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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

Animal models of metronomic chemotherapy and radiation therapy.(a) The scheme for generating each animal model is provided, where blue represents tumor growth phase, red represents treatment phase, and green represents imaging phase. (b) Tumor size was measured over time from the initiation of treatment, with fold-volume change relative to pre-treatment provided for untreated (black), metronomic chemotherapy (blue, 3x DOX) or radiation treatment (green, 7.6 Gy Radiation). (c) Western blot showing activation of caspase-3 (cleaved caspase-3) two days following radiation therapy or the end of metronomic chemotherapy. Values are cleaved caspase-3 band intensities normalized to actin loading control. (d) Prior to MR imaging, caspase-3 activation in tumors was determined using our fluorescent, quenched C-SNAM analog (Q-C-SNAF), confirming elevated caspase-3 activity following radiation and chemotherapy relative to untreated animals. (e) Tumor-to-leg fluorescence intensity ratio is provided for untreated (black), or mice treated with metronomic chemotherapy (blue) or radiation therapy (green). *p < 0.05 (ANOVA), n = 4.
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f2: Animal models of metronomic chemotherapy and radiation therapy.(a) The scheme for generating each animal model is provided, where blue represents tumor growth phase, red represents treatment phase, and green represents imaging phase. (b) Tumor size was measured over time from the initiation of treatment, with fold-volume change relative to pre-treatment provided for untreated (black), metronomic chemotherapy (blue, 3x DOX) or radiation treatment (green, 7.6 Gy Radiation). (c) Western blot showing activation of caspase-3 (cleaved caspase-3) two days following radiation therapy or the end of metronomic chemotherapy. Values are cleaved caspase-3 band intensities normalized to actin loading control. (d) Prior to MR imaging, caspase-3 activation in tumors was determined using our fluorescent, quenched C-SNAM analog (Q-C-SNAF), confirming elevated caspase-3 activity following radiation and chemotherapy relative to untreated animals. (e) Tumor-to-leg fluorescence intensity ratio is provided for untreated (black), or mice treated with metronomic chemotherapy (blue) or radiation therapy (green). *p < 0.05 (ANOVA), n = 4.

Mentions: HeLa tumor-bearing nude mice were left either untreated, or received doxorubicin chemotherapy (metronomic, 8 mg/kg q4d)15 or single dose radiation therapy (7.6 Gy with 225 kV beam) through a lead shield exposing only the tumor to radiation, with imaging performed 2 days after the final treatment (Fig. 2a). Doxorubicin dose was selected to approximate clinical metronomic chemotherapeutic doses20, and the radiation treatment mimics a single fractionated dose received during current stereotactic ablative radiotherapy treatment regimens employed in the clinic21. Both the metronomic chemotherapy and the radiation therapy resulted in a substantial tumor growth delay relative to the untreated controls (Fig. 2b), but did not result in a reduction of tumor size relative to pre-treatment. However, the therapy-induced tumor growth delay was accompanied by an elevation of caspase-3 activation in both treatment groups (Fig. 2c). In vivo caspase-3 activity was assayed 4 hr prior to MRI utilizing a quenched fluorescent caspase-3 probe, Q-C-SNAF, we have previously reported15 (Supplementary Fig. S1). This imaging result confirmed more extensive fluorescence retention in chemo- or radiation-treated tumors (Fig. 2d) and a significant enhancement of tumor caspase-3 activity normalized to background intensities quantified in the leg (ANOVA, P < 0.05, Fig. 2e). These results demonstrate that the chosen clinically relevant metronomic chemotherapy and low-dose radiation therapy models selected provide elevated levels of caspase-3, and support their suitability for the interrogation of therapy response monitoring by C-SNAM through molecular MRI.


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)

Animal models of metronomic chemotherapy and radiation therapy.(a) The scheme for generating each animal model is provided, where blue represents tumor growth phase, red represents treatment phase, and green represents imaging phase. (b) Tumor size was measured over time from the initiation of treatment, with fold-volume change relative to pre-treatment provided for untreated (black), metronomic chemotherapy (blue, 3x DOX) or radiation treatment (green, 7.6 Gy Radiation). (c) Western blot showing activation of caspase-3 (cleaved caspase-3) two days following radiation therapy or the end of metronomic chemotherapy. Values are cleaved caspase-3 band intensities normalized to actin loading control. (d) Prior to MR imaging, caspase-3 activation in tumors was determined using our fluorescent, quenched C-SNAM analog (Q-C-SNAF), confirming elevated caspase-3 activity following radiation and chemotherapy relative to untreated animals. (e) Tumor-to-leg fluorescence intensity ratio is provided for untreated (black), or mice treated with metronomic chemotherapy (blue) or radiation therapy (green). *p < 0.05 (ANOVA), n = 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Animal models of metronomic chemotherapy and radiation therapy.(a) The scheme for generating each animal model is provided, where blue represents tumor growth phase, red represents treatment phase, and green represents imaging phase. (b) Tumor size was measured over time from the initiation of treatment, with fold-volume change relative to pre-treatment provided for untreated (black), metronomic chemotherapy (blue, 3x DOX) or radiation treatment (green, 7.6 Gy Radiation). (c) Western blot showing activation of caspase-3 (cleaved caspase-3) two days following radiation therapy or the end of metronomic chemotherapy. Values are cleaved caspase-3 band intensities normalized to actin loading control. (d) Prior to MR imaging, caspase-3 activation in tumors was determined using our fluorescent, quenched C-SNAM analog (Q-C-SNAF), confirming elevated caspase-3 activity following radiation and chemotherapy relative to untreated animals. (e) Tumor-to-leg fluorescence intensity ratio is provided for untreated (black), or mice treated with metronomic chemotherapy (blue) or radiation therapy (green). *p < 0.05 (ANOVA), n = 4.
Mentions: HeLa tumor-bearing nude mice were left either untreated, or received doxorubicin chemotherapy (metronomic, 8 mg/kg q4d)15 or single dose radiation therapy (7.6 Gy with 225 kV beam) through a lead shield exposing only the tumor to radiation, with imaging performed 2 days after the final treatment (Fig. 2a). Doxorubicin dose was selected to approximate clinical metronomic chemotherapeutic doses20, and the radiation treatment mimics a single fractionated dose received during current stereotactic ablative radiotherapy treatment regimens employed in the clinic21. Both the metronomic chemotherapy and the radiation therapy resulted in a substantial tumor growth delay relative to the untreated controls (Fig. 2b), but did not result in a reduction of tumor size relative to pre-treatment. However, the therapy-induced tumor growth delay was accompanied by an elevation of caspase-3 activation in both treatment groups (Fig. 2c). In vivo caspase-3 activity was assayed 4 hr prior to MRI utilizing a quenched fluorescent caspase-3 probe, Q-C-SNAF, we have previously reported15 (Supplementary Fig. S1). This imaging result confirmed more extensive fluorescence retention in chemo- or radiation-treated tumors (Fig. 2d) and a significant enhancement of tumor caspase-3 activity normalized to background intensities quantified in the leg (ANOVA, P < 0.05, Fig. 2e). These results demonstrate that the chosen clinically relevant metronomic chemotherapy and low-dose radiation therapy models selected provide elevated levels of caspase-3, and support their suitability for the interrogation of therapy response monitoring by C-SNAM through molecular MRI.

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