Molecular Magnetic Resonance Imaging of Tumor Response to Therapy.

Adam J Shuhendler,Kimberly D Brewer,Paul Kempen,Brian Rutt,Magdalena Bazalova-Carter,Jianghong Rao,Deju Ye,Kyung-Hyun Lee,Edward E Graves,K Dane Wittrup

doi:10.1038/srep14759

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.

Highlights

Molecular changes to tumor tissue following treatment precede changes in tumor morphology[2,9,10], and include key events driving therapy-induced tumor cell death
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been used to assess therapeutic response non-invasively over the entire tumor volume: a positive response is indicated by a reduction in standardized uptake value (SUV) over the entire tumor region of interest[10,12]
This work represents an in depth investigation of the ability of our caspase-sensitive nanoaggregation Magnetic resonance imaging (MRI) contrast agent (C-SNAM) to monitor therapy response in animal models of tumor therapy that approximate metronomic doxorubicin chemotherapy or x-ray beam radiation therapy relative to non-aggregatable control probes

Summary

Introduction

Molecular changes to tumor tissue following treatment precede changes in tumor morphology[2,9,10], and include key events driving therapy-induced tumor cell death. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been used to assess therapeutic response non-invasively over the entire tumor volume: a positive response is indicated by a reduction in standardized uptake value (SUV) over the entire tumor region of interest[10,12] This imaging method resulting in a reduction of tumor signal requires comparisons to pre-treatment imaging[8], and is limited in its utility when applied to therapies that induce FDG-avid inflammation such as radiation therapy[10,12]. We have recently described a small molecule imaging probe scaffold unique in its ability to undergo self-assembly into nanoparticles in living animals when acted upon by a target enzyme of interest[13,14,15] This probe scaffold provides three signal amplification mechanisms that we hypothesize will overcome the low sensitivity associated with MRI, and facilitate molecular MR imaging. Utilizing our strategy of enzyme-triggered self-assembly in vivo, which integrates three mechanisms of signal amplification, one of which is unique to MRI, monitoring of treatment response for both chemotherapy and radiation therapy by in vivo imaging is shown to be possible

Methods

Results

Conclusion