Proton imaging of siloxanes to map tissue oxygenation levels (PISTOL): a tool for quantitative tissue oximetry

Abstract

Hexamethyldisiloxane (HMDSO) has been identified as a sensitive proton NMR indicator of tissue oxygenation (pO₂) based on spectroscopic spin-lattice relaxometry. A rapid MRI approach has now been designed, implemented, and tested. The technique, proton imaging of siloxanes to map tissue oxygenation levels (PISTOL), utilizes frequency-selective excitation of the HMDSO resonance and chemical-shift selective suppression of residual water signal to effectively eliminate water and fat signals and pulse-burst saturation recovery ¹H echo planar imaging to map T₁ of HMDSO and hence pO₂. PISTOL was used here to obtain maps of pO₂ in rat thigh muscle and Dunning prostate R3327 MAT-Lu tumor-implanted rats. Measurements were repeated to assess baseline stability and response to breathing of hyperoxic gas. Each pO₂ map was obtained in 3½ min, facilitating dynamic measurements of response to oxygen intervention. Altering the inhaled gas to oxygen produced a significant increase in mean pO₂ from 55 Torr to 238 Torr in thigh muscle and a smaller, but significant, increase in mean pO₂ from 17 Torr to 78 Torr in MAT-Lu tumors. Thus, PISTOL enabled mapping of tissue pO₂ at multiple locations and dynamic changes in pO₂ in response to intervention. This new method offers a potentially valuable new tool to image pO₂ in vivo for any healthy or diseased state by ¹H MRI.

INTRODUCTION

There is increasing evidence that hypoxia stimulates angiogenesis and metastasis and that hypoxic tumors are more aggressive (1). Furthermore, extensive hypoxia has been associated with poor clinical prognosis for several tumor types, notably cervical and head and neck, based on electrode measurements (2–4). Extensive hypoxia has also been identified in prostate, breast, and brain tumors (5–7). It is expected from definitive observations in cell culture (8) and preclinical investigations in rats and mice (1,9–11) that hypoxic tumors resist radiotherapy. Measurement of tumor hypoxia is becoming increasingly pertinent, as therapy can now be tailored to the characteristics of individual tumors, i.e. personalized medicine. An adjuvant intervention may be applied to patients with hypoxic tumors, e.g. hyperoxic gas breathing to reduce hypoxic fraction. Alternatively, for tumors that resist modulation, a radiation boost may be applied using intensity modulated radiation therapy, or a hypoxic-cell-selective cytotoxin, such as tirapazamine, may be administered.

The ability to measure tissue oxygen tension (pO₂) non-invasively may be important in understanding the physiology, pathophysiology, and, potentially, clinical prognosis of diseases such as cancer and stroke. To date, many assays have examined hypoxia, rather than pO₂ itself. Radionuclide approaches using fluoromisonidazole and copper diacetyl-bis(N⁴-methylthiosemicarbazone) can identify hypoxia and have shown predictive value in clinical studies (1). Likewise, immunohistochemistry of biopsy samples after pimonidazole or EF5 (a fluorinated derivative of etanidazole) administration and trapping in tumor tissues have been correlated with outcome (7,12). MRI is particularly suitable for multiple repeat measurements for observing dynamic changes in tissue oxygenation in response to intervention, and blood-oxygen-level-dependent (BOLD) contrast gives an indication of vascular oxygenation, albeit usually qualitative (13–15). ¹⁹F NMR can provide quantitative oximetry based on spin-lattice relaxation of perfluorocarbons (16), although it is currently limited to preclinical studies, as reviewed in detail (17,18). The technique has been used to evaluate the ability to manipulate tumor pO₂ based on hyperoxic gas breathing. Most significantly, correlations have been shown between pO₂ at the time of irradiation and growth delay in Dunning prostate R3327-HI and R3327-AT1 rat tumors (10,11) using hexafluorobenzene (HFB) as a reporter molecule.

Although ¹⁹F-MR oximetry is well established and continues to make important contributions to basic research, its clinical translation is hampered by the continuing lack of ¹⁹F capability on most clinical MRI scanners. Recently, hexamethyldisiloxane (HMDSO) was identified as a ¹H-NMR probe of pO₂, and the feasibility of tissue oximetry was presented using ¹H-NMR spectroscopic relaxometry of HMDSO, after direct intra-tissue injection (19). With the use of the spectroscopic approach, localization was achieved by virtue of a discrete injection site. The present study demonstrates the implementation of an imaging-based method: proton imaging of siloxanes to map tissue oxygenation levels (PISTOL). As proof of principle, phantom studies are presented and this pO₂ reporter molecule is used to investigate dynamic changes in pO₂ in rat thigh muscle and syngeneic Dunning prostate R3327-MAT-Lu tumors in response to respiratory challenge with oxygen. A comparative ¹⁹F-MR oximetry study was also carried out in rat thigh muscle using HFB.

METHODS

Pulse sequence for measuring pO₂

NMR experiments were performed using a Varian Inova^® 4.7 T horizontal-bore system equipped with actively shielded gradients. A chemical-shift selective (CHESS) spin-echo sequence was used to identify the location of HMDSO. A spin-echo echo planar imaging (EPI)-based pulse sequence (Fig. 1) was then used for measuring T₁ values for this slice location. The sequence consisted of an initial pulse-burst saturation recovery (PBSR) preparation sequence with 20 non-selective saturation pulses (inter-pulse delay = 50 ms) followed by a variable delay, t, for magnetization recovery. Three CHESS (20) pulses can be included at the end of τ for optional frequency-selective saturation of water and fat. A spin-echo EPI acquisition, consisting of a frequency-selective π/2 pulse (on-resonance for HMDSO), a slice-selective π pulse, and an EPI readout, follows τ. A long echo time (~50 ms) was used, which aided suppression of the fat resonance. This combination of PBSR with frequency-selective excitation EPI (HMDSO) and suppression (water, fat) allowed T₁ mapping of HMDSO in 3½ min. For ¹⁹F-MR oximetry experiments, FREDOM (fluorocarbon relaxometry using echo planar imaging for dynamic oxygen mapping) was applied using a standard EPI sequence with PBSR (17). The location of HFB was easily determined by using a standard spin-echo sequence, because of the lack of ¹⁹F background signal. In both cases (¹H and ¹⁹F), T₁ values were obtained using the corresponding sequence with the ARDVARC (alternating relaxation delays with variable acquisitions for reduction of clearance effects) protocol (21). Varying τ in the range 0.1–55 s, gave a total acquisition time of 3½ min per T₁ measurement for PISTOL. T₁, R₁ (=1/T₁) and pO₂ maps were computed on a voxel-by-voxel basis using a home-built program written in Matlab (Mathworks Inc., Nattick, MA, USA). For a given voxel, the T₁ value was obtained by a three-parameter least-squares curve fit of the signal intensities corresponding to 16 τ values using the Levenberg–Marquardt algorithm. The R₁ maps were converted into pO₂ maps using previously published calibration curves (19).

Figure 1.

Pulse sequence for HMDSO relaxometry with optional CHESS fat and water suppression (PISTOL). Magnetization preparation consists of 20 π/2 saturation pulses followed by a variable recovery time τ. The π/2 pulse is frequency selective for the HMDSO resonance, whereas the π pulse is slice selective. EPI readout enables T₁ mapping in 3½ min.

Phantom experiments

A phantom consisting of tubes containing water, mineral oil (to simulate fat), and HMDSO was used to optimize the pulse sequence and test water and fat suppression. To measure the pO₂ vs R₁ calibration curve by imaging, a second phantom consisting of four gas-tight John Young NMR tubes (Wilmad Labglass, Buena, NJ, USA) containing 1 mL HMDSO each bubbled with different concentrations of O₂ (0%, 5%, 10%, and 21% calibrated gases; Airgas Southwest, Dallas, TX, USA) was used. Temperature was kept constant with aD₂O-filled circulating water pad and monitored using a fiber-optic temperature probe (FISO Technologies Inc., Quebec City, Quebec, Canada). Mean intensities of each region of interest corresponding to each tube were obtained from the T₁ maps and converted into R₁ values. Measurements were repeated six times to provide mean R₁ values to obtain a calibration curve.

In vivo experiments

The animal investigations were approved by the Institutional Animal Care and Use Committee. Ten healthy Copenhagen-2331 rats (Harlan, Indianapolis, IN, USA) were used to obtain pO₂ data in the thigh muscle (six rats for HMDSO studies and four separate rats for HFB studies). A further six male Copenhagen rats were implanted with Dunning prostate R3327 MAT-Lu tumors subcutaneously on the thigh, to obtain pO₂ data in tumors. Tumors were allowed to grow to a range of sizes from 1.2 to 10.6 cm³ (five were > 3cm³). For MRI, rats were maintained under general gaseous anesthesia (air and 1.5% isoflurane; Baxter International Inc, Deerfield, IL, USA). For pO₂ measurements in vivo, 50 μL HMDSO (99.7%; Alfa Aesar, Ward Hill, MA, USA) was administered along two or three tracks in the thigh muscle (n = 6) or MAT-Lu tumors (n = 6) in a single plane using a Hamilton syringe with a 32G needle, as described in detail previously for the analogous ¹⁹F-NMR approach (17). For comparative ¹⁹F-MR pO₂ measurements, 50 μL HFB (99.9%; Lancaster Co., Pelham, NH, USA) was administered in the thigh muscle, in a separate cohort of animals (n = 4), as above. The rats were placed in the magnet in the prone position, and body temperature was maintained using a warm water blanket. The thigh or tumor was placed inside a size-matched single-turn ¹H/¹⁹F tunable volume coil. A cross-section through the thigh or tumor was imaged after HMDSO or HFB was located, as described above. In order to modulate tissue oxygenation, the rats were subjected to respiratory challenge in the sequence, air (20 min) – oxygen (30 min) – air (30 min), and T₁ datasets were acquired every 5 min. pO₂ values were obtained from the R₁ values. Typically, 16 pO₂ maps were obtained over a period of 80 min. The statistical significance of changes in pO₂ was assessed by using analysis of variance on the basis of Fisher's protected least-squares difference test at 95% confidence level (Statview, SAS Institute, Carey, NC, USA).

RESULTS

Phantom studies

Suppression of water and mineral oil signals using the spectrally selective spin-echo EPI sequence (Fig. 1) was successful in a water-filled phantom containing smaller tubes of HMDSO and mineral oil (Fig. 2a,b). T₁ measurements from the phantom comprising sealed HMDSO tubes with different oxygen concentrations (at 36.5°C) yielded T₁ values essentially identical with those reported previously by spectroscopy (19) (Fig. 2c,d,e). A linear fit to the data yielded a calibration curve R₁ = (0.108 ± 0.001) + (0.00130 ± 0.00001) × pO₂ at 36.5°C.

Figure 2.

Water and fat suppression. (a) T₁-weighted spin-echo image of phantom with smaller tubes containing mineral oil (F) and HMDSO (H) inside a tube containing water (W), and (b) EPI image of the same phantom with fat and water suppression. (c) T₁-weighted spin-echo image and (d) T₁ maps of a phantom comprising HMDSO saturated with gases at different concentrations of oxygen (clockwise from bottom left: 0%, 5%, 10% and 21%) obtained using PISTOL. (e) A linear fit to the data (mean region of interest intensities, six measurements) yields the calibration curve: R₁ = (0.108 ± 0.001) + (0.00130 0.001) × pO₂ at 36.5°C.

Tissue oxygenation

HMDSO was readily observed in thigh muscle and tumors by PISTOL with complete suppression of fat and water signals. Discrete distribution of HMDSO was seen in thigh muscle (Fig. 3a,b) and a MAT-Lutumor (Fig. 3f,g) using the CHESS spin-echo sequence. These appear spatially similar to the images of HMDSO and the corresponding pO₂ maps acquired using PISTOL (Fig. 3c–e and 3h–j). The imaging data revealed the pO₂ distribution, showing the effect of breathing oxygen. Baseline pO₂ values were obtained by averaging four baseline pO₂ measurements while the rats breathed air. In rat thigh muscle (n = 6), mean baseline pO₂ ranged from 27 to 71 Torr (mean = 55 ± 17 Torr), but was stable in any given muscle (mean variation = ±4 Torr over 20 min). On alteration of inhaled gas to oxygen, mean pO₂ increased significantly (Fig. 4a) and continued to increase over 20 min. For the group of thigh muscles, mean pO₂ was significantly elevated (P < 0.05) compared with baseline by the first measurement (5 min) after the switch of inhaled gas to oxygen and reached values of 163–290 Torr (mean pO₂ = 238 ± 59 Torr) after 30 min of breathing oxygen. On return to air breathing, mean pO₂ had decreased significantly by the first measurement (5 min) and had returned to a value not significantly different from baseline by the second measurement (10 min). Measurements of pO₂ in thigh muscle using HFB yielded similar results (Fig. 4b). For this group (n = 4), mean baseline pO₂ ranged from 23 to 51 Torr (mean = 35 ± 11 Torr), and was stable in any given muscle (mean variation = 3 Torr over 20 min). In response to oxygen breathing, mean pO₂ was significantly elevated (P < 0.05) compared with baseline by the first measurement (5 min) after the switch of inhaled gas to oxygen and had reached values of 152–305 Torr (mean pO₂ = 211 ± 79 Torr) after 30 min of breathing oxygen. On return to air breathing, mean pO₂ had decreased significantly by the third measurement (15 min) and had returned to a value not significantly different from baseline by the fourth measurement (20 min).

Figure 3.

Monitoring changes in oxygenation of rat thigh muscle and Dunning prostate R3327 prostate MAT-Lu tumors implanted in Copenhagen rat thigh in vivo with respect to oxygen challenge. Spin-echo images of a representative rat thigh muscle (a) and MAT-Lu tumor (f). CHESS spin-echo images of silane injected into thigh muscle (b) and tumor (g) showing the distribution of the injected HMDSO. The corresponding time course PISTOL pO₂ maps (c, h, baseline air breathing; d, i, 30 min oxygen; e, j, 30 min after return to air breathing) showing the response to hyperoxic gas intervention in each case.

Figure 4.

Dynamic changes in tissue oxygenation measured in vivo in rat thigh muscle. Individual curves are shown for mean pO₂ values using (a) HMDSO (n = 6) and (b) HFB (n = 4).

In rat prostate MAT-Lu tumors (n = 6), mean baseline pO₂ ranged from −0.5 to 41 Torr (mean = 17 ± 16 Torr), but was stable in each tumor (mean variation = ±2 Torr over 20 min). Tumors 1–5 showed a mean baseline pO₂ = 12 ± 12 Torr with a mean variation of ±2 Torr. For these five tumors, mean pO₂ was significantly elevated (P < 0.05) compared with baseline by the fifth measurement (25 min) after the switch of inhaled gas to oxygen (Fig. 5). When oxygen was breathed for 30 min, mean pO₂ reached 30 ± 27 Torr (range 7–69). On switching back to air from oxygen, mean pO₂ had returned to a value not significantly different from baseline by the second measurement (10 min). Tumor 6 exhibited particularly high pO₂ response to breathing oxygen (mean pO₂ = 323 ± 44 Torr after 30 min of oxygen breathing), which was very different from the other tumors. Comparing the ¹H anatomical (H₂O) and selective HMDSO images showed that the HMDSO was deposited in the tumor periphery and was probably not representative of the tumor bulk. Hence, it has been excluded from Fig. 5. Figure 6 shows histograms of pO₂ distributions for pooled voxels from rat thigh muscle (Fig. 6a) and MAT-Lu tumors (Fig. 6b) and changes in the distribution after 30 min of oxygen breathing. Figure 7 shows the changes in representative voxels (five each) from a representative muscle (Fig. 7a) and tumor (Fig. 7b, same tumor as shown in Fig. 3). Data for individual tumors are summarized in Table 1.

Figure 5.

Dynamic changes in mean tissue oxygenation measured in vivo in MAT-Lu tumors (five out of total six) with respect to oxygen challenge. Tumor 6 showed HMDSO only in the tumor periphery and displayed uncharacteristically large response to oxygen challenge. It was excluded from the figure for better visualization of the rest of the data.

Figure 6.

Distribution of tissue oxygenation measured in vivo by PISTOL. Histograms of pO₂ distributions for pooled voxels from (a) rat thigh muscle (n = 6) and (b) MAT-Lu tumors (n = 6) with respect to oxygen challenge.

Figure 7.

Dynamic changes in pO₂ values of representative voxels from (a) thigh muscle and (b) rat prostate MAT-Lu tumor. Five voxels were selected from each tissue in Fig. 3 and examined with respect to oxygen challenge. The values are shown during air breathing, 30 min after switching to oxygen, and 30 min after switching back to air. Error bars represent the standard error of curve fit.

Table 1.

Mean + SD pO₂ and hypoxic fraction (HF₅, percentage voxels with pO₂ < 5 Torr) for individual tumors with respect to hyperoxic gas challenge in the sequence: air–oxygen–air

	Intervention
	Air (baseline)		Oxygen		Air (return)
Tumor number and size (cm3)	pO2 (Torr)	HF5 (%)	pO2 (Torr)	HF5 (%)	pO2 (Torr)	HF5 (%)
1 (1.2)	11.5 ± 3.2	50	9.1 ± 16.9	72	9.8 ± 11.2	33
2 (10.3)	–0.5 ± 1.2	70	69 ± 7.6*	2**	11.4 ± 1.8*	42**
3 (10.8)	3.6 ± 1.0	71	6.9 ± 0.1*	45*	3.2 ± 2.7	58
4 (3.7)	12.7 ± 1.4	38	16.6 ± 3.2	54	8.6 ± 1.1	57
5 (9.1)	32.7 ± 4.7	56	49.2 ± 4.9**	60	26.6 ± 0.6	58
6a (5.6)	40.5 ± 2.7	0	318 ± 6**	0	39.7 ± 2.0	0
Mean ± SD (n = 6)	17 ± 16	48 ± 26	78 ± 120*	39 ± 31	17 ± 14*	41 ± 23
Mean ± SD (n = 5, Nos 1–5)	12 ± 12	57 ± 14	30 ± 27**	47 ± 27	12 ± 19*	50 ± 12

For individual tumors, mean pO₂ or HF₅ was compared between baseline air breathing and the last two measurements with oxygen breathing or return to air.

^*P < 0.05.

^**P < 0.01.

^aTumor 6 showed unusually high pO₂ and response, and comparison of the ¹H anatomical (H₂O) and selective HMDSO MR images showed that HMDSO had been deposited in the tumor periphery.

DISCUSSION

HMDSO has previously been shown to be a promising ¹H-MR-based pO₂ reporter molecule for spectroscopic in vivo studies based on the linear dependence of its spin-lattice relaxation rate R₁ on pO₂ at a given temperature in the range 26–46°C (19). The present study demonstrates the feasibility of imaging dynamic changes in tissue oxygenation using frequency-selective EPI of HMDSO, after direct injection into tissue.

In seeking a proton NMR pO₂ reporter molecule, HMDSO was selected for its similarity to traditional ¹⁹F-NMR perfluorocarbon agents. HMDSO is hydrophobic and is essentially immiscible with aqueous solutions. Thus, gas exchange with the surrounding tissue occurs without exchange of ions, which might influence the spin lattice relaxation; thus, the validity of in vitro calibrations is maintained for in vivo determinations. HMDSO is readily available, inexpensive, and easy to store. Although HMDSO was used here, other symmetric, hydrophobic siloxanes may also be effective pO₂ reporter molecules, and this new concept is open to development and optimization. In the perfluorocarbon field, many different molecules have been exploited for in vivo oximetry over the years (22,23). Initially, perfluorocarbon blood substitute emulsions were favored for their biocompatibility, but multi-resonance molecules, such as perfluorotributylamine and perflubron (perfluoro-octylbromide) were suboptimal for oximetry, because of relatively low R₁ dependence on pO₂ and high dependence on temperature (22). Moreover, the multi-resonance spectra caused considerable signal loss for imaging (24). Ultimately, HFB and perfluoro-15-crown-5 ether were identified as superior because of their single resonances (18,25,26), and HFB is particularly attractive because of its low temperature dependence and ready commercial availability. Just as the perfluorocarbon oximetry field has evolved, other siloxanes may be identified or developed that may be superior to HMDSO.

Mapping pO₂ was demonstrated using frequency-selective excitation of the HMDSO resonance with efficient frequency-selective fat and water suppression in vitro and in vivo. The calibration curve obtained here with imaging compares well with the calibration curve obtained previously by spectroscopy (19). Clearance of HMDSO from tissues (half-life ~35 h) is relatively slow compared with clearance of HFB used in the analogous ¹⁹F-MR oximetry (FREDOM) (17,27), so that there is minimal clearance during a typical investigation of oxygen dynamics in response to acute interventions (19). Thus, although FREDOM provides sensitive assessment of acute changes in response to respiratory challenge or vascular targeting agents, the slower clearance of HMDSO may facilitate studies of chronic changes in tumor oxygenation accompanying tumor growth or long-term chemotherapy. Application of HMDSO to breast studies could be difficult in the presence of silicone implants because of the similar chemical shifts.

In rat thigh muscle, the range of baseline pO₂ values measured by PISTOL and pO₂ response to oxygen challenge were similar to those measured here by the well-established ¹⁹F-MR oximetry technique and those reported previously using ¹H spectroscopy of HMDSO (19) or ¹⁹F MRI of HFB (28), needle electrodes, fiber optical probes (29,30), or electron paramagnetic resonance (31,32). The response of individual voxels and muscles in separate rats to oxygen breathing depends on voxel location (Figs. 3, 4, 6, and 7), but the baseline values and response are generally higher than seen in tumors. As also reported by Yeh et al. (33), based on measurements using oxygen electrodes, the pO₂ of Dunning prostate tumors tends to be lower than in skeletal muscle. The baseline pO₂ values and pO₂ response to oxygen challenge are quite similar to those reported previously for large MAT-Lu tumors using ¹⁹F-MR oximetry (34). Different rat prostate and breast tumor types are reported to exhibit a range of baseline oxygenations, and the response to interventions is highly variable. In some cases, hypoxic fractions resist modulation with hyperoxic gas breathing [e.g. Dunning prostate R3327-AT1 tumors (10,35)]. In other tumors, notably with a well-developed and highly perfused vasculature, hyperoxic gas essentially eliminated hypoxia [large Dunning prostate R3327-HI tumors (11)].

Direct intratumoral injection of the reporter molecule has benefits and drawbacks. It allows immediate measurement of any region of interest after minimally invasive administration. By contrast, reporter molecules administered systemically initially report vascular oxygenation (36) and even after clearance tend to sequester in well-perfused regions biasing measurements (37). Of course, direct injection does limit measurements to accessible tissues. It would be preferable to exploit endogenous molecules as used in BOLD contrast, but this reveals vascular oxygenation and is subject to variations in vascular volume, hematocrit, and flow (13,14). Direct measurements of tissue water T₁ are attractive (38,39), but they may be influenced by many factors in addition to pO₂. Like perfluorocarbons, HMDSO is lipophilic and is essentially immiscible in aqueous solutions. It could be emulsified for systemic delivery to help circumvent the need for direct intra-tissue injections, and such an attempt is currently underway. Some silanes are highly reactive, whereas HMDSO is quite inert, and is reported to exhibit minimal toxicity (40,41). In a 13-week subchronic inhalation toxicity study in Fischer 344 rats exposed to 5000 ppm of HMDSO, no treatment-related signs of toxicity or mortality, or other significant histological changes were found (40). After oral (300 mg/kg) or intravenous administration (80 mg/kg, as emulsion) of HMDSO, various polar metabolites were found in the urine as a result of the oxidation of the Si–CH₃ bond (42). Another study reported no irritation in Draize tests of skin or eye irritancy and no acute toxicity in rats (LD₅₀ > 3.8 g/kg) (43). In our studies, we saw no overt signs of inflammation or discomfort, although no microscopic analyses were performed. For future routine use as an intra-tissue-injected pO₂ reporter molecule, further investigation of possible local inflammatory response after direct injection of siloxanes is warranted.

In summary, PISTOL is a sensitive, quantitative ¹H-MR method for imaging oxygen tension and dynamic changes in response to interventions. This new technique opens up further opportunities to evaluate pO₂ in vivo. Rapid translation of this method to the clinical setting is feasible with current state-of-the-art MR hardware, as clinical instruments can routinely generate effective water and fat suppression as used in detection of metabolites such as choline, lactate, and citrate. A further advantage of PISTOL is that it will now be possible to add quantitative oximetry to a protocol consisting of other ¹H-MR-based functional techniques routinely used for research as well as clinical diagnosis, such as dynamic contrast enhancement, diffusion measurements, and MRS.

Abbreviations used

ARDVARC

alternating relaxation delays with variable acquisitions for reduction of clearance effects data acquisition protocol

BOLD

blood oxygen level dependent

CHESS

chemical-shift selective

EPI

echo planar imaging

FREDOM

fluorocarbon relaxometry using echo planar imaging for dynamic oxygen mapping

HFB

hexafluorobenzene

HMDSO

hexamethyldisiloxane

MAT-Lu

Dunning prostate R3327-AT tumor subline metastatic to lungs

PBSR

pulse-burst saturation recovery

pO₂

oxygen tension

PISTOL

proton imaging of siloxanes to map tissue oxygenation levels