Whole Body Tumor Staging
Radiographic staging tests are essential for the diagnosis of childhood tumors, because the extent of the primary tumor and the number and location of metastases determine appropriate therapies. However, recent studies have shown that the radiation exposure associated with radiographic imaging tests may increase the risk of developing secondary malignancies later in life. This risk is particularly concerning for children, because pediatric patients are more sensitive to radiation than adult patients and they life long enough to encounter secondary cancers. We are developing novel whole body diffusion-weighted MR imaging technologies as a radiation-free alternative to standard PET/CT staging procedures. We add cell-specific contrast agents to improve the sensitivity and specificity of these new whole body staging tests. This new radiation-free imaging test may solve the conundrum of long-term side effects from radiographic staging procedures.
Developing Cancer Therapy without Side Effects
The efficacy of traditional cancer chemotherapies is hindered by undesired dose-limiting activity upon non-cancerous organs and a lack of tools for in vivo monitoring of drug biodistributions. Approaches to improving therapeutic efficacy and monitoring whilst simultaneously reducing dose-limiting toxicities are critically needed. A new, emerging strategy is to deliver vascular-disrupting therapeutic agents (VDAs), which easily reach their target endothelial cells, and trap and dose intensify therapeutics at the tumor site. In order to avoid concomitant toxic effects in normal organs, nontoxic VDA-prodrugs can be designed, which are activated by specific enzymes in the tumor microenvironment. We integrated the concepts of MMP-14 (matrix metallo-proteinase) activatable VDA prodrugs with iron oxide nanocarrier platforms, which allows for in vivo drug tracking with MR imaging and tumor delivery of a significantly increased drug payload. We are studiing the diagnostic and therapeutic properties of novel MMP-14 activatable theranostic nanoparticles (TNPs), which exert selective vascular disruption and toxic effects in MMP-14 expressing cancers, but not normal organs, and enable real-time monitoring of drug accumulation in tumors with MR imaging.
Imaging Tumor Associated Macrophages
The presence of tumor associated macrophages (TAM) in cancer correlates strongly with tumor progression and poor outcome. While the degree of TAM infiltration has been correlated with tumor aggressiveness and overall survival in a wide range of malignant tumors, no diagnostic tool currently exists which could assess TAM quantities in a given patient's tumor non-invasively and repetitively. We are developing immediately clinically applicable, non-invasive imaging assays for selective targeting and visualization of TAM in malignant lymphomas, sarcomas, adenocarcinomas and glioblastomas. The approach is based on "off label" use of the FDA-approved iron supplement ferumoxytol as a contrast agent for MR imaging. Ferumoxytol is composed of iron oxide nanoparticles, which are phagocytosed by TAM and which can be detected with MR imaging. The new TAM imaging test can be used as a novel prognostic assay for stratifying individual patients to personalized therapies and to monitor response to novel immunotherapies that are currently entering clinical practice.
Improving Drug Delivery to Tumors
Advances in our understanding of cellular, molecular and genomic characteristics of malignant tumors has led to the development of a wide range of cell-targeted imaging probes, which are designed to provide more sensitive and specific information about the underlying tumor than conventional, non-specific contrast agents. However, one major bottleneck for successful clinical translation of these new imaging probes is their large size, which limits their delivery to tumor cells or other target cells in the tumor microenvironment. Thus, these probes currently only exert a fraction of their maximal potential. Two major barriers for efficient delivery of macromolecular drugs to the tumor interstitium include limited permeability of tumor microvessels to macromolecules and high interstitial fluid pressure (IFP) in cancers. We are developing and testing novel drug strategies that decrease IFP and increase tumor microvascular permeability and imaging enhancement of diagnostic and therapeutic macromolecular drugs (Figure shows delivery of superparamagnetic iron oxide nanoparticles to a MMTV PyMT adenocarcinoma (arrow), as demonstrated by strong negative (dark) tumor enhancement on a T2-weighted MR scan).