From Spherical to Osmotically Shrunken Paramagnetic Liposomes: An Improved Generation of LIPOCEST MRI Agents with Highly Shifted Water Protons

Abstract

Honey, I shrunk the …︁ The chemical shift of intraliposomal water protons of LIPOCEST MRI agents may be enhanced by exploiting a contribution arising from bulk magnetic susceptibility. The effect was attained by osmotically shrinking liposomes to attain nonspherical compartments, with the largest shifts observed for systems containing paramagnetic Tm or Dy complexes either entrapped in the inner cavity or incorporated in the liposome membrane (see picture).

Determination of water permeability of paramagnetic liposomes of interest in MRI field

“…Usually, relatively high amounts (>100 mM) [23,26] of a mononuclear and monohydrated Gd(III) complex are encapsulated in order to make the longitudinal relaxation rate dependent on P w . However, we have recently observed that the actual intraliposomal concentration of a Ln(III) complex may be lower than that one used during the encapsulating procedure, particularly when the latter is rather high (approximately higher than 200 mM for a neutral mononuclear complex) [18,19]. Since the P w determination is based on the assumption that the intraliposomal concentration of the complex is equal to the amount provided during the encapsulation procedure, this finding might be detrimental for the accuracy of the measurement.…”

“…Liposomes loaded with paramagnetic Mn(II)-or Gd(III)-based imaging reporters or superparamagnetic iron oxide particles have been investigated for many applications including passive and active tumor visualization [3][4][5][6][7], detection of myocardium infarcted areas [8], imaging of lymph nodes [9], visualization of atherosclerotic plaques [10], detection of multiple sclerosis [11], bone marrow visualization [12], detection of apoptosis [13], in vivo monitoring of temperature [14] or pH [15], and imaging of drug delivery [16,17]. In addition, liposomes loaded with paramagnetic lanthanide(III) complexes, mostly different from Gd(III), have been recently proposed as highly sensitive MRI agents acting as chemical exchange saturation transfer (CEST) probes [18][19][20][21] or as T 2 susceptibility agents [22].…”

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

“…This approach was further improved by shrinking liposomes into a nonspherical shape by exposing them under hypertonic conditions, thus further shifting the resonance frequency of intraliposomal water away from bulk water via the bulk magnetic susceptibility effect. 19 Furthermore, Aime et al encapsulated a gadolinium T 1 agent inside shrunken liposomes and found that the nanoparticles exhibit not only good T 1 and T 2 relaxivities but also good CEST contrast, thus creating the first versatile agent with T 1 , T 2 , and CEST capabilities all in one package. 20 Liposomes as delivery vehicles for CEST agents present a great potential for MRI and therapy because they are biocompatible and well-established as a drug delivery platform that can easily be translated into the clinic.…”

Magnetic Resonance Methods and Applications in Pharmaceutical Research

“…Among them we will focus on two main classes, namely PARACEST CAs and Reporter Genes. 101,102 Paracest. The use of complexes of paramagnetic metal ions is based on the large shift in the resonance of the nuclei surrounding it; this causes a more efficient transfer of the magnetization.…”