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Molecular Magnetic Resonance Imaging of Tumor Response to Therapy.

Shuhendler AJ, Ye D, Brewer KD, Bazalova-Carter M, Lee KH, Kempen P, Dane Wittrup K, Graves EE, Rutt B, Rao J - Sci Rep (2015)

Bottom Line: The poor sensitivity of MRI has limited the development of activatable molecular MR contrast agents.To overcome this limitation of molecular MRI, a novel implementation of our caspase-3-sensitive nanoaggregation MRI (C-SNAM) contrast agent is reported.Importantly, C-SNAM is inert to immune activation, permitting radiation therapy monitoring.

View Article: PubMed Central - PubMed

Affiliation: Molecular Imaging Program at Stanford, Stanford, California 94305, USA.

ABSTRACT
Personalized cancer medicine requires measurement of therapeutic efficacy as early as possible, which is optimally achieved by three-dimensional imaging given the heterogeneity of cancer. Magnetic resonance imaging (MRI) can obtain images of both anatomy and cellular responses, if acquired with a molecular imaging contrast agent. The poor sensitivity of MRI has limited the development of activatable molecular MR contrast agents. To overcome this limitation of molecular MRI, a novel implementation of our caspase-3-sensitive nanoaggregation MRI (C-SNAM) contrast agent is reported. C-SNAM is triggered to self-assemble into nanoparticles in apoptotic tumor cells, and effectively amplifies molecular level changes through nanoaggregation, enhancing tissue retention and spin-lattice relaxivity. At one-tenth the current clinical dose of contrast agent, and following a single imaging session, C-SNAM MRI accurately measured the response of tumors to either metronomic chemotherapy or radiation therapy, where the degree of signal enhancement is prognostic of long-term therapeutic efficacy. Importantly, C-SNAM is inert to immune activation, permitting radiation therapy monitoring.

No MeSH data available.


Related in: MedlinePlus

Imaging the therapeutic response to metronomic chemotherapy in HeLa tumor-bearing mice.(a) Representative MR images of untreated (left) and treated mice (center) receiving C-SNAM, and treated mice receiving NC-ctrl (right) pre-contrast (top) and 50 min post-contrast (bottom). Tumor is indicated by white arrow, hot spot is indicated by yellow arrowhead. Water and 0.5 mM Dotarem phantoms are shown on bottom left and right, respectively, of each image. (b) Representative voxel histograms for untreated (black) and treated (blue) mice receiving C-SNAM, and treated mice receiving NC-ctrl (red). Histograms are shown 50 min post-contrast (solid bars) and 110 min post-contrast (open bars). (c) The percent signal enhancement (%SE) for the hotspot signal enhancement (mean signal within the top quartile of the enhancement histogram) is plotted over time for untreated (black) and treated (blue) mice receiving C-SNAM, and treated mice receiving NC-ctrl (red). Values are mean ± s.d., *p < 0.05 (general linear model repeated measures), and n = 4 per group.
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f3: Imaging the therapeutic response to metronomic chemotherapy in HeLa tumor-bearing mice.(a) Representative MR images of untreated (left) and treated mice (center) receiving C-SNAM, and treated mice receiving NC-ctrl (right) pre-contrast (top) and 50 min post-contrast (bottom). Tumor is indicated by white arrow, hot spot is indicated by yellow arrowhead. Water and 0.5 mM Dotarem phantoms are shown on bottom left and right, respectively, of each image. (b) Representative voxel histograms for untreated (black) and treated (blue) mice receiving C-SNAM, and treated mice receiving NC-ctrl (red). Histograms are shown 50 min post-contrast (solid bars) and 110 min post-contrast (open bars). (c) The percent signal enhancement (%SE) for the hotspot signal enhancement (mean signal within the top quartile of the enhancement histogram) is plotted over time for untreated (black) and treated (blue) mice receiving C-SNAM, and treated mice receiving NC-ctrl (red). Values are mean ± s.d., *p < 0.05 (general linear model repeated measures), and n = 4 per group.

Mentions: A single MRI imaging session at 1T was conducted 2 days following the final dose of doxorubicin chemotherapy, identified as the peak of caspase-3 activity based on previous study with this model15. Images were acquired prior to C-SNAM injection (pre-contrast) and every 10 min following C-SNAM injection (post-contrast). Reference standards containing water (left of the mouse) or 0.5 mM Dotarem® (right of the mouse) were imaged to allow for the normalization of image contrast as previously described2223. Pre- and post-contrast images were used to normalize between scan sessions. Representative images of a tumor pre-contrast (Fig. 3a, top row) and 50 min post-contrast (Fig. 3a, bottom row) are provided for untreated (left) and mice treated with metronomic chemotherapy and administered C-SNAM (middle), and treated mice administered the non-cyclizable NC-ctrl probe (right). Hotspots of C-SNAM activation and retention can be observed in the treated mice receiving active probe (Fig. 3a, yellow arrowheads), with fewer and less intense hotspots notable in untreated mice, and in treated mice receiving NC-ctrl control probe. While tumor-averaged signal enhancement was not substantially different between the three groups (Supplementary Fig. S2a), significant differences were revealed through analysis of hotspot signal (General linear model repeated measure analysis, P < 0.05). In order to analyze the appearance of hotspots, tumor signals were quantified through voxel signal histograms over the entire volume of the tumor, as has been previously reported2425. Voxel histogram analysis provides the ability to detect heterogeneous regions of signal enhancement (i.e. hotspots) as necessitated by molecular MRI1 (Fig. 3b). Hotspots were conservatively defined as those voxels within the top quartile of the histogram, isolating the extent of elongation of the right tail of the histogram due to C-SNAM nanoaggregation. A substantial elongation of the right tail of the voxel histogram of doxorubicin-treated mice administered C-SNAM (Fig. 3b, blue) can be seen relative to untreated mice administered C-SNAM (Fig. 3b, black) and treated mice administered the NC-ctrl (Fig. 3b, red) at 50 min post-contrast. Furthermore, the histograms shift to the left over time (50 min versus 110 min, Fig. 3b) to a substantially greater extent for treated mice receiving NC-ctrl relative to those receiving C-SNAM, suggesting a more rapid washout of the non-cyclized probe relative to the nanoaggregates. The change in tumor hotspot contrast over time was quantified as the percent increase of the mean hotspot signal relative to pre-contrast for a given time point (Fig. 3c). The signal enhancement was significantly greater for mice treated with metronomic chemotherapy and administered C-SNAM (Fig. 3c, blue) relative to both untreated mice (Fig. 3c, black) and treated mice administered NC-ctrl (Fig. 3c, red) (General linear model repeated measures analysis, P < 0.05, n = 4 mice per group). While the %SE from treated mice administered NC-ctrl increased initially relative to untreated mice administered C-SNAM, it rapidly decreased (within 70 min) to the levels of untreated mice, whereas C-SNAM maintained prolonged retention even beyond 2 hr. This rapid washout of NC-ctrl relative to C-SNAM is likely due to its inability to cyclize or self-assemble.


Molecular Magnetic Resonance Imaging of Tumor Response to Therapy.

Shuhendler AJ, Ye D, Brewer KD, Bazalova-Carter M, Lee KH, Kempen P, Dane Wittrup K, Graves EE, Rutt B, Rao J - Sci Rep (2015)

Imaging the therapeutic response to metronomic chemotherapy in HeLa tumor-bearing mice.(a) Representative MR images of untreated (left) and treated mice (center) receiving C-SNAM, and treated mice receiving NC-ctrl (right) pre-contrast (top) and 50 min post-contrast (bottom). Tumor is indicated by white arrow, hot spot is indicated by yellow arrowhead. Water and 0.5 mM Dotarem phantoms are shown on bottom left and right, respectively, of each image. (b) Representative voxel histograms for untreated (black) and treated (blue) mice receiving C-SNAM, and treated mice receiving NC-ctrl (red). Histograms are shown 50 min post-contrast (solid bars) and 110 min post-contrast (open bars). (c) The percent signal enhancement (%SE) for the hotspot signal enhancement (mean signal within the top quartile of the enhancement histogram) is plotted over time for untreated (black) and treated (blue) mice receiving C-SNAM, and treated mice receiving NC-ctrl (red). Values are mean ± s.d., *p < 0.05 (general linear model repeated measures), and n = 4 per group.
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f3: Imaging the therapeutic response to metronomic chemotherapy in HeLa tumor-bearing mice.(a) Representative MR images of untreated (left) and treated mice (center) receiving C-SNAM, and treated mice receiving NC-ctrl (right) pre-contrast (top) and 50 min post-contrast (bottom). Tumor is indicated by white arrow, hot spot is indicated by yellow arrowhead. Water and 0.5 mM Dotarem phantoms are shown on bottom left and right, respectively, of each image. (b) Representative voxel histograms for untreated (black) and treated (blue) mice receiving C-SNAM, and treated mice receiving NC-ctrl (red). Histograms are shown 50 min post-contrast (solid bars) and 110 min post-contrast (open bars). (c) The percent signal enhancement (%SE) for the hotspot signal enhancement (mean signal within the top quartile of the enhancement histogram) is plotted over time for untreated (black) and treated (blue) mice receiving C-SNAM, and treated mice receiving NC-ctrl (red). Values are mean ± s.d., *p < 0.05 (general linear model repeated measures), and n = 4 per group.
Mentions: A single MRI imaging session at 1T was conducted 2 days following the final dose of doxorubicin chemotherapy, identified as the peak of caspase-3 activity based on previous study with this model15. Images were acquired prior to C-SNAM injection (pre-contrast) and every 10 min following C-SNAM injection (post-contrast). Reference standards containing water (left of the mouse) or 0.5 mM Dotarem® (right of the mouse) were imaged to allow for the normalization of image contrast as previously described2223. Pre- and post-contrast images were used to normalize between scan sessions. Representative images of a tumor pre-contrast (Fig. 3a, top row) and 50 min post-contrast (Fig. 3a, bottom row) are provided for untreated (left) and mice treated with metronomic chemotherapy and administered C-SNAM (middle), and treated mice administered the non-cyclizable NC-ctrl probe (right). Hotspots of C-SNAM activation and retention can be observed in the treated mice receiving active probe (Fig. 3a, yellow arrowheads), with fewer and less intense hotspots notable in untreated mice, and in treated mice receiving NC-ctrl control probe. While tumor-averaged signal enhancement was not substantially different between the three groups (Supplementary Fig. S2a), significant differences were revealed through analysis of hotspot signal (General linear model repeated measure analysis, P < 0.05). In order to analyze the appearance of hotspots, tumor signals were quantified through voxel signal histograms over the entire volume of the tumor, as has been previously reported2425. Voxel histogram analysis provides the ability to detect heterogeneous regions of signal enhancement (i.e. hotspots) as necessitated by molecular MRI1 (Fig. 3b). Hotspots were conservatively defined as those voxels within the top quartile of the histogram, isolating the extent of elongation of the right tail of the histogram due to C-SNAM nanoaggregation. A substantial elongation of the right tail of the voxel histogram of doxorubicin-treated mice administered C-SNAM (Fig. 3b, blue) can be seen relative to untreated mice administered C-SNAM (Fig. 3b, black) and treated mice administered the NC-ctrl (Fig. 3b, red) at 50 min post-contrast. Furthermore, the histograms shift to the left over time (50 min versus 110 min, Fig. 3b) to a substantially greater extent for treated mice receiving NC-ctrl relative to those receiving C-SNAM, suggesting a more rapid washout of the non-cyclized probe relative to the nanoaggregates. The change in tumor hotspot contrast over time was quantified as the percent increase of the mean hotspot signal relative to pre-contrast for a given time point (Fig. 3c). The signal enhancement was significantly greater for mice treated with metronomic chemotherapy and administered C-SNAM (Fig. 3c, blue) relative to both untreated mice (Fig. 3c, black) and treated mice administered NC-ctrl (Fig. 3c, red) (General linear model repeated measures analysis, P < 0.05, n = 4 mice per group). While the %SE from treated mice administered NC-ctrl increased initially relative to untreated mice administered C-SNAM, it rapidly decreased (within 70 min) to the levels of untreated mice, whereas C-SNAM maintained prolonged retention even beyond 2 hr. This rapid washout of NC-ctrl relative to C-SNAM is likely due to its inability to cyclize or self-assemble.

Bottom Line: The poor sensitivity of MRI has limited the development of activatable molecular MR contrast agents.To overcome this limitation of molecular MRI, a novel implementation of our caspase-3-sensitive nanoaggregation MRI (C-SNAM) contrast agent is reported.Importantly, C-SNAM is inert to immune activation, permitting radiation therapy monitoring.

View Article: PubMed Central - PubMed

Affiliation: Molecular Imaging Program at Stanford, Stanford, California 94305, USA.

ABSTRACT
Personalized cancer medicine requires measurement of therapeutic efficacy as early as possible, which is optimally achieved by three-dimensional imaging given the heterogeneity of cancer. Magnetic resonance imaging (MRI) can obtain images of both anatomy and cellular responses, if acquired with a molecular imaging contrast agent. The poor sensitivity of MRI has limited the development of activatable molecular MR contrast agents. To overcome this limitation of molecular MRI, a novel implementation of our caspase-3-sensitive nanoaggregation MRI (C-SNAM) contrast agent is reported. C-SNAM is triggered to self-assemble into nanoparticles in apoptotic tumor cells, and effectively amplifies molecular level changes through nanoaggregation, enhancing tissue retention and spin-lattice relaxivity. At one-tenth the current clinical dose of contrast agent, and following a single imaging session, C-SNAM MRI accurately measured the response of tumors to either metronomic chemotherapy or radiation therapy, where the degree of signal enhancement is prognostic of long-term therapeutic efficacy. Importantly, C-SNAM is inert to immune activation, permitting radiation therapy monitoring.

No MeSH data available.


Related in: MedlinePlus