Gd3+-loaded polyion complex for pH depiction with magnetic resonance imaging

Abstract

In clinical diagnosis, gadolinium (Gd) ion/low molecular weight chelater complexes have been used as MRI contrast agents that disperse throughout a particular tissue and cause a brighter appearance in MRI. In order to provide a novel imaging concept for MRI, a contrast agent in which the T(1)-relaxation shortening activity (R(1) relaxivity) changes in response to the pH differences was studied. We prepared a polyion complex (PIC) consisting of a polyanionic Gd-chelater, poly(diethylenetriamine-N,N,N',N", N"-pentaaceto, DTPA) (1,3-propanediamide) (denoted as 1a) loaded with Gd ions at a [Gd]/[DTPA unit] ratio of 0.2 (denoted as 1b), and a polycation, poly[2-(diethylamino)ethyl methacrylate] (denoted as 2). The stoichiometric (based on ionic groups) mixture of 1b and 2 formed complex coacervates from pH 5 to pH 8. The R(1) relaxivity of Gd(3+) in the complex was considerably influenced by the pH, and the relative signal intensity changed from 4 at pH 7.2 to 11 at pH 5.0, as determined by an MRI phantom study. The pH responsivity of the complex solution varied with the composition of the PIC (i.e., the mixing ratio of 1b and 2), allowing us to modulate the pH sensibility. The ionic charge balance and swelling of PIC seemingly were related to the pH-dependent R(1) relaxivity change. It is expected that the PIC-based MRI contrast agent may provide a novel category of MRI methods and be useful in improving the detectability of an MRI-based diagnosis.

Renal and systemic pH imaging by contrast‐enhanced MRI

“…The pH-sensitive 31 P MR resonance of 3-aminopropylphosphate (3-APP) has been used by us and other researchers to measure extracellular pH of tumors and normal tissues in mice (4,5,10). Molecules with pH-sensitive 19 F and 1 H resonances have also been reported. Ojugo et al (10) reported that pH measurements with excellent signalto-noise ratio (SNR) per time period are possible with the extracellular 19 F-containing pH probe, ZK-150471.…”

“…Molecules with pH-sensitive 19 F and 1 H resonances have also been reported. Ojugo et al (10) reported that pH measurements with excellent signalto-noise ratio (SNR) per time period are possible with the extracellular 19 F-containing pH probe, ZK-150471. They list the lack of potentially interfering endogenous 19 F resonances, and the higher NMR and pH sensitivity of ZK-150471 as advantages of the 19 F probe compared to 3-APP.…”

“…Ojugo et al (10) reported that pH measurements with excellent signalto-noise ratio (SNR) per time period are possible with the extracellular 19 F-containing pH probe, ZK-150471. They list the lack of potentially interfering endogenous 19 F resonances, and the higher NMR and pH sensitivity of ZK-150471 as advantages of the 19 F probe compared to 3-APP. Both 3-APP and ZK-150471 are cell-impermeant and report only the extracellular pH, although 31 P MRS of 3-APP offers the possibility of simultaneous measurement of intracellular pH from the P i resonance.…”

“…Both 3-APP and ZK-150471 are cell-impermeant and report only the extracellular pH, although 31 P MRS of 3-APP offers the possibility of simultaneous measurement of intracellular pH from the P i resonance. Mason and coworkers (11) reported that a fluorinated derivative of vitamin B6, 6-fluoropyridoxol, readily enters cells, and they used this single molecule to measure the intra-and extracellular pH in rodent tumors by 19 F MRS.…”

“…pH-sensitive gadolinium complexes (17,18) and gadolinium-containing pH-sensitive polyion complexes (19) offer the possibility of imaging pH with a spatial resolution comparable to standard MRI. However, the enhancement observed in an image will be dependent on not only the pH, but also the local concentration of the agent.…”