In vivo multicolor molecular MR imaging using diamagnetic chemical exchange saturation transfer liposomes

Abstract

A variety of (super)paramagnetic contrast agents are available for enhanced MR visualization of specific tissues, cells, or molecules. In order to develop alternative contrast agents without the presence of metal ions, liposomes were developed containing simple bioorganic and biodegradable compounds that produce diamagnetic Chemical Exchange Saturation Transfer (DIACEST) MR contrast. This DIACEST contrast is frequency-dependent, allowing the unique generation of “multi-color” images. The contrast can be turned on and off at will, and standard images do not show the presence of these agents. As an example, glycogen, L-arginine, and poly-L-Lysine were encapsulated inside liposomes and injected intradermally into mice to image the lymphatic uptake of these liposomes. Using a frequency-dependent acquisition scheme, it is demonstrated that multi-color MRI can differentiate between different contrast particles in vivo following their homing to draining lymph nodes. Being non-metallic and bioorganic, these DIACEST liposomes form an attractive novel platform for multi-color imaging in vivo.

Oxidation-responsive Eu2+/3+-liposomal contrast agent for dual-mode magnetic resonance imaging

“…These results are fully consistent with a recent demonstration of a CEST effect using diamagnetic liposomes that contained cholesterol and, of particular importance, the proton signal at ~1 ppm downfield from bulk water was assigned to hydroxyl protons. 27 Additional support for our observations can be found in a previous report of magnetization transfer for a lipid and cholesterol system in which magnetization transfer exhibited a strong dependence on cholesterol concentration (30–60 mol%), 29 and the concentration of cholesterol in our system (42 mol%) falls in this range. Furthermore, our data provide an explanation for the observation of CEST before oxidation of Eu 2+ by revealing an exchange between the liposome membrane and bulk water.…”

“…2), which demonstrates that the CEST effect does not change after Eu(2.2.2) 2+ has oxidized to Eu(2.2.2) 3+ . Although this shift is small, it is possible to image such shifts in vivo : 27,28 in vivo CEST has been observed between bulk water and exchangeable protons of liposomes shifted by as little as 0.8 ppm. 27 …”

Nuts and bolts of chemical exchange saturation transfer MRI

“…Contrary to other MRI contrast mechanisms such as T1, T2, and diffusion weighting, CEST specifically probes molecular targets carrying exchangeable protons in a frequency specific manner, (at the chemical shift of their exchangeable protons) making it a unique technology for molecular imaging. Because of this chemical shift (frequency offset) dependence of CEST contrast, multiple agents possessing exchangeable protons with distinct chemical shifts can be designed such that CEST MRI schemes may detect and discriminate between these agents simultaneously, which has been called multi-color (3-5) or multi-frequency MRI (6,7). This is similar to the most attractive feature found in optical imaging agents, which is difficult to realize with conventional 1 H MRI contrast agents.…”

“…This is problematic for most DIACEST and LIPOCEST agents whose offsets are typically less than 5ppm from water. While the apparent MTR asym will be ‘contaminated’ by asymmetric MTC, this metric is useful to quantify the change in CEST contrast, especially the difference between pre-contrast and post-contrast (51,65), or the difference between target and control tissue (3,40,89), with the assumption that asymmetric MTC is constant. Currently MTR asym is still the most widely used metric for CEST studies.…”

Proton Chemical Exchange Saturation Transfer (CEST) MRS and MRI

“…The primary conditions for selective saturation are (i) the chemical shift of the labile proton should be sufficiently separate from that of water and (ii) the exchange rate constant should lie in the slow to intermediate range, i.e., ≥ k sw . The simplest pulse scheme for obtaining CEST data consists of a long (low-bandwidth) CW saturation pulse (t sat < 5T 1 ) at a particular offset frequency, followed by any image acquisition scheme, for instance, fast spin echo, 42,43 rapid acquisition with relaxation enhancement (RARE), 48 fast imaging with steady precession (FISP), 49 or three-dimensional (3-D) gradient and spin echo (GRASE) 50 sequences. To measure CEST effects, it is common to obtain a kind of 'absorption-like' spectrum, in which images of the water signal intensity (S sat ) normalized with respect to signal intensity without irradiation (S 0 ) are acquired as a function of offset frequency (Figure 4c).…”