Multimodal optical-nuclear molecular imaging of tumors

Accurate diagnosis and treatment of various pathologic conditions can be achieved by integrating multimodal imaging systems that furnish complementary information to improve patient management. The availability of high-resolution tomography systems, fast computers, and image reconstruction algorithms has improved disease diagnosis and treatment management. As medical practice moves into the molecular era, the realization that no single imaging method can provide solutions to the complex information derived from molecular imaging has heightened interest in the use of multimodal imaging to harness the strengths of different imaging methods. For example, co-registration of pathologic tissues with computed tomography (CT) and radionuclear platform provides complementary anatomical and functional diagnostic information, respectively. Optical imaging (OI) promises to complement established imaging methods by reporting molecular events with high detection sensitivity. Although combining molecular optical contrasts with MRI or CT provides co-registered reference anatomy, the disparate contrast agent concentrations needed for OI and MRI or CT present a barrier to integration. An alternative approach is to combine OI with an established imaging modality possessing similar detection sensitivity but complementary reporting strategies. Because of the high sensitivity of both nuclear and OI methods and the compatibility of their imaging agents, incorporating nuclear to OI will provide a unique opportunity to fuse the imaging datasets with identical pharmacokinetics but different contrast mechanisms. To appreciate the potential benefits of combining optical and SPECT/PET, we have tabulated the similarities and differences between the two imaging methods in Table 1 (1). Based on these properties, several potential opportunities to combine the two platforms become apparent. (Figure Presented) To minimize data analysis errors due to differences in the biodistribution of different imaging agents used for nuclear and OI, elegant molecular designs have been developed. Instead of preparing one imaging agent for each method, a new trend is to fuse their signaling moieties into one molecule (2-6). Figure 1 illustrates the use of the same imaging agent to obtain optical image and scintigraphy of a tumor in mice. The short-lived radioisotope could be used to localize tumors in all parts of the body, followed by longitudinal monitoring of treatment response of specific tissue with OI. In addition to single molecules, quantum dots and a cross-linked NIR fluorescent polymer core were recently labeled with ⁶⁴Cu and ¹¹¹In for dual optical-PET and optical-SPECT imaging studies, respectively (7, 8). The polyvalent nature of nanoparticles is attractive for multimodal imaging because normalization of differences in the detection sensitivity of different contrast mechanisms can be achieved by incorporating the appropriate number of signaling molecules per particle. From instrumentation view point, diffuse optical tomography (DOT), a high resolution and quantitative OI method, is most effective when coupled with established imaging modalities. Several groups have explored the use of anatomical knowledge (9-11) to aid the light modeling in tissue. Both MRI and X-ray techniques have been used to provide prior anatomical information (11). An unresolved issue is determining the optimal mechanism for incorporating the spatial information into the models. One approach is to assume that the tissue is composed of homogenous tissue types (10, 12) and assign optical properties according to the segmentation. Another approach is to assume a correlation between the contrast of the alternate modality and an optical property (either absorption (11) or scattering (13, 14)) and provide a bias to the mean value of each voxel. Both of these approaches suffer greatly when the correlation between the contrast in the alternate modality and the optical contrast is unknown or variable. Therefore, an important future direction is to develop a hybrid optical-nuclear imaging system for co-registering images from both methods using a hybrid multimodal imaging agent. These studies are in progress at our institution. (Figure Presented)