Research

Improved Drug Delivery to Tumors Using Novel Tissue Perfusion Approaches (Eureka R01CA140943)

Tumor accumulation of intravenously administered cytotoxic drugs depends on multiple variables including blood flow, transendothelial solute/drug permeability, interstitial fluid pressure (IFP), and interstitial volume. Since the altered permeability of tumor microvessels limits delivery of macromolecular cytotoxic drugs, and high IFP in solid tumors further reduces drug extravasation from vessels to tumor interstitium, a major clinical objective is the development of novel delivery strategies that overcome tissue perfusion/accumulation barriers to enhance drug delivery and improved clinical outcome. Thus, the major goal of this project is to examine how short-term inhibition of ALK5 in vivo alters hemodynamics and tissue perfusion in mouse models of cancer. We utilize quantitative estimates of tumor microvascular permeability as determined by macromolecular contrast media-enhanced MR imaging as a surrogate to predict tumor accumulation and/or response of macromolecular cytotoxic drugs following Alk5 blockade in early and late mammary carcinomas.

Imaging of Tumor-Associated Macrophages with Ferumoxytol (R21 CA156124)

The presence of tumor-associated macrophages (TAM) in cancer correlates strongly with tumor progression and poor outcome. Purpose of this study is to develop a clinically applicable, non-invasive diagnostic assay for selective targeting and visualization of TAM in various types of cancer, based on magnetic resonance (MR) imaging and the FDA-approved iron oxide nanoparticle ferumoxytol. An imaging test, which could detect and quantify TAM non-invasively, could be employed as a novel prognostic assay for stratifying individual patients to more intensive or specific anti-inflammatory therapies.

(Society for Pediatric Radiology)

Monitoring of Stem Cell Engraftment in Arthritic Joints with MR Imaging (R01AR054458)

Matrix associated stem cell implants (MASI) represent a promising approach in the treatment of degenerative and inflammatory arthritis due to their capacity to regenerate hyaline cartilage. Complications include MASI dislocation, disappearance of the stem cells from the transplantation site or apoptosis of the transplanted cells within the cartilage defect. Goal of this study is to evaluate if MR imaging can diagnose these complications when the transplanted stem cells are iron oxide labeled and, thus, directly visualized. We label human mesenchymal stem cells (hMSCs) with iron oxide nanoparticles, transplant them into arthritic joints and investigate their long term signal characteristics on MR images. We compare the MR signal of nanoparticle labeled viable and apoptotic stem cells and we compare signal characteristics of transplanted cells that engraft in cartilage defects versus cells that are removed by macrophages. Initial in vitro studies suggest that cell-bound iron oxide nanoparticles in viable cells provide less MR signal than released nanoparticles from apoptotic cells. Thus, MR signal characteristics may allow non-invasive conclusions about the viability of MASI transplants. Studies in animal models are ongoing to further evaluate this phenomenon in vivo.

Novel Imaging Approach to Monitor Chondrogenic Differentiation of iPS Cells

(R21AR059861)

In order to regenerate hyaline cartilage in arthritic joints, transplanted stem cells must not only survive and engraft, but also differentiate into chondrocytes. Goal of this project is to develop a novel, “smart” imaging technique for non-invasive in vivo visualization of the differentiation of hiPS cells into chondrocytes. The approach relies on vector-transfected hiPS cells which are marked by a cell lineage-specific expression of β-galactosidase after chondrogenic differentiation and the galactopyranose coated MR contrast agent EgadMe, which generates only an MR signal after cleavage by β-galactosidase. Chondrogenic differentiation of EgadMe-labeled hiPS cells can be detected with MR imaging when the galactopyranose coat is cleaved by β-galactosidase expression in chondrocytes, resulting in activation of the contrast agent and a positive signal on MR images.

Optimizing Labeling of Human embryonic stem cell derived cardiomyocytes (hESC-CM) with FDA-approved SPIO (RS1-00381-1)

Transplantation of hESC-CM into damaged myocardium is a promising and developing treatment. However, challenges for these treatments result from death and loss of transplanted cells from target sites. An imaging technique to non-invasively and repetitively monitor transplanted hESC-CM could guide improvements in transplantation techniques and advance therapies. Goal of this study is to develop an efficient and clinically applicable labeling technique for hESC-CM with FDA-approved superparamagnetic iron oxide nanoparticles (SPIO). In addition to MR imaging used to evaluate the signal effects of labeling CM before and after differentiation, cell viabilities and potential impairments to the differentiation process are also examined to determine an efficient labeling protocol. Results demonstrate SPIO labeling of hESC-CM should occur prior to CM differentiation. These findings permit monitoring delivery and engraftment of hESC-CM for potential advancements of stem cell-based therapies in the reconstruction of damaged myocardium.