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In Vivo NMR and MRI Using Injection Delivery of Laser-Polarized Xenon (Xenon Injection͞optical Pumping)

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In Vivo NMR and MRI Using Injection Delivery of Laser-Polarized Xenon (Xenon Injection͞optical Pumping) Proc. Natl. Acad. Sci. USA Vol. 94, pp. 14725–14729, December 1997 Medical Sciences In vivo NMR and MRI using injection delivery of laser-polarized xenon (xenon injectionyoptical pumping) B. M. GOODSON*, Y.-Q. SONG*, R. E. TAYLOR*, V. D. SCHEPKIN*, K. M. BRENNAN*, G. C. CHINGAS*, T. F. BUDINGER*†,G.NAVON*‡, AND A. PINES*§ *Lawrence Berkeley National Laboratory and University of California, Berkeley, CA 94720; and †Department of Radiology, University of California, San Francisco, CA 94143 Contributed by Alexander Pines, October 7, 1997 ABSTRACT Because xenon NMR is highly sensitive to the were performed following direct intramuscular or intrave- local environment, laser-polarized xenon could be a unique nous injection of biologically compatible solvents presatu- probe of living tissues. Realization of clinical and medical rated with polarized xenon. Additionally, the advantages and science applications beyond lung airspace imaging requires limitations of this method are described in light of a one- methods of efficient delivery of laser-polarized xenon to compartment xenon uptakeywashout model.i tissues, because of the short spin-lattice relaxation times and relatively low concentrations of xenon attainable in the body. Preliminary results from the application of a polarized xenon BACKGROUND injection technique for in vivo 129Xe NMRyMRI are extrap- olated along with a simple model of xenon transit to show that To date, tissue delivery of polarized xenon has been performed the peak local concentration of polarized xenon delivered to using xenon respiration (9, 13, ¶). Respiration is ideally suited as tissues by injection may exceed that delivered by respiration a means of introducing polarized gases into the body for pulmo- by severalfold. nary studies, but it may be less efficient for certain studies involving remote organs, such as blood flow in the brain or In certain systems, the angular momentum of circularly po- muscular tissue. Recent simulations considering various physio- larized light can be transferred to nuclear spins by optical logical and experimental parameters have investigated the feasi- pumping (OP) (1–3), thus increasing the NMR sensitivity by bility of using xenon respiration for such experiments by predict- four to five orders of magnitude. This potential for enormous ing the time-dependent concentration of polarized xenon in a signal enhancement has been the driving force behind the chosen tissue (20, 21**). study of ‘‘polarized’’ noble gases for possible clinical and One possible alternative to respiration delivery of polarized biomedical applications. MRI of polarized 129Xe and 3He in xenon is the localized injection of nontoxic solutions contain- the gas phase has already been utilized to image the void spaces ing dissolved polarized xenon. Injection has been used as a in lungs (4–13), the oral cavity (14), and materials (15). The 133 sensitivity enhancement obtained through OP well outweighs means of delivering radioactive xenon isotopes (e.g., Xe) to the loss in signal suffered from imaging low-density gas-phase tissues for studies of muscular blood flow (22, 23). In circum- media. stances where the invasiveness of injection is acceptable, Because of the sensitivity of the NMR parameters of 129Xe polarized xenon injection would be advantageous when higher to its environment (16) and its safety for medical applications local concentrations of polarized xenon could be delivered to (17), it is hoped that dissolved polarized xenon could serve as tissues relative to the concentration attainable by respiration. a probe of tissues and blood flow in living organisms. Recent In the following, we adapt a simple, illustrative model to in vivo work in this direction includes imaging of xenon in the estimate the effective concentration of polarized xenon†† that brain¶ and xenon NMR of blood and other tissues following could be delivered to tissues by direct injection. respiration of polarized xenon by laboratory animals (9) and Consider a one-compartment uptakeywashout model using humans (13). a bolus injection of an inert, freely diffusible tracer (polarized One of the major challenges for the application of dis- xenon) (see, for example, ref. 24). Such an injection could in solved polarized xenon for in vivo studies is its efficient principle be performed intravenously, intraarterially, or di- delivery to the blood and tissues while maintaining its large rectly into the target organ. One can use the following relation nonequilibrium spin polarization. With current respiration methods (4–13), the dissolved xenon is diluted throughout the body via blood flow from the lungs; furthermore, because Abbreviations: OP, optical pumping; MR, magnetic resonance. Xe ‡Permanent address: School of Chemistry, Tel Aviv University, Tel the spin-lattice relaxation time (T1 ) of xenon in tissues is ' Aviv 69978, Israel. generally short (18) [e.g., 5 s in blood (19)], loss of xenon §To whom reprint requests should be addressed at: D-64 Hildebrand polarization can occur in transit before a significant con- Hall, Department of Chemistry, University of California, Berkeley, centration can accumulate in tissues. In previous work (19), CA 94720-1460. e-mail: [email protected]. a polarized xenon injection technique was developed and ¶Swanson, S. D., Rosen, M. S., Agranoff, B. W., Coulter, K. P., Welsh, used to perform in vitro magnetic resonance (MR) studies. R. C. & Chupp, T. E., 38th Experimental Nuclear Magnetic Reso- nance Conference, March 23–27, 1997, Orlando, FL. In this paper, the feasibility of using polarized xenon injec- i 129 This work was presented in part at the 38th Experimental Nuclear tion for in vivo studies is demonstrated. Xe NMR and MRI Magnetic Resonance Conference, March 23–27, 1997, Orlando, FL. **An interactive web site containing a xenon respiration model can be yy y y The publication costs of this article were defrayed in part by page charge found at http: ric.uthscsa.edu staff charlesmartinphd.html. ††The effective concentration of polarized xenon refers to the number payment. This article must therefore be hereby marked ‘‘advertisement’’ in of moles of 100% polarized, 100% isotopically labeled 129Xe per unit accordance with 18 U.S.C. §1734 solely to indicate this fact. volume, given an actual amount of xenon with known fractional © 1997 by The National Academy of Sciences 0027-8424y97y9414725-5$2.00y0 polarization and isotopic labeling. For simplicity, we assume 100% PNAS is available online at http:yywww.pnas.org. isotopic labeling when using the model. 14725 Downloaded by guest on September 30, 2021 14726 Medical Sciences: Goodson et al. Proc. Natl. Acad. Sci. USA 94 (1997) for the effective concentration C of polarized xenon in the targeted tissue following injection:‡‡ # 0, t Td; k1A 2 y Xe 2~ 2 ! z Td T1s z @ 2 t Td k2# , # C~t! 5 e 1 e , Td t Tp; 5 k2 2~ 2 ! z t Tp k2, , CTp e Tp t, [1] where k1 is the specific volume flow in the tissue, k2 is the effective washout rate defined by k 1 5 S 1 1 D k2 l Xe ; [2] T1 l y Xe (where is the tissue blood partition coefficient), T1s is the spin-lattice relaxation time of xenon in the solventyblood 5 1 environment, the peak time Tp Td Ti, and CTp is the effective concentration of polarized xenon in the tissue at Tp. This model will be used to estimate expected NMR signal intensities after xenon injection. MATERIALS AND METHODS FIG. 1. Schematic of experimental procedure after OP. Before Detailed descriptions of both the polarized xenon injection acquisition the sidearm of the shaker was removed from the liquid technique (19) and the OP apparatus (25, 26) can be found nitrogen and the polarized xenon was sublimated and admitted to the elsewhere. Approximately 5 3 1024 mol of isotopically en- solution. After a brief period of vigorous shaking, the saturated xenon riched 129Xe (80% 129Xe; EG & G Mound, Miamisburg, OH) solution was withdrawn with a syringe and injected into a laboratory was placed in a glass cell with a small quantity of rubidium and rat by means of a catheter. was optically pumped with a 1.3-W Titan Ti:sapphire laser ' Before each experiment the rat was placed in lateral recum- (continuous wave, 794.7 nm) for 30 min. The OP apparatus bency into the magnet. Afterward the catheter was removed typically produces xenon samples with 5–10% nuclear polar- and the rat was returned to its cage to recover from anesthesia. ization. The 129Xe magnetic resonance (MR) images and spectra The remainder of the experimental procedure is shown were obtained on a home-built NMR spectrometer interfaced schematically in Fig. 1. After OP, the xenon was frozen into the with a 2.35-T magnet (xenon frequency, 27.68 MHz; bore sidearm of the shaker in the presence of a magnetic field (50 diameter, 25 cm). The receiver–transmitter surface coil had a mT) provided by a small permanent magnet. A delay of diameter of 3.5 cm. For the spectroscopy experiment, spectra approximately 20 min between polarization and injection was were obtained every second (pulse angle ' 20°). For the necessary to transport the polarized xenon to the location of imaging experiment, axial images were acquired perpendicular the imaging apparatus; however, the T1 of solid xenon at the to the coil by using the FLASH pulse sequence (28) shown in described magnetic field strength and temperature is on the Fig. 2. order of hours (27). The xenon was sublimated and admitted to the degassed solvent [3 ml of 20% Intralipid emulsion (Pharmacia) or 3 ml of partially deuterated saline water, 0.9% RESULTS AND DISCUSSION 5 by weight] under approximately 5 atm (1 atm 101.3 kPa) of Preliminary in Vivo Xenon Injection Experiments. In the initial xenon pressure. In each experiment, 1 ml of the satu- spectroscopy experiment, a series of xenon NMR spectra were rated xenon solution was withdrawn into a syringe through the taken from the start of the intravenous injection of the rubber septum of the shaker prior to injection.
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