Background:

Cellular Imaging is a new discipline which combines cellular biology and in vivo imaging. While standard imaging methods, such as CT, MRI , and ultrasound focus predominantly on anatomical and functional measurements at the organ level, cellular imaging provides non-invasive in vivo detection of specific cell populations within target organs. Cellular imaging can be achieved by ex vivo labeling of specific cell populations before the cells’ subsequent in vivo administration. Examples include dynamic in vivo imaging of the engraftment process of labeled stem cells to monitor organ regeneration or tracking the tumor accumulation of tumor-targeted, labeled lymphocytes as an early surrogate for tumor response. Other approaches of cellular imaging use targeted contrast agents which are injected intravenously and which specifically bind to surface receptors on certain cell populations in the body, such as tumor cells. Our research program focuses on Cellular Imaging Techniques for Magnetic Resonance (MR) Imaging and Optical Imaging.

Major goals: (1) to develop imaging techniques to track stem cells in vivo for non-investigative assessments of stem cell engraftment outcomes with variations of stem cell viability, stem cell type, associated scaffolds and host organ environment; (2) to monitor the efficacy of cellular immunotherapies that are designed to specifically eradicate cancer cells and (3) to target cancer cells in vivo for improved cancer detection and characterization. These goals require a multi-disciplinary approach, bringing together chemists, biologists, physicists and physicians to design and evaluate targeted contrast agents and imaging techniques required to achieve functional cellular imaging in vivo.

Ongoing research:

Monitoring Stem Cell Engraftment in Arthritic Joints with MR Imaging:
Matrix-associated stem cell implantation (MASI) is currently evaluated for cartilage regeneration of arthritic joints. We d eveloped techniques to label stem cells with iron oxide nanoparticles, transplant the labeled stem cells into cartilage defects of knee joints of athymic rats and follow the engraftment of the transplanted stem cells with MR imaging. Ongoing studies are directed towards the differentiation of imaging characteristics of transplanted viable versus non-viable stem cells during the engraftment process. The overall hypothesis is that iron oxide based contrast agents can yield estimates of the viability of the transplanted stem cells by differences in the T2-effect of intracellular iron oxides in viable cells and extracellular iron oxides, released from apoptotic cells. In a systematic, step-by-step approach, experiments are carried out in cell cultures, then ex vivo in pig knees with focal cartilage defects, then in vivo in knee joints of rats with focal cartilage defects and, finally, in vivo in knee joints of rats with an active antigen-induced arthritis. Complementary optical imaging studies as well as electron microscopy, immunohistochemistry, confocal microscopy and spectrometry studies are correlated with the MR findings. A better understanding of the signal characteristics of contrast agent labeled viable versus non-viable stem cells on MR images will lead the way to a rational and more effective use of preclinical and clinical MASI applications.

Tracking of natural killer cells to cancers:
A new treatment option for breast cancer is the administration of tumor-targeted natural killer (NK) cells, which have been genetically modified to specifically recognize and lyse cancer cells in vivo. Central aim of this project is to develop a non-invasive magnetic resonance (MR) imaging technique for monitoring the in vivo distribution, tumor accumulation and cytotoxicity of NK cells, which are directed against ErbB2-positive breast cancers. Genetically engineered NK cells, directed against the ErbB2 antigen on breast cancer cells, are labeled with iron oxide nanoparticles, and injected intravenously into athymic rats with implanted ErbB2-positive and ErbB2-negative human breast carcinomas. The in vivo distribution of the labeled NK cells is monitored with MR imaging. The tumor accumulation of the labeled NK-cells can be depicted by a significant decline in tumor signal intensity on these MR images. The NK cell accumulation in the tumor tissue, as diagnosed by MR imaging on day 1 and 2 after NK cell administration, will be correlated with a subsequent NK-cell induced tumor cytotoxicity, as measured by an impaired tumor growth several days after NK cell administration. Complementary histopathologic and spectrometric studies, correlated with the MR findings, examine the underlying NK cell tumor accumulation that influences the observed MR signal characteristics and tumor response.

MR Imaging of Ovarian Cancer with Folate-Receptor targeted Contrast Agents:
The folate receptor (FR) is overexpressed on cancer cells of epithelial origin, including breast and ovarian cancers, but not on cells of normal organs outside of the central nervous system. The goal of this study is to improve the diagnosis of ovarian cancers with new, FR-targeted contrast agents for magnetic resonance (MR) imaging. We hypothesize, that FR-targeted contrast agents accumulate specifically in ovarian cancers, thereby providing “cancer-specific” imaging. The study comprises in vitro and in vivo investigations, in cell cultures and in rats with implanted human FR-positive ovarian cancers. The uptake of new MR contrast agents with various proportions of MR signal inducing moieties (contrastophores) and FR-directed moieties (pharmacophores) into ovarian cancers with different levels of FR-overexpression is evaluated with MR imaging. Comparative studies are obtained after administration of free folic acid as a competitor in order to prove the FR-specific uptake of the contrast agents. The signal enhancement of the ovarian cancers on MR images will be correlated with the quantity of FR on the tumor cell surface, as determined by FR-stains, and with the cellular contrast agent uptake, as determined by mass spectrometry. This research should lead to an earlier diagnosis of ovarian cancers and a better differentiation of cancers from normal tissues.