Characterization of a lanthanide complex encapsulated with MRI contrast agents into liposomes for biosensor imaging of redundant deviation in shifts (BIRDS)

Abstract

Purposely-designed magnetic resonance imaging (MRI) probes encapsulated in liposomes, which alter contrast by their paramagnetic effect on longitudinal (T1) and transverse (T2) relaxation times of tissue water, hold promise for molecular imaging. However a challenge with liposomal MRI probes that are solely dependent on enhancement of water relaxation is lack of specific molecular readouts, especially in strong paramagnetic environments, thereby reducing the potential for monitoring disease treatment (e.g., cancer) beyond the generated MRI contrast. Previously it has been shown that molecular imaging with magnetic resonance is also possible by detecting the signal of non-exchangeable protons emanating from paramagnetic lanthanide complexes themselves (e.g., TmDOTP5−, which is a Tm3+-containing biosensor based on a macrocyclic chelate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate), DOTP5−) with a method called Biosensor Imaging of Redundant Deviation in Shifts (BIRDS). Here we show that BIRDS is useful for molecular imaging with probes like TmDOTP5− even when they are encapsulated inside liposomes with ultra-strong T1 and T2 contrast agents (e.g., Magnevist and Molday ION, respectively). We demonstrate that molecular readouts like pH and temperature determined from probes like TmDOTP5− are resilient, because sensitivity of the chemical shifts to the probe’s environment is not compromised by presence of other paramagnetic agents contained within the same nanocarrier milieu. Because high liposomal encapsulation efficiency allows for robust MRI contrast and signal amplification for BIRDS, nanoengineered liposomal probes containing both monomers like TmDOTP5− and paramagnetic contrast agents could allow high spatial resolution imaging of disease diagnosis (with MRI) and status monitoring (with BIRDS).

Employing paramagnetic shift for responsive MRI probes

“…Hyder et al encapsulated [TmL 7 ] 5complex ( Figure 8) in 1,2-dipalmitoyl-sn-glycerophosphocholine (DPPC) liposomes in order to enhance local concentrations, and the encapsulation process apparently had little effect on the chemical shifts of the [TmL 7 ] 5protons [74]. In vitro MRSI experiments suggested signal amplification could be achieved using nanomolar amounts of liposomes compared to free [Tm.L 7 ] 5-.…”

“…These approaches include the use of multimeric complexes, where the probes are conjugated to a passive biocompatible entity, [75] or the use of noncovalently assembled adducts where the probes are locally concentrated inside a liposome or micelle. [74] Such higher molecular volume systems clear more slowly form the body, lengthening the detection window. In the future, conjugation to efficient and cheap targeting vectors can be envisioned, for example based on medium MW peptide carriers.…”

Towards longitudinal mapping of extracellular pH in gliomas

“…Biosensor imaging of redundant deviation in shifts (BIRDS) is an ultrafast chemical shift imaging (CSI) platform for molecular imaging in which paramagnetically shifted nonexchangeable protons (i.e. CH x ) on DOTA-based macrocyclic complexes are directly detected (15)(16)(17)(18)(19)(20)(21). BIRDS has some unusual properties.…”

Mapping Extracellular pH of Gliomas in Presence of Superparamagnetic Nanoparticles: Towards Imaging the Distribution of Drug-Containing Nanoparticles and Their Curative Effect on the Tumor Microenvironment

“…With advanced k-space sampling of ultra-fast chemical shift imaging (CSI), the spatiotemporal resolution of BIRDS has improved [ 61 ]. Previously we observed in vitro that the pH sensitivities and readout with BIRDS agents are not compromised by the presence of SPIO-NPs [ 62 ]. Here we hypothesized that BIRDS-based pH e readout in glioma-bearing rats remains uncompromised by the presence of SPIO-NPs.…”