Self-confirming "AND" logic nanoparticles for fault-free MRI

Abstract

Achieving high accuracy in the imaging of biological targets is a challenging issue. For MRI, to enhance imaging accuracy, two different imaging modes with specific contrast agents are used; one is a T1 type for a "positive" MRI signal and the other is a T2 type for a "negative" signal. Conventional contrast agents respond only in a single imaging mode and frequently encounter ambiguities in the MR images. Here, we propose a "magnetically decoupled" core-shell design concept to develop a dual mode nanoparticle contrast agent (DMCA). This DMCA not only possesses superior MR contrast effects but also has the unique capability of displaying "AND" logic signals in both the T1 and T2 modes. The latter enables self-confirmation of images and leads to greater diagnostic accuracy. A variety of novel DMCAs are possible, and the use of DMCAs can potentially bring the accuracy of MR imaging of diseases to a higher level.

Figure 1

Magnetic coupling between T1 and T2 contrast materials and the structures for a dual mode nanoparticle contrast agent (DMCA). (a) Electronic spins of paramagnetic T1 contrast materials are affected by a magnetic field from superparamagnetic T2 contrast materials when they are in close proximity. (b) Possible structure for a dual mode nanoparticle contrast agent with separating layers to prevent magnetic coupling between them.

Figure 2

T1 and T2 MR imaging of DMCA with a separating layer of SiO₂. (a) Schematic and transmission electron microscope (TEM) image of core-shell type DMCA [MnFe₂O₄@SiO₂@Gd₂O(CO₃)₂]. (b) TEM images of DMCA with variable separating layer thickness (4, 8, 12, 16 and 20 nm), having a fixed MnFe₂O₄ core (15 nm in diameter) and a Gd₂O(CO₃)₂ shell (1.5 nm). (c) T1- and (d) T2-weighted MR images and their color coded images of DMCA with various SiO₂ thickness by using 4.7 T MRI. Contrast agents: 200 μM (Gd) for T1 image, 100 μM (Mn+Fe) for T2 images. The images of Gd-DTPA and Feridex were taken together for the comparison purpose. In the color coded image, positive and negative contrasts were indicated by red and blue color, respectibly. (e) Graph of r1 vs. SiO₂ thickness. (f) Graph of T1 quenching vs. SiO₂ thickness [T1 quenching (%) = {(r1_{SiO2@GdO2(CO3)2}-r1_DMCA)/r1_{SiO2@Gd2O(CO3)2}}×100, r1_{SiO2@Gd2O(CO3)2} = 31 mM^-1s^-1 (Table S1)]. (g) Graph of r2 vs. SiO₂ thickness. (h) r1 and r2 of DMCA, MnFe₂O₄, Gd-DTPA and Feridex.

Figure 3

DMCA as AND logic contrast agent. (a) T1- and T2-weighted MR images of DMCA [MnFe₂O₄@SiO₂@Gd₂O(CO₃)₂, SiO₂ = 16 nm], Feridex, Gd-DTPA and water. In T1 mode, positive (or bright) MR image was “ON” state, while negative (or dark) image was “OFF” state. In T2 mode, dark image was “ON” state, while bright image was “OFF” state. Only DMCA exhibited “ON” state in both T1- and T2-weighted images to give its AND logic. (b) T1- and T2-weighted transverse MR images of a mouse where 1 mm diameter tubings containing DMCA, Feridex and Gd-DTPA were implanted near abdomen. Changes of relaxivity R1 and R2 (ΔRi/ Ri_pre-contrast (%) = (Ri − Ri_pre-contrast)/ Ri_pre-contrast; i=1,2) were measured for eight different regions of interest (ROI) by comparing pre- and post-contrast image. Higher Ri indicates enhanced contrast effects. In T1 image, ROI #2 (Gd-DTPA) and ROI #3 (DMCA) exhibited relaxivity change of 30% and 35%. In T2 image, ROI #1 (Feridex) and ROI #3 (DMCA) exhibited relaxivity change of 35% and 72%. All the other ROIs exhibited minimal signals (∼5%) in both T1 and T2 image. Only DMCA exhibited simultaneously high signal in both T1 and T2 to satisfy “ON” output for AND logic. T1 images were obtained by using fat suppression sequence and all images were taken by using 3 T MRI. Contrast agents: 200 μM (Gd) for T1 image, 100 μM (Fe) for T2 image.