Size-Induced Enhancement of Chemical Exchange Saturation Transfer (CEST) Contrast in Liposomes

Abstract

Liposome-based chemical exchange saturation transfer (lipoCEST) agents have shown great sensitivity and potential for molecular magnetic resonance imaging (MRI). Here we demonstrate that the size of liposomes can be exploited to enhance the lipoCEST contrast. A concise analytical model is developed to describe the contrast dependence on size for an ensemble of liposomes. The model attributes the increased lipoCEST contrast in smaller liposomes to their larger surface-to-volume ratio, causing an increased membrane water exchange rate. Experimentally measured rates correlate with size, in agreement with the model. The water permeability of liposomal membrane is found to be 1.11 ± 0.14 μm/s for the specific lipid composition at 22 °C. Availability of the model allows rational design of the size of liposomes and quantification of their properties. These new theoretical and experimental tools are expected to benefit applications of liposomes to sensing the cellular environment, targeting and imaging biological processes, and optimizing drug delivery properties.

Entrapment of a neutral Tm(III)‐based complex with two inner‐sphere coordinated water molecules into PEG‐stabilized vesicles: towards an alternative strategy to develop high‐performance LipoCEST contrast agents for MR imaging

“…Conversely, at sufficiently high B 1 , all populations can contribute to saturation transfer and exhibit a maximum efficiency averaged by the entire liposome size distribution. This has been recently verified experimentally in the case of [Tm(III)-DOTA]-loaded liposomes (19). Besides, it cannot be totally ruled out that the complex encapsulation rate might slightly vary from one liposome to the other so that the range of signal resonance offset of the intra-liposomal protons would be further enlarged.…”

“…The rate of chemical exchange is then governed by the permeability to water molecules of the lipid bilayer delimiting the vesicle structure. These innovative systems referred to as LipoCEST agents have been widely demonstrated by a series of eloquent studies providing better than a proof of concept (7,8,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). While conventional CEST agents are efficient in the millimolar concentration range, LipoCEST-induced contrast can indeed be detected at sub-nanomolar concentrations (7,8,10).…”

Proton Chemical Exchange Saturation Transfer (CEST) MRS and MRI

“…Another important development is the use of CEST agents in liposomes (lipoCEST) 142,143 to detect picomolar concentrations of these nanoparticles via the exchange of water between intra-and extraliposomal environments. 16,142,143,163,164 While the paraCEST, lipoCEST, and hyperCEST agents show much potential, due to space limitations this remaining section will focus on some of the diaCEST applications that have actually been applied in humans.…”

13C‐TmDOTA as versatile thermometer compound for solid‐state NMR of hydrated lipid bilayer membranes

“…[26] However, the 13 C chemical shift has not been thoroughly investigated because of the low sensitivity of the 13 C signal, which leads to the line broadening effect of the paramagnetic element. For thermometric application, we report the synthesis of 13 C-labeled TmDOTA ( were chemically synthesized from a commercially available compound (details are presented in the Supporting Information [27][28][29] ). [1][2][3][4][5][6][7][8][9][10][11][12][13] C]bromoacetate and [1][2][3][4][5][6][7][8][9][10][11][12][13] C] stearic acid were purchased from Cambridge Isotope Laboratory Inc. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) was obtained from Avanti Polar Lipid.…”