MIR Preclinical Services
MRI
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MIR utilizes a high field (7 Tesla) Varian™ small animal MRI system.

 

Unlike other CRO’s that offer services through collaborations with academic institutions or utilize  inferior equipment, MIR owns and operates their state-of-the-art equipment on site.

 MIR Preclinical Services uses a Varian high field strength (7 Tesla) preclinical MRI. This state-of-the-art preclinical MRI system is owned and operated on site. This system is ideal for the imaging of human tumor xenograft, syngeneic tumors and transgenic animals in cancer research. Preclinical MRI is also becoming useful in tracking the progression of disease in models of inflammation, such as rheumatoid arthritis, osteoarthritis and other disease states. Other contract research organizations (CRO’s) that offer imaging services usually either subcontract to academic institutions or use equipment that is not suitable for preclinical work (such as using a human MRI scanner instead of a preclinical MRI instrument). MIR is a leader in preclinical imaging and no other CRO can offer the suite of imaging services that MIR can offer its clients.
ANATOMICAL IMAGING

T1 and T2 weighted MRI provides image contrast which can be used for visualizing anatomy and distinguishing tissues and organs. T2 weighting generally provides sufficient contrast to highlight tumors, however, it provides very little distinction between localized edema and solid tumor. T1 weighting is usually used in the presence of a contrast agent, which will tend to accumulate in tumors due to their generally leaky and chaotic vasculature. The T2 weighted image following orthotopic glioma growth, shown below to the left, demonstrates the utility of preclinical MRI. From the image data, we can determine log cell kill and other tumor growth parameters after treatment by calculating the pre- and post-treatment tumor doubling time (Td). B.D. Ross, et.al. Proc. Natl. Acad. Sci. USA 95: 7012-7017 (1998).

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This preclinical MRI is an example of an orthotopic syngeneic glioma implanted in the brain of a rat. Preclinical MRI is a non-invasive technique and the glioma can be followed over time in the same animal. A highly quantitative measure of tumor burden can be calculated from these images, allowing treated animals to be directly compared to controls.
This is a quantitative plot of the tumor burden measured from the preclinical MRI images of an orthotopic syngeneic glioma implanted in the brain of a rat. Because MIR Preclinical Services uses such high resolution instruments, a highly quantitative measure of tumor burden can be calculated, allowing treated animals to be directly compared to controls. The typical endpoint for these types of studies is net log cell kill calculated from tumor growth delay (T-C).
FOLLOWING GROWTH AND THERAPY OF INTRACRANIAL 9L TUMORS
Validation studies show that high resolution preclinical MRI studies are more accurate than traditional studies in orthotopic models of glioma. These studies also require fewer animals to be used than those used in traditional pharmacology studies that require large cohorts of animals to be sacrificed at different time points.

Traditional non-imaging methods have relied on animal survival, CFE (colony-forming efficiency assays of cells disaggregated from solid tumors) and excised tumor weights in determination of cell kill/efficacy in orthotopic models of glioma. This study showed that MRI-determined log kill may be more accurate. In addition, fewer animals are needed because animals do not have to be sacrificed at each time point.

MONITORING JOINT INFLAMMATION IN A RAT MODEL OF ARTHRITIS
 

This Preclinical MRI image highlights the utility of magnetic resonance imaging in models of arthritis and inflammation. These preclinical MRI images were taken in rats with and without streptococcal cell wall (SCW) induced rheumatoid arthritis. This technology could also be applied to a collagen induced arthritis (CIA) model of rheumatoid arthritis, meniscectomy induced model of osteoarthritis and others. MIR is the only contract research organization (CRO) that is applying high resolution preclinical MRI to image disease progression in models of inflammation and is willing to work with clients to meet their unmet needs.

Preclinical MRI in the rat streptococcal cell wall (SCW) model of rheumatoid arthritis (RA) during the acute phase of the disease. Four contiguous slices are shown through approximately the same anatomical region for a control ankle and an arthritic ankle.

 
 
CONTRAST ENHANCED IMAGING

The use of various intravenous contrast agents provides additional image contrast over pure T1- or T2 weighting. This additional contrast may assist in distinguishing cancerous lesions from normal tissues and highlights differences in the vasculature of normal tissue and tumors. MIR Preclinical Services has extensive experience utilizing all types of commercially available MRI contrast agents as well as experimental contrast agents for preclinical MRI.
QUANTIFICATION OF EDEMA

Comparison of contrast enhanced T1 and T2 weighted preclinical MRI images allows delineation of tumor and edema. This can be used to measure changes in each over time.

 
Example Slice 1

Example Slice 2

T2-weighted shows both tumor and edema
An example of the ability of preclinical MRI to distinguish between actual tumor burden and edema in syngeneic tumor and human tumor xenograft; in this case using the orthotopic implantation of a syngeneic glioma in rat.
An example of the ability of preclinical MRI to distinguish between actual tumor burden and edema in syngeneic tumor and human tumor xenograft; in this case using the orthotopic implantation of a syngeneic glioma in rat.

T1-weighted
gadolinium contrast shows tumor only
An example of the ability of preclinical MRI to image actual tumor burden without edema in syngeneic tumor and human tumor xenograft; in this case using the orthotopic implantation of a syngeneic glioma in rat.
An example of the ability of preclinical MRI to image actual tumor burden without edema in syngeneic tumor and human tumor xenograft; in this case using the orthotopic implantation of a syngeneic glioma in rat.
DIFFUSION MRI

In preclinical oncology assessments, diffusion MRI is a reliable surrogate marker for therapeutic efficacy and directly translatable to clinical trials. The diffusion of water, as assessed by quantitative diffusion MRI, is highly sensitive to tissue structure at the cellular and subcellular level. Studies of human and animal tumors have demonstrated strong diffusion differences between solid tumors relative to necrotic and cystic regions. This consistent observation provides the rationale for using diffusion as a monitor of cellular changes following anti-cancer therapies. [TL Chenevert, et al., Clinical Cancer Research, vol.3, 1457-1466 (1997)].

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DIFFUSION HYPOTHESIS
Diffusion MRI is a technique that is in clinical trials as an early indicator of response to an effective therapy. MIR Preclinical Services has a license that allows this technology to be applied to preclinical MRI. This technology has been used to characterize the response of human tumor xenograft models and syngeneic tumor models in mice and rats. MIR is the only contract research organization licensed to use the proprietary technology needed to perform diffusion MRI studies.

Diffusion MRI measures a parameter called the apparent diffusion coefficient (ADC), which is a sensitive measure of changes in tumor cellularity.

In the normal brain, where cellularity hinders the diffusion of water, the ADC is relatively lower than that in CSF, where water is less restrictive and the ADC is close to that of free water. In an intact tumor, high cellularity restricts extracellular space and cell membranes act as boundaries which restrict water diffusion. An effective therapy causes tumor cellularity to decrease and cell membranes are compromised. Increased extracellular space leads to an increase in water diffusion and an increase in ADC.

Diffusion MRI provides an isotropic functional diffusion map (FDM), in which each image pixel represents the spacially localized ADC.

Segmentation and analysis of the FDMs reveal ADC changes due to drug induced changes in tumor cellularity.

Preclinical MRI imaging assessment of therapy response is translatable to the clinical setting.

 

Using preclinical MRI, the apparent diffusion coefficient (ADC) of water can be used to determine the breakdown of cell membranes and cell-cell adhesion. This has been correlated with effective therapy.
APPLICATION OF DIFFUSION MRI TO CANCER THERAPY

Application of diffusion MRI to efficacy determination in a rat 9L glioma model

At each time point following treatment at day zero, we acquire an ADC map.

Treatment efficacy is determined by a right-shift in the ADC histogram.

In treated animals an increase in ADC was observed before a reduction in tumor volume was detectable.

ADC for control animals does not change.

Chenevert, Stegman, Taylor, Robertson, Greenberg, Rehemtulla, Ross, J. Natl. Cancer Inst. 90: 2029-2036 (2000)

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These are images of MRI diffusion maps generated using preclinical MRI in rats orthotopic implanted 9L gliomas. The data shows that diffusion MRI indicated a response to therapy before the size of the tumor was effected. This demonstrates the ability of diffusion MRI to be an early indicator of response to therapy.
DYNAMIC CONTRAST-ENHANCED (DCE) MRI

DCE preclinical MRI is a clinically proven method for the quantification of the effect of anti-angiogenic or vascular targeted therapies. DCE utilizes the imaging of gadolinium uptake into the interstitial space for the quantification of vascular permeability, vascular surface area and blood flow. This quantitative technology can be applied to both clinical and preclinical studies. To the right is a color overlay showing the permeability of tissues based on the uptake of contrast agent. Below are 2 figures that quantify permeability/blood flow of contrast agent for a particular region of interest (ROI) within the tumor.

Dynamic contrast enhanced (DCE) preclinical MRI is useful in determining the blood flow, perfusion and vascular surface area in sygeneic and human xenograft tumors. MIR preclinical Services has protocols that closely follow protocols used in the clinic so that the data is clinically translatable. This image is a DCE map of a subcutaneous human tumor xenograft in an immunodeficient mouse. This demonstrates the decrease in blood flow to the tumor after an effective therapy. DCE preclinical MRI is also useful in that it details the heterogeneity of the response and which part of the tumor is responding to therapy and which are not responding.
ARTERIAL SPIN LABELING (ASL) MRI

Arterial Spin Labeling (ASL) is a preclinical MRI technique that can be used to measure blood flow in the brain

Color Overlay of Blood Flow

This figure shows the growth of 9L tumor cells implanted into the brain of a rat. VEGF (vascular endothelial growth factor) was over-expressed in one group of tumors. The figure shows a corresponding transition from blue to red, indicating increased blood flow within the tumor.

This is a non-invasive method that does not use contrast agents, but is merely a manipulation of the proton spin of water molecules within the vasculature.
 
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updated:  9/19/08