Organically coated iron oxide crystallites with diameters of 5-50 nm ("nanoparticles") are potential magnetic resonance imaging contrast agents. 1/T1 and 1/T2 of solvent water protons are increased dramatically by magnetic interactions in the "outer sphere" environment of the nanoparticles; subsequent diffusive mixing distributes this relaxation throughout the solvent. Published theory, valid for the solute magnetic energy small compared with thermal energy, is applicable to small magnetic solutes (e.g., gadolinium and manganese diethylenetriaminopentaacetic acid, and nitroxide free radicals) at generally accessible fields (< or = 50 T). It fails for nanoparticles at fields above approximately 0.05 T, i.e., at most imaging fields. The authors have reformulated outer sphere relaxation theory to incorporate progressive magnetic saturation of solute nanoparticles and, in addition, indicate how to use empirical magnetization data for realistic particles when their magnetic properties are not ideal. It is important to handle the effects of rapid thermally induced reorientation of the magnetization of the nanoparticles (their "superparamagnetism") effectively, including their sensitivity to particle size. The theoretical results are presented as the magnetic field dependence (NMRD profiles) of 1/T1 and 1/T2, normalized to Fe content, for three sizes of particles, and then compared with the limited data extant for well-characterized material.
Since 1/T2 of protons of tissue water is generally much greater than 1/T1 at typical imaging fields, small single-ion contrast agents--such as Gd(DTPA), which make comparable incremental contributions and therefore smaller fractional contributions to 1/T2 compared to 1/T1--are not as desirable for contrast-enhancement as agents that could enhance 1/T2 preferentially. In principle, such specialized agents will only be effective at higher fields because the field dependence (dispersion) of 1/T1 is such that it approaches zero at high fields whereas 1/T2 approaches a constant value. The residual 1/T2 is called the "secular" contribution and arises from fluctuations in time--as sensed by the protons of diffusing solvent or tissue water molecules--of the component of the magnetic field parallel to the static applied field. For solutions or suspensions of sufficiently large paramagnetic or ferromagnetic particles (greater than or equal to 250 A diameter), the paramagnetic contributions to the relaxation rates satisfy 1/T2 much greater than 1/T1 at typical imaging fields. We examine the theory of secular relaxation in some detail, particularly as it applies to systems relevant to magnetic resonance imaging, and then analyze the data for solutions, suspensions, or tissue containing ferritin, erythrocytes, agar-bound magnetite particles, and liver with low-density composite polymer-coated magnetite. In most cases we can explain the relaxation data, often quantitatively, in terms of the theory of relaxation of protons (water molecules) diffusing in the outer sphere environments of magnetized particles. The dipolar field produced by these particles has a strong spatial dependence, and its apparent fluctuations in time as seen by the diffusing protons produce spin transitions that contribute to both 1/T1 and /T2 comparably at low fields; for the larger particles, because of dispersion, the secular term dominates at fields of interest. On the basis of the agreement of theory with data for solutions of small paramagnetic complexes, large magnetite particles, and liver containing low-density polymer-coated magnetite agglomerates, it is argued that the theory is sufficiently reliable so that, e.g., for ferritin--for which 1/T2 is unexpectedly large--the source of its large relaxivity must reside in nonideal chemistry of the ferritin core. For blood, it appears that diffusion through intracellular gradients determines 1/T2.
Using measurements of the magnetic-field dependence of the nuclear magnetic relaxation rate ( I / T l ) of solvent water protons over a wide range of field values (corresponding to proton Larmor frequencies from 0.01 to 50 MHz), we have investigated the interaction of Mn2+ and Ca2+ ions with concanavalin A (Con A) over the pH range 5.3 to 6.4, at 5 and 25 "C. Particular attention was given to time-dependent effects that occur upon addition or removal of metals. Limited amounts of Mn2+ added to solutions of apo-Con A bind at SI (the usual "transition-metal"site) to form a binary complex characterized by a large and pH-dependent dissociation constant, rapid exchange of Mn2+ ions with solvent, and a relatively large and pH-independent contribution to the proton relaxation rate. With SI occupied, Ca2+ ions can bind at S2 (the usual "calcium-binding'' site) to form a metastable ternary complex characterized by a relatively large and pHdependent dissociation constant for Ca2+ ions, rapid exchange of Ca2+ ions with solvent, and a relatively low and pH-independent contribution to the proton relaxation rate. We find that this metastable ternary complex undergoes a first-order transition to a stable ternary complex, with a pH-independent time constant of 17 f 1 min at 5 " C and an activation energy of 22 kcal M-I. This stable ternary complex has the same relaxation contribution as the initial metastable complex, but differs in that the dissociation constant of Ca2+ is very low; the off-rate of both metals is of the order of days at 25 OC. Saccharide binding and agglutination studies are generally done with this form of Con A. We have also found that, in the abc o n c a n a v a l i n A, a metallo-protein isolated from the jack bean (Canavalia ensijormis), is one of a number of plant lectins. These proteins agglutinate cells in suspension with a selectivity that relates to the ability of lectins to bind to specific saccharides on cell surfaces (cf. Sharon and Lis, 1972; Lis and Sharon, 1973, for reviews). Interest in Con AI in particular arises from additional biological effects associated with the +From the IBM Thomas A ternary complex, respectively, of one particular conformation (called "unlocked") of Con A; PL, MPL, MMPL, and CMPL, the analogous forms of another conformation (called "locked") of Con A; MPE and CMPE, the thermal equilibrium states of samples of apo-Con A to which Mn2+, and subsequently Ca2+, respectively, have been added; [PSI, [MPS], and [MMPS], the sums of the concentrations of the respective unlocked and locked complexes; M and C, Mn2+ and Ca2+ ions, respectively, free in solution; EDTA, ethylenediaminetetraacetic acid. sence of Ca2+, Mn2+ can bind at S2 as well as at SI (S2 was previously thought to bind only Ca2+ and Cd2+) to form a metastable ternary complex which, like the metastable Mn2+-Ca2+-Con A complex, undergoes a transition to a stable state, but with a time constant that is much larger than for the Ca2+-containing ternary complex. In contrast to the stable Ca2+-Mn2+-Con A complex, the stab...
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