We describe the development of multifunctional polymeric micelles with cancer-targeting capability via alpha(v)beta(3) integrins, controlled drug delivery, and efficient magnetic resonance imaging (MRI) contrast characteristics. Doxorubicin and a cluster of superparamagnetic iron oxide (SPIO) nanoparticles were loaded successfully inside the micelle core. The presence of cRGD on the micelle surface resulted in the cancer-targeted delivery to alpha(v)beta(3)-expressing tumor cells. In vitro MRI and cytotoxicity studies demonstrated the ultrasensitive MRI imaging and alpha(v)beta(3)-specific cytotoxic response of these multifunctional polymeric micelles.
Paramagnetic lanthanide complexes that display unusually slow water exchange between an inner sphere coordination site and bulk water may serve as a new class of MRI contrast agents with the use of chemical exchange saturation transfer (CEST) techniques. To aid in the design of paramagnetic CEST agents for reporting important biological indices in MRI measurements, we formulated a theoretical framework based on the modified Bloch equations that relates the chemical properties of a CEST agent (e.g., water exchange rates and bound water chemical shifts) and various NMR parameters (e.g., relaxation rates and applied B 1 field) to the measured CEST effect. Numerical solutions of this formulation for complex exchanging systems were readily obtained without algebraic manipulation or simplification. For paramagnetic CEST agents of the type used here, the CEST effect is relatively insensitive to the bound proton relaxation times, but requires a sufficiently large applied B 1 field to highly saturate the Ln 3؉ -bound water protons. This in turn requires paramagnetic complexes with large Ln 3؉ -bound water chemical shifts to avoid direct excitation of the exchanging bulk water protons. Although increasing the exchange rate of the bound protons enhances the CEST effect, this also causes exchange broadening and increases the B 1 required for saturation. For a given B 1 , there is an optimal exchange rate that results in a maximal CEST effect. This numerical approach, which was formulated for a three-pool case, was incorporated into a MATLAB nonlinear least-square optimization routine, and the results were in excellent agreement with experimental Zspectra obtained with an aqueous solution of a paramagnetic CEST agent containing two different types of bound protons (bound water and amide protons Most MRI contrast agents in clinical use or under current scientific investigation are based upon paramagnetic complexes that increase the relaxation rate (T 1 or T 2 ) of bulk water (1). Gadolinium (III) is widely used for this purpose because of the favorable magnetic (electron spin relaxation) and coordination (high coordination number and easy access of water to the inner coordination sphere) properties of complexes formed by this ion with a variety of ligands. An alternative and potentially powerful way to alter tissue contrast is to simply change the amount of water detected in an imaging experiment. Recently, Ward et al. (2) demonstrated that low-molecular-weight compounds with slowly exchanging -NH or -OH protons may also be used to alter tissue contrast via chemical exchange saturation transfer (CEST) of presaturated spins to bulk water. One important feature of this type of contrast agent is that one can switch the image contrast on or off at will by gating the RF presaturation pulse. For example, barbituric acid has two amide protons that resonate ϳ5 ppm downfield of bulk water. By applying a selective presaturation RF pulse at that frequency, the bulk water signal intensity can be reduced by ϳ30% in the presence of 125 mM ...
Proton NMR spectroscopy at 7 Tesla (7T) was evaluated as a new method to quantify human fat composition noninvasively. In validation experiments, the composition of a known mixture of triolein, tristearin, and trilinolein agreed well with measurements by 1 H NMR spectroscopy. Triglycerides in calf subcutaneous tissue and tibial bone marrow were examined in 20 healthy subjects by 1 H spectroscopy. Ten well-resolved proton resonances from triglycerides were detected using stimulated echo acquisition mode sequence and small voxel (?0.1 ml), and T 1 and T 2 were measured. Triglyceride composition was not different between calf subcutaneous adipose tissue and tibial marrow for a given subject, and its variation among subjects, as a result of diet and genetic differences, fell in a narrow range. After correction for differential relaxation effects, the marrow fat composition was 29.1 6 3.5% saturated, 46.4 6 4.8% monounsaturated, and 24.5 6 3.1% diunsaturated, compared with adipose fat composition, 27.1 6 4.2% saturated, 49.6 6 5.7% monounsaturated, and 23.4 6 3.9% diunsaturated. Proton spectroscopy at 7T offers a simple, fast, noninvasive, and painless method for obtaining detailed information about lipid composition in humans, and the sensitivity and resolution of the method may facilitate longitudinal monitoring of changes in lipid composition in response to diet, exercise, and
This tutorial review examines the fundamental aspects of a new class of contrast media for MRI based upon the chemical shift saturation transfer (CEST) mechanism. Several paramagnetic versions called PARACEST agents have shown utility as responsive agents for reporting physiological or metabolic information by MRI. It is shown that basic NMR exchange theory can be used to predict how parameters such as chemical shift, bound water lifetimes, and relaxation rates can be optimized to maximize the sensitivity of PARACEST agents.Magnetic resonance imaging (MRI) is arguably the most important diagnostic imaging tool in clinical medicine today offering exquisite anatomical images of soft tissues based upon detection of protons largely in water and fat. Image contrast is readily manipulated by choosing from a standard set of pulse sequences that weight signal intensities based upon differences in proton densities and T 1 and T 2 relaxation rates. For many clinical applications, however, it now common practice to administer an exogenous contrast agent to highlight specific tissue regions based upon flow or agent biodistribution. MRI contrast agents so far have been largely confined to small paramagnetic metal complexes, typically gadolinium(III) complexes, that alter signal intensity by shortening the relaxation times of the water protons. 1 The mechanism of action of this class of agents is described in more detail in a separate review in this edition. Although such first generation agents are widely used in clinical medicine, the physical properties of such agents are limited when considering a new generation of MRI contrast agents that will provide functional as well as anatomical information. 2 New agents that operate by a CEST mechanism may ultimately be able to provide important metabolic information with exquisite anatomical resolution. What is CEST?CEST is an acronym for Chemical Exchange Saturation Transfer, the basics of which are well established in NMR spectroscopy. In early experiments, it was also referred to as Saturation Transfer or Magnetization Transfer (MT). As its name suggests CEST involves chemical exchange of a nucleus in the NMR experiment from one site to a chemically different site. Before introducing CEST, it is necessary to consider briefly the origin of an NMR signal, more © The Royal Society of Chemistry 2006Correspondence to: A. Dean Sherry. NIH Public Access Author ManuscriptChem Soc Rev. Author manuscript; available in PMC 2009 July 30. Published in final edited form as:Chem Soc Rev. 2006 June ; 35(6): 500-511. doi:10.1039/b509907m. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript detailed descriptions are available elsewhere. 3 When a nucleus having a net magnetic spin (the proton spin quantum number, I, equals ½) is placed in a magnetic field, the spins orient either in the same direction as the magnetic field (low energy-α) or against the field (high energy-β) (Fig. 1). The distribution of spins between these two energy states is determined by the Boltz...
Scientific interest in optimizing the properties of gadolinium (III) complexes as MRI contrast agents has led to many new insights into lanthanide ion coordination chemistry in the last two decades. Among these was the surprising observation that water exchange in lanthanide (III) derivatives of DOTA can be modulated dramatically by judicious choice of ligand side chain and Ln(3+) ionic radii. This resulted in the discovery of paramagnetic CEST agents for altering MRI image contrast based upon the chemical exchange saturation transfer mechanism. The goal of this article is to review the factors that govern water molecule and water proton exchange in these complexes and to compare the potential sensitivity of PARACEST agents versus Gd(3+)-based T(1) relaxation agents for altering tissue contrast.
Detection of glycogen in vivo would have utility in the study of normal physiology and many disorders. Presently, the only magnetic resonance (MR) method available to study glycogen metabolism in vivo is 13 C MR spectroscopy, but this technology is not routinely available on standard clinical scanners. Here, we show that glycogen can be detected indirectly through the water signal by using selective radio frequency (RF) saturation of the hydroxyl protons in the 0.5-to 1.5-ppm frequency range downfield from water. The resulting saturated spins are rapidly transferred to water protons via chemical exchange, leading to partial saturation of the water signal, a process now known as chemical exchange saturation transfer. This effect is demonstrated in glycogen phantoms at magnetic field strengths of 4.7 and 9.4 T, showing improved detection at higher field in adherence with MR exchange theory. Difference images obtained during RF irradiation at 1.0 ppm upfield and downfield of the water signal showed that glycogen metabolism could be followed in isolated, perfused mouse livers at 4.7 T before and after administration of glucagon. Glycogen breakdown was confirmed by measuring effluent glucose and, in separate experiments, by 13 C NMR spectroscopy. This approach opens the way to image the distribution of tissue glycogen in vivo and to monitor its metabolism rapidly and noninvasively with MRI.glucose ͉ liver ͉ water imaging ͉ noninvasive
Magnetic resonance imaging (MRI) contrast agents have become an important tool in clinical medicine. The most common agents are Gd(3+)-based complexes that shorten bulk water T(1) by rapid exchange of a single inner-sphere water molecule with bulk solvent water. Current gadolinium agents lack tissue specificity and typically do not respond to their chemical environment. Recently, it has been demonstrated that MR contrast may be altered by an entirely different mechanism based on chemical exchange saturation transfer (CEST). CEST contrast can originate from exchange of endogenous amide or hydroxyl protons or from exchangeable sites on exogenous CEST agents. This has opened the door for the discovery of new classes of responsive agents ranging from MR gene reporter molecules to small molecules that sense their tissue environment and respond to biological events.
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