What’s Wrong with Small Animal Imaging?

By Staf C. Van Cauter, EVP, Bioscan Inc., Washington, DC

The high-visibility impact of imaging on the practice of human medicine, and the availability of purpose-built imaging devices for small animals, has lead many institutes and companies to invest in molecular imaging for the discovery of new therapies. Because the nuclear imaging techniques Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) have become clinical standards of care, they are used regularly in preclinical small-animal research. Unlike optical imaging, PET and SPECT can probe subtle molecular signals deep within tissue, and the probes are typically low-mass, biologically relevant molecules and thus are unlikely to perturb the natural states of cells and tissues. Therefore, pre-clinical discoveries and developments with PET and SPECT are more likely to translate into the clinic.

Still, careful thought must be given in planning how best to use nuclear small-animal imaging for drug discovery. Technological limitations in terms of spatial resolution of the instrumentation often preclude imaging small subjects such as mice with the same image detail as can be obtained from scanning humans. This often necessitates the use of animals in which the disease is modeled in a directly observable location. Perhaps the best example of the incongruence between the potential of nuclear imaging and the current drug discovery process with small animals is to be found in oncology research. The limited spatial resolution of many nuclear imagers often necessitates reliance upon flank xenograft models. While such models have aided greatly in the discovery of existing chemotherapies, they have also inherent drawbacks, especially an inappropriate tumor microenvironment.

Meeting the Challenge of Imaging Small Animals with NanoPET® or NanoSPECT®

The challenge to developing technology for imaging small laboratory animals, and in particular the mouse, is that of achieving the necessary spatial resolution which must be comparable with that realized in man. In round numbers, the linear dimensions in mice are ten times smaller in each dimension than in humans. Therefore, if imaging studies in small animals are to be “equivalent” to human studies, the spatial resolution of an animal scanner must be about ten times better than a human scanner. “Equivalent” in this context means that the animal organ is visualized on the animal scale with the same relative acuity as the human organ is imaged on the human scale. Taking 6-8 mm as an achievable PET and SPECT resolution in humans, the scaled up resolution to achieve anatomical parody for a mouse is 0.6 to 0.8 mm (or sub-µL in volumetric terms). Conventional nuclear small animal scanners, commonly called micro-PET and micro-SPECT scanners, cannot reach this required spatial resolution. Therefore, researchers aiming at deriving the translational benefit from integrating imaging into their pre-clinical research should look into the use of nuclear small-animal imagers with sub-mm resolution capabilities, such as available in the latest NanoSPECT and NanoPET scanners.

The ability of NanoSPECT and NanoPET (Bioscan Inc, Washington, DC) to image mice with the same visual acuity as humans enables pre-clinical researchers to eliminate reliance upon flank xenografts in favor of studying small-animal models that are more predictive for human cancers.

Seeing the Cancer We-Should-Study versus a Cancer We-Can-See

In the clinic, cancer most often presents itself as multiple disseminated lesions, many of these asymptomatic, within the internal organs of the body. Therefore, imaging is the only technology making it possible to non-invasively visualize these hidden lesions in-situ. In contrast, drug discovery research using traditional resolution-limited micro-PET or micro-SPECT imaging equipment deals with the issue of difficult-to-follow hidden diseases by developing animal models in which the cancer has been moved entirely out of the internal organs to a directly observable location; the subcutaneous flank xenograft models. However, this convenience of observation comes at a cost. It requires sacrificing the host’s immuno function, it moves the tumor away from its proper stromal microenvironment, it precludes morbidity associated with host tissue displacement and destruction, and the model does not recapitulate distant metastases at all – all issues of profound importance in cancer.

More advanced models, such as spontaneous, carcinogen-induced and transgenic models, offer many theoretical advantages. However, their superiority remains largely unproven, due to their infrequent use in drug discovery as the result of the lack of nuclear imaging technologies with sub-mm resolution capabilities. Therefore, research centers wanting to derive the fullest benefit from integrating small-animal imaging into their preclinical research efforts may want to invest in the new NanoSPECT and NanoPET imagers while making a parallel investment in developing, testing and refining advanced animal models of cancer. The rewards offered by such efforts include the use of more predictive models, the opportunity to target and study the tissue-specific morbidities of cancer, and pre-clinical study endpoints that are more directly translatable into the clinic.