Cellular Imaging Research
Cells are the basic units of life. They determine normal organ function and disease development. Observations of living cells are vital to understanding, diagnosing, and successfully treating disease. Our research program focuses on the development of novel “Cellular Imaging” technologies, which combine advances in cell biology and in vivo imaging technologies and generate detailed information about specific cells in the body. Our goal is to develop innovative solutions for significant problems encountered in our daily clinical practice. We utilize cellular imaging technologies for improved cancer detection, diagnosis of cancer-associated inflammation, evaluation of novel cancer immunotherapies and monitoring of novel stem cell therapies. Currently, diagnostic evaluations of our patients almost always involve acquiring and repeating multiple imaging tests, which are time-consuming, cause direct and indirect accumulated expenses and accumulated radiation exposures. We ultimately aim to combine personalized cellular imaging technologies with whole body imaging tools in order to create one comprehensive diagnostic test for “one-stop” evaluations of our patients.
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).
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.
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.
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.
Monitoring of Stem Cell Engraftment in Arthritic Joints
Cartilage defects are the major source of pain in arthritic joints. Current treatments, whilst alleviating some of the clinical symptoms, prove insufficient to cure the underlying irreversible cartilage loss. Stem cells represent a unique source for restoration of cartilage defects. However, a major challenge with various approaches of stem cell and chondrocyte transplants is lack of engraftment, death of the transplanted cells and resultant insufficient defect repair. Matrix associated stem cell implants (MASI) represent a promising approach for treatment of arthritis. We are developing imaging tests for in vivo tracking of stem cell engraftment and for non-invasive diagnoses of complications of the engraftment process, such as MASI dislocation from the transplant site, stem cell death due to apoptosis or immune responses that lead to rejection. Studies in animal models are ongoing and studies in patients will follow soon.
Imaging Chondrogenic Differentiation of human iPS Cells
In order to regenerate hyaline cartilage in arthritic joints, transplanted stem cells must not only survive and engraft, but also differentiate into chondrocytes. We are developing novel, “smart” imaging approaches for non-invasive in vivo visualization of in vivo differentiation processes of induced pluripotent stem cells (iPS cells) into chondrocytes, using activatable contrast agents and multi-modality imaging technologies.
Imaging Host Immune Responses to Stem Cell Transplants
Bone injuries are amongst the most costly and debilitating to individuals and our society. Achieving successful repair of large bone defects represents one of the most challenging problems in reconstructive surgery. Stem cell-scaffold nanocomposites have many advantages over bone grafts, such as higher tissue regeneration potential, immediate availability, potentially unlimited quantities and generally better engraftment outcomes. However, allogeneic adult stem cells, embryonic stem cell-derived progenitors and even induced pluripotent stem cells can possess major and minor histocompatibility antigen differences, which can be recognized as foreign by the host immune system and lead to their rejection. Considering that the use of allogeneic ("off the shelf") stem cells is commonly advocated, and thus rejection may be a common occurrence, a non-invasive diagnostic test for in vivo detection of stem cell rejection is urgently needed to detect transplant failure early enough for corrective interventions. We are developing novel imaging tests for in vivo tracking of macrophages and T-cells into stem cell transplants, which could lead to rejection. Information from these new imaging tests may facilitate timely recognition and treatment of host immune responses to stem cell transplants, and ultimately, better engraftment outcomes.