pH-responsive Contrast Agent Research Articles

Tumor pH Imaging Using Chemical Exchange Saturation Transfer (CEST)-MRI.

Magnetic resonance imaging (MRI) is a noninvasive imaging technique that allows for physiological and functional studies of the tumor microenvironment. Within MRI, the emerging field of chemical exchange saturation transfer (CEST) has been largely exploited for assessing a salient feature of all solid tumors, extracellular acidosis. Iopamidol-based tumor pH imaging has been demonstrated to provide accurate and high spatial resolution extracellular tumor pH maps to elucidate tumor aggressiveness and for assessing response to therapy, with a high potential for clinical translation. Here, we describe the overall setup and steps for measuring tumor extracellular pH of tumor models in mice by exploiting MRI-CEST pH imaging with a preclinical MRI scanner following the administration of iopamidol. We address issues of pH calibration curve setup, animal handling, pH-responsive contrast agent injection, acquisition protocol, and image processing for accurate quantification and visualization of tumor acidosis.

Fe-Based Theranostic Agents Respond to the Tumor Microenvironment for MRI-Guided Ferroptosis-/Apoptosis-Inducing Anticancer Therapy.

Tumor microenvironment-specific magnetic resonance imaging (MRI) contrast agents are conducive to accurate diagnoses by visualization of biochemical and pathological changes for suitable treatment. Herein, we reported a pH-responsive contrast agent DFeZd NP with MRI diagnosis and tumor treatment capabilities. DFeZd NPs can map the pH change by modulating the MR signal in different acid-base environments. Moreover, T1 signals are stronger in the tumor site, which proves efficient in distinguishing malignant tumors from normal tissues, as well as demarcating the tumor boundary. Subsequently, sustained supply of Fe through the Fe-based contrast agent leads to Fe redox cycling and lipid peroxides, inducing ferroptosis in tumor cells. Furthermore, under an acidic tumor microenvironment, in the presence of ascorbic acid, increased Fe2+ is generated, which serves as a stronger inducer of ferroptosis. Moreover, due to the different relaxivity of Fe3+ and Fe2+, redox cycling and ferroptosis in tumors can be monitored by MRI. Therefore, we propose DFeZd NPs as accessible and promising Fe-based dopamine-derived contrast agents for specific MRI imaging and ferroptosis induction for anticancer therapy.

Stable and Inert Mn(II)-Based and pH-Responsive Contrast Agents

Smart/intelligent contrast agent candidates for MRI based on Mn(II) ion are rare, as it usually forms labile complexes with polyaminocarboxylate-type ligands. Here, we report the first example of a Mn(II) complex that can be activated by changing the pH of its local environment. The PC2A-EA ligand with an ethylamine pendant arm was found to form a thermodynamically stable (log KMnL = 19.01, pMn = 9.27) and kinetically inert complex with Mn(II) with respect to trans-chelation with a metal ion such as Cu(II). The [MnH(PCA2-EA)] complex displays a relatively slow water exchange rate ((4.0 ± 0.2) × 107 s-1), but the pH-dependent coordination of the ethylamine moiety occurs in the pH range of 6-8 (log KMnLH = 6.88), enabling the complex to exhibit pH-sensitive relaxivity in the biologically relevant pH range.

Eu(III) Complex with DO3A-amino-phosphonate Ligand as a Concentration-Independent pH-Responsive Contrast Agent for Magnetic Resonance Spectroscopy (MRS).

A new DOTA-like ligand H5do3aNP with a 2-[amino(methylphosphonic acid)]ethyl-coordinating pendant arm was prepared, and its coordinating properties were studied by NMR spectroscopy and potentiometry. The study revealed a rare slow exchange (on the 1H and 31P NMR time scale) between protonated and unprotonated complex species with a corresponding acidity constant pKA ∼ 8.0. This unusually slow time scale associated with protonation is caused by a significant geometric change from square-antiprismatic (SA) arrangement observed for protonated complex SA-[Eu(Hdo3aNP)]- to twisted-square-antiprismatic (TSA) arrangement found for deprotonated complex TSA-[Eu(do3aNP)]2-. This behavior results in simultaneous occurrence of the signals of both species in the 31P NMR spectra at approximately -118 and +70 ppm, respectively. Such an unprecedented difference in the chemical shifts between species differing by a proton is caused by a significant movement of the principal magnetic axis and by a change of phosphorus atom position in the coordination sphere of the central Eu(III) ion (i.e., by relative movement of the phosphorus atom with respect to the principal magnetic axis). It changes the sign of the paramagnetic contribution to the 31P NMR chemical shift. The properties discovered can be employed in the measurement of pH by MRS techniques as presented by proof-of-principle experiments on phantoms.

In Vivo Imaging of Tumor Metabolism and Acidosis by Combining PET and MRI-CEST pH Imaging.

The vast majority of cancers exhibit increased glucose uptake and glycolysis regardless of oxygen availability. This metabolic shift leads to an enhanced production of lactic acid that decreases extracellular pH (pHe), a hallmark of the tumor microenvironment. In this way, dysregulated tumor pHe and upregulated glucose metabolism are linked tightly and their relative assessment may be useful to gain understanding of the underlying biology. Here we investigated noninvasively the in vivo correlation between tumor 18F-FDG uptake and extracellular pH values in a murine model of HER2+ breast cancer. Tumor extracellular pH and perfusion were assessed by acquiring MRI-CEST (chemical exchange saturation transfer) images on a 3T scanner after intravenous administration of a pH-responsive contrast agent (iopamidol). Static PET images were recorded immediately after MRI acquisitions to quantify the extent of 18F-FDG uptake. We demonstrated the occurrence of tumor pHe changes that report on acidification of the interstitial fluid caused by an accelerated glycolysis. Combined PET and MRI-CEST images reported complementary spatial information of the altered glucose metabolism. Notably, a significant inverse correlation was found between extracellular tumor pH and 18F-FDG uptake, as a high 18F-FDG uptake corresponds to lower extracellular pH values. These results show how merging the information from 18F-FDG-uptake and extracellular pH measurements can improve characterization of the tumor microenvironment. Cancer Res; 76(22); 6463-70. ©2016 AACR.

Prototropic Exchange Governs T1 and T2 Relaxivities of a Potential MRI Contrast Agent Nanozeolite Gd−LTL with a High pH Responsiveness

Aqueous suspensions of lanthanide exchanged zeolite LTL have been investigated by 1H, 17O NMR, and EPR relaxivity studies. Both the longitudinal and the transverse relaxivity of these Gd3+ loaded materials are strongly pH dependent and therefore, they have great potential as pH responsive contrast agents. For example, LTL-nanocrystals loaded with 3.5 wt % Gd show a dramatic decrease in the longitudinal relaxivity from 32 to 7 s–1 mM–1 (7.5 T and 25 °C) when going from pH 4 to 9. 1H and 17O NMR show that this phenomenon can be rationalized by a decrease in proton mobility between the zeolite interior and the exterior due to a change from a fast prototropic exchange to a 3 orders of magnitude slower water exchange mechanism. The same material also has a high transverse relaxivity (98 s–1 mM–1 at 7.5 T, 25 °C, and pH 5 as measured with the CPMG pulse sequence), which is governed by proton exchange too, while water diffusion plays a minor role. The high relaxivities and pH dependence render Gd-loaded LTL mate...

A novel class of polymeric pH-responsive MRI CEST agents

In this communication, we report that ionizable, tertiary amine-based block copolymers can be used as pH-responsive contrast agents for magnetic resonance imaging (MRI) through the chemical exchange saturation transfer (CEST) mechanism. The CEST signal is essentially "off" when the polymers form micelles near physiological pH but is activated to the "on" state when the micelles dissociate in an acidic environment.

Imaging the pH evolution of an acute kidney injury model by means of iopamidol, a MRI-CEST pH-responsive contrast agent

To investigate in vivo possible pH level alterations following an acute renal failure disease using a MRI-CEST pH responsive contrast agent. The impact of functional evolution in different renal compartments over time was also investigated. a mouse model of acute kidney injury was obtained by glycerol-induced rhabdomyolysis. pH maps were obtained using Iopamidol (0.75 g iodine/kg b.w. corresponding to 2.0 mmol/kg) in a control group (n = 3) and in the acute kidney injury group (n = 6) at 1, 3, 7, 14, and 21 days after the damage induction at 7T. Histology assessment of renal damage and blood urea nitrogen levels were compared with pH maps. during the acute kidney injury, there was a robust increase of pH values, which peaked after 3 days, compared with the predamage situation. In addition, it was possible to detect changes in contrast detection between the different functional regions of the damaged kidneys. Moreover, a slow restoration of normal pH values was observed three weeks after the glycerol injection. pH appears to be a good parameter to assess the early detection of kidney injury as well as it acts as a reporter of the recovery toward the physiologic functionality.

A conjugated polymer-Gd (III) complex as pH sensitive contrast agent in magnetic resonance imaging

A novel pH-responsive contrast agent (PFP-aa/Gd) for magnetic resonance imaging (MRI) was prepared by binding Gd(III) to a water-soluble conjugated polyfluorene with pendant carboxylate and amine moieties. The PFP-aa is a good chelator for Gd3+ and the PFP-aa/Gd complex has good stability. As the pH changes from 10.0 to 4.0, both the carboxylate and amine are protonated, thus PFP-aa exhibits positive charges and forms tight aggregation, which reduces molecular tumbling and accelerates the exchange of bound water leading to the increase of relaxivity R 1. More importantly, the R 1 increases by about eight fold as the pH changes from 8.0 to 6.0, which makes PFP-aa/Gd suitable as a potential marker of the pH below physiological level. In comparison to other contrast agents, the unique sensitivity of the water relaxivity of PFP-aa/Gd indicates that this complex could be used in MRI experiments to monitor physiological pH change.

Chemistry of paramagnetic and diamagnetic contrast agents for Magnetic Resonance Imaging and Spectroscopy: pH responsive contrast agents

We provide a brief overview of the chemistry and most relevant properties of paramagnetic and diamagnetic contrast agents (CAs) for Magnetic Resonance Imaging and Magnetic Resonance Spectroscopic Imaging. Paramagnetic CAs for MRI consist mainly of Gd(III) complexes from linear or macrocyclic polyaminopolycarboxylates. These agents reduce, the relaxation times T 1 and T 2 of the water protons in a concentration dependent manner, increasing selectively MRI contrast in those regions in which they accumulate. In most instances they provide anatomical information on the localization of lesions and in some specific cases they may allow to estimate some physiological properties of tissues including mainly vascular performance. Because of its ability to discriminate easily between normal and diseased tissue, extracellular pH (pH e) has been added recently, to the battery of variables amenable to MRI investigation. A variety of Gd(III) containing macrocycles sensitive to pH, endogenous or exogenous polypeptides or even liposomes have been investigated for this purpose, using the pH dependence of their relaxivity or magnetization transfer rate constant (chemical exchange saturation transfer, CEST). Many environmental circumstances in addition to pH affect, however, relaxivity or magnetization transfer rate constants of these agents, making the results of pH measurements by MRI difficult to interpret. To overcome these limitations, our laboratory synthesized and developed a novel series of diamagnetic CAs for Magnetic Resonance Spectroscopic Imaging, a new family of monomeric and dimeric imidazolic derivatives able to provide unambiguous measurements of pH e, independent of water relaxivity, diffusion or exchange.