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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 single dose radiation therapy in HeLa tumor-bearing mice.(a) Box plot showing hotspot %SE due to caspase-3 activation for untreated mice (black), or for mice receiving 7.6 Gy tumor irradiation and imaged 1 (blue), 2 (red), or 3 days (green) later. All imaging was performed with C-SNAM. *p < 0.05 (ANOVA), n = 4 mice per group. (b) Western blot following cleaved caspase-3 expression in untreated mice and over time after tumor irradiation. Values are cleaved caspase-3 band intensities normalized to actin loading control. (c) 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, and hot spots are indicated by yellow arrowhead. Water and 0.5 mM Dotarem phantoms are shown on bottom left and right, respectively, of each image. (d) 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). (e) The percent signal enhancement (%SE) for 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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f4: Imaging the therapeutic response to single dose radiation therapy in HeLa tumor-bearing mice.(a) Box plot showing hotspot %SE due to caspase-3 activation for untreated mice (black), or for mice receiving 7.6 Gy tumor irradiation and imaged 1 (blue), 2 (red), or 3 days (green) later. All imaging was performed with C-SNAM. *p < 0.05 (ANOVA), n = 4 mice per group. (b) Western blot following cleaved caspase-3 expression in untreated mice and over time after tumor irradiation. Values are cleaved caspase-3 band intensities normalized to actin loading control. (c) 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, and hot spots are indicated by yellow arrowhead. Water and 0.5 mM Dotarem phantoms are shown on bottom left and right, respectively, of each image. (d) 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). (e) The percent signal enhancement (%SE) for 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: In order to determine the ideal imaging window for radiation treatment, mice were left untreated, or treated with a single 7.6 Gy dose of radiation from a 225 kV beam and imaged either 1, 2, or 3 days later (Fig. 4a,b). The maximum signal enhancement was observed 2 days following treatment (Fig. 4a) (ANOVA, P < 0.05, n = 4 mice per group). Tumor lysates were analyzed for cleaved caspase-3 expression, revealing that these levels increased from day 1 to day 2, and at day 3 began to decrease toward untreated levels (Fig. 4b), showing substantial variability at day 3 that corresponds well with the observed variation in imaging signal enhancement on that day (Fig. 4a, green). Therefore, the optimal imaging window for measuring caspase-3 activation of HeLa tumors under this experiment condition occurs 2 days following the radiation treatment.


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 single dose radiation therapy in HeLa tumor-bearing mice.(a) Box plot showing hotspot %SE due to caspase-3 activation for untreated mice (black), or for mice receiving 7.6 Gy tumor irradiation and imaged 1 (blue), 2 (red), or 3 days (green) later. All imaging was performed with C-SNAM. *p < 0.05 (ANOVA), n = 4 mice per group. (b) Western blot following cleaved caspase-3 expression in untreated mice and over time after tumor irradiation. Values are cleaved caspase-3 band intensities normalized to actin loading control. (c) 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, and hot spots are indicated by yellow arrowhead. Water and 0.5 mM Dotarem phantoms are shown on bottom left and right, respectively, of each image. (d) 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). (e) The percent signal enhancement (%SE) for 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4594000&req=5

f4: Imaging the therapeutic response to single dose radiation therapy in HeLa tumor-bearing mice.(a) Box plot showing hotspot %SE due to caspase-3 activation for untreated mice (black), or for mice receiving 7.6 Gy tumor irradiation and imaged 1 (blue), 2 (red), or 3 days (green) later. All imaging was performed with C-SNAM. *p < 0.05 (ANOVA), n = 4 mice per group. (b) Western blot following cleaved caspase-3 expression in untreated mice and over time after tumor irradiation. Values are cleaved caspase-3 band intensities normalized to actin loading control. (c) 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, and hot spots are indicated by yellow arrowhead. Water and 0.5 mM Dotarem phantoms are shown on bottom left and right, respectively, of each image. (d) 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). (e) The percent signal enhancement (%SE) for 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: In order to determine the ideal imaging window for radiation treatment, mice were left untreated, or treated with a single 7.6 Gy dose of radiation from a 225 kV beam and imaged either 1, 2, or 3 days later (Fig. 4a,b). The maximum signal enhancement was observed 2 days following treatment (Fig. 4a) (ANOVA, P < 0.05, n = 4 mice per group). Tumor lysates were analyzed for cleaved caspase-3 expression, revealing that these levels increased from day 1 to day 2, and at day 3 began to decrease toward untreated levels (Fig. 4b), showing substantial variability at day 3 that corresponds well with the observed variation in imaging signal enhancement on that day (Fig. 4a, green). Therefore, the optimal imaging window for measuring caspase-3 activation of HeLa tumors under this experiment condition occurs 2 days following the radiation treatment.

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