No abstract

Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), an ultrafast chemical shift imaging technique, requires infusion of paramagnetic probes like 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate (DOTP8−) complexed with thulium (Tm3+) ion (i.e., TmDOTP5−), where the pH-sensitive resonances of hyperfine-shifted nonexchangeable protons contained within the paramagnetic magnetic resonance probe are detected. While imaging extracellular pH (pHe) with BIRDS meets an important cancer research need by mapping the intratumoral-peritumoral pHe gradient, the surgical intervention used to raise the probe’s plasma concentration limits longitudinal scans on the same subject. Here we describe using probenecid (i.e., an organic anion transporter inhibitor) to temporarily restrict renal clearance of TmDOTP5−, thereby facilitating molecular imaging by BIRDS without surgical intervention. Co-infusion of probenecid with TmDOTP5− increased the probe’s distribution into various organs, including the brain, compared with when infusing TmDOTP5− alone. In vivo BIRDS data using probenecid/TmDOTP5− co-infusion method in rats bearing RG2, 9L, and U87 brain tumors showed intratumoral-peritumoral pHe gradients that were unaffected by the probe dose. This co-infusion method can be used for pHe mapping with BIRDS in preclinical models for tumor characterization and therapeutic monitoring given the possibility of repeated scans with BIRDS (e.g., over days and even weeks) in the same subject. The longitudinal pHe readout by probenecid/TmDOTP5− co-infusion method for BIRDS adds translational value in tumor assessment and treatment.

Ferrite-based ferri/superparamagnetic nanoparticles can be rapidly heated by an external alternating magnetic field (AMF) to induce tissue necrosis of the adjacent microenvironment, but in addition provide magnetic resonance imaging (MRI) contrast utilizing enhanced water relaxivity. Here we characterized nanoensembles of Fe-Co mixed spinel ferrites (i.e. Fe Co Fe O , where x ranges from 0.2 to 0.8) synthesized by chemical co-precipitation. With nanoensembles of increasing Co content the saturation magnetization improved, while lattice parameter remained relatively constant. MRI water (transverse) relaxivity at 11.7 T was also boosted with increasing Co content. Efficiency of AMF-induced heating was quite comparable for the nanoensembles with either chitosan or polyethylene glycol (PEG) coating except for PEG-coated Fe Co Fe O , which was twice as less efficient as others. While toxicity of the nanoensembles with either coating examined on 9L tumor cell cultures showed no significant differences, upon AMF exposure (i.e. heat-induced necrosis) Fe Co Fe O composition with different values of x showed quite dramatic effects on cell death of tumor cells with both coatings. This study lays the ground work for further characterization of other mixed spinel ferrites, and in addition we expect that chitosan and PEG coated Fe Co Fe O of all the compositions will have good potential for preclinical applications in vivo. Copyright © 2016 John Wiley & Sons, Ltd.

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).

Since brain's microvasculature is compromised in gliomas, intravenous injection of tumor-targeting nanoparticles containing drugs (D-NPs) and superparamagnetic iron oxide (SPIO-NPs) can deliver high payloads of drugs while allowing MRI to track drug distribution. However, therapeutic effect of D-NPs remains poorly investigated because superparamagnetic fields generated by SPIO-NPs perturb conventional MRI readouts. Because extracellular pH (pHe) is a tumor hallmark, mapping pHe is critical. Brain pHe is measured by biosensor imaging of redundant deviation in shifts (BIRDS) with lanthanide agents, by detecting paramagnetically shifted resonances of nonexchangeable protons on the agent. To test the hypothesis that BIRDS-based pHe readout remains uncompromised by presence of SPIO-NPs, we mapped pHe in glioma-bearing rats before and after SPIO-NPs infusion. While SPIO-NPs accumulation in the tumor enhanced MRI contrast, the pHe inside and outside the MRI-defined tumor boundary remained unchanged after SPIO-NPs infusion, regardless of the tumor type (9L versus RG2) or agent injection method (renal ligation versus coinfusion with probenecid). These results demonstrate that we can simultaneously and noninvasively image the specific location and the healing efficacy of D-NPs, where MRI contrast from SPIO-NPs can track their distribution and BIRDS-based pHe can map their therapeutic impact.