ABSTRACT
Tissue oximetry can assist in diagnosis and prognosis of many diseases and enable personalized therapy. Previously, we reported the ability of hexamethyldisiloxane (HMDSO) for accurate measurements of tissue oxygen tension (pO2) using Proton Imaging of Siloxanes to map Tissue Oxygenation Levels (PISTOL) magnetic resonance imaging. Here we report the feasibility of several commercially available linear and cyclic siloxanes (molecular weight 162-410 g/mol) as PISTOL-based oxygen reporters by characterizing their calibration constants. Further, field and temperature dependence of pO2 calibration curves of HMDSO, octamethyltrisiloxane (OMTSO) and polydimethylsiloxane (PDMSO) were also studied. The spin-lattice relaxation rate R1 of all siloxanes studied here exhibited a linear relationship with oxygenation (R1 = A' + B'*pO2) at all temperatures and field strengths evaluated here. The sensitivity index η( = B'/A') decreased with increasing molecular weight with values ranged from 4.7 × 10-3-11.6 × 10-3 torr-1 at 4.7 T. No substantial change in the anoxic relaxation rate and a slight decrease in pO2 sensitivity was observed at higher magnetic fields of 7 T and 9.4 T for HMDSO and OMTSO. Temperature dependence of calibration curves for HMDSO, OMTSO and PDMSO was small and simulated errors in pO2 measurement were 1-2 torr/°C. In summary, we have demonstrated the feasibility of various linear and cyclic siloxanes as pO2-reporters for PISTOL-based oximetry.
ABSTRACT
Genetically engineered mouse models (GEMMs) of lung cancer closely recapitulate the human disease but suffer from the difficulty of evaluating tumor growth by conventional methods. Herein, a novel automated image analysis method for estimating the lung tumor burden from in vivo micro-computed tomography (micro-CT) data is described. The proposed tumor burden metric is the segmented soft tissue volume contained within a chest space region of interest, excluding an estimate of the heart volume. The method was validated by comparison with previously published manual analysis methods and applied in two therapeutic studies in a mutant K-ras GEMM of non-small cell lung carcinoma. Mice were imaged by micro-CT pre-treatment and stratified into four treatment groups: an antibody inhibiting vascular endothelial growth factor (anti-VEGF), chemotherapy, combination of anti-VEGF and chemotherapy, or control antibody. In the first study, post-treatment imaging was performed 4 weeks later. In the second study, mice were scanned serially on a high-throughput scanner every 2 weeks for 8 weeks during treatment. In both studies, the automated tumor burden estimates were well correlated with manual metrics (r value range: 0.83-0.93, P < .0001) and showed a similar, significant reduction in tumor growth in mice treated with anti-VEGF alone or in combination with chemotherapy. Given the fully automated nature of this technique, the proposed analysis method can provide a valuable tool in preclinical drug research for screening and randomizing animals into treatment groups and evaluating treatment efficacy in mouse models of lung cancer in a highly robust and efficient manner.
ABSTRACT
Quantitative in vivo oximetry has been reported using (19) F MRI in conjunction with reporter molecules, such as perfluorocarbons, for tissue oxygenation (pO(2) ). Recently, hexamethyldisiloxane (HMDSO) has been proposed as a promising alternative reporter molecule for (1) H MRI-based measurement of pO(2) . To aid biocompatibility for potential systemic administration, we prepared various nanoemulsion formulations using a wide range of HMDSO volume fractions and HMDSO to surfactant ratios. Calibration curves (R(1) versus pO(2) ) for all emulsion formulations were found to be linear and similar to neat HMDSO for low surfactant concentrations (<10% v/v). A small temperature dependence in the calibration curves was observed, similar to previous reports on neat HMDSO, and was characterized to be approximately 1 Torr/ °C under hypoxic conditions. To demonstrate application in vivo, 100 µL of this nanoemulsion was administered to healthy rat thigh muscle (Fisher 344, n=6). Dynamic changes in mean thigh tissue pO(2) were measured using the PISTOL (proton imaging of siloxanes to map tissue oxygenation levels) technique in response to oxygen challenge. Changing the inhaled gas to oxygen for 30 min increased the mean pO(2) significantly (p<0.001) from 39 ± 7 to 275 ± 27 Torr. When the breathing gas was switched back to air, the tissue pO(2) decreased to a mean value of 45 ± 6 Torr, not significantly different from baseline (p>0.05), in 25 min. A first-order exponential fit to this part of the pO(2) data (i.e. after oxygen challenge) yielded an oxygen consumption-related kinetic parameter k=0.21 ± 0.04 min(-1) . These results demonstrate the feasibility of using HMDSO nanoemulsions as nanoprobes of pO(2) and their utility to assess oxygen dynamics in vivo, further developing quantitative (1) H MRI oximetry.
