron oxide nanoparticles for molecular MR imaging of inflamed atherosclerotic plaques

In a number of literature reports iron oxide nanoparticles have been investigated for use in imaging atherosclerotic plaques and found to accumulate in plaques via uptake by macrophages, which are critical in the process of atheroma initiation, propagation, and rupture. However, the uptake of these agents is non-specific; thus the labeling efficiency for plaques in vivo is not ideal. We have developed targeted agents to improve the efficiency for labeling macrophage-laden plaques. These probes are based on iron oxide nanoparticles coated with dextran sulfate, a ligand of macrophage scavenger receptor type A (SR-A). We have sulfated dextran-coated iron oxide nanoparticles (DIO) with sulfur trioxide, thereby targeting our nanoparticle imaging agents to SR-A. The sulfated DIO (SDIO) remained mono-dispersed and had an average hydrodynamic diameter of 62 nm, an r_1 relaxivity of 18.1 mM^(−1) s^(−1), and an r_2 relaxivity of 95.8 mM^(−1) s^(−1) (37 °C, 1.4 T). Cell studies confirmed that these nanoparticles were nontoxic and specifically targeted to macrophages. In vivo MRI after intravenous injection of the contrast agent into an atherosclerotic mouse injury model showed substantial signal loss on the injured carotid at 4 and 24 h post-injection of SDIO. No discernable signal decrease was seen at the control carotid and only mild signal loss was observed for the injured carotid post-injection of non-sulfated DIO, indicating preferential uptake of the SDIO particles at the site of atherosclerotic plaque. These results indicate that SDIO can facilitate MRI detection and diagnosis of vulnerable plaques in atherosclerosis

Activatable T₁ and T₂ magnetic resonance imaging contrast agents.

Magnetic resonance imaging (MRI) has become one of the most important diagnosis tools available in medicine. Typically MRI is not capable of sensing biochemical activities. However, recently emerged activatable MRI contrast agents (CAs), whose relaxivity is variable in response to a specific parameter change in the surrounding physiological microenvironment, potentially allow for MRI to indicate biological processes. Among the various factors influencing the relaxivity of a CA, the number of inner-sphere water molecules (q) directly coordinated to the metal center, the residence time of the coordinated water molecule (τ (m)), and the rotational correlation time representing the molecular tumbling time of a complex (τ (R)) contribute strongly to the relaxivity of an activatable CA. Tuning the ligand structure and properties has been the subject of intensive research for activatable MR CA designs. This review summarizes a variety of activatable MRI CAs sensitive to common variables in microenvironment in vivo, i.e., pH, luminescence, metal ions, redox, and enzymes, etc., with emphasis on the influence of ligand design on parameters q, τ (m), and τ (R)