2012 MIPS Molecular Imaging Seminar Series

Tumor microenvironment plays a critical role in cancer survival, angiogenesis, proliferation and metastasis. Molecular imaging of biomarkers in tumor microenvironment provides accurate characterization of tumor angiogenesis, earlier detection and diagnosis of malignant tumors and non-invasive evaluation of anticancer therapeutics efficacy. We have designed and developed polydisulfide-based biodegradable macromolecular MRI contrast agents for evaluating tumor angiogenesis and targeted nanoglobular MRI contrast agents for detecting a cancer-related biomarker expressed in the extracellular matrix of malignant tumors. The biodegradable macromolecular contrast agents are effective for characterizing tumor angiogenesis and non-invasive evaluation of tumor response to cancer therapies in DCE-MRI. The targeted contrast agents specifically bind to the biomarker in tumor extracellular matrix, resulting in strong and prolonged contrast enhancement in the tumor tissue, not in normal tissues. The novel MRI contrast agents have shown a potential for accurate characterization of tumor angiogenesis, timely evaluation of anticancer therapeutic efficacy and specific cancer molecular imaging with MRI.

For centuries, lens-based microscopy, such as light, phase-contrast, fluorescence, confocal and electron microscopy, has played an important role in the evolution of modern sciences and technologies. In 1999, a novel form of microscopy, i.e. coherent diffraction microscopy (also denoted coherent diffraction imaging or lensless imaging) was developed and transformed our traditional view of microscopy, in which the physical lenses are replaced with a Fourier-based iterative algorithm. In this talk, I will briefly discuss the principle of lensless X-ray microscopy and present some biological and biomedical applications. In the second part of my talk, I will show that this Fourier-based iterative algorithm can be combined with a novel data acquisition scheme to form equally sloped tomography (EST). Using the European Synchrotron Radiation Facility in France, several tilt series of phase-contrast X-ray images were measured from a human breast cancer sample. Our reconstruction results indicated that EST with 512 projections visually produced a 3D image with comparable or better image quality than conventional tomography with 2000 projections. In addition, EST 512 and FBP 2000 reconstructions were blindly evaluated by six independent radiologists. They unanimously confirmed that the EST 512 reconstruction is superior to the FBP 2000 reconstruction. The Mean Glandular Dose (MGD) was estimated to be 2.3 mGy for the EST 512 reconstruction, which is less than the average dose in a dual-view screening routine exam.

Molecular Imaging technologies that have been applied to various aspects of cancer drug discovery will be discussed. Examples of imaging applications in target validation, screening, compound optimization and companion diagnostics will be described along with their impact on the development of novel cancer therapeutics.

We recently developed a new x-ray source technology utilizing the carbon nanotubes (CNTs) as the electron field emitters. This distributed x-ray source array technology with flexible source configuration and digital control of radiation opens up new possibilities for designing x-ray tomography scanners with enhanced resolution and scanning speed, and for developing novel radiotherapy systems. Several imaging and radiation therapy systems are currently at difference stages of development. A stationary digital tomosynthesis scanner for detection of human breast tumor has been demonstrated which offers a higher spatial resolution, a faster scanning speed, and potentially a higher sensitivity for micro-calcification compared to the current rotating-gantry tomosynthesis scanners. We have also initiated an effort on microbeam radiotherapy, which is an experimental andpreclinical technique that has been shown in synchrotron based animal studies to be effective for eradication of brain tumor while sparing normal tissue. In this talk we will provide an update on the status of the CNT x-ray source technology and will introduce the stationary digital breast tomosynthesis and microbeam radiation therapy systems currently under development at UNC.

Nanoconstructs are multifunctional, particle-based devices for the 'smart' delivery of therapeutic and imaging agents. In this lecture, first, an integrated approach will be presented for the rational design of nanoconstructs with high level of accumulation within the diseased tissue and minimal sequestration by the organs of the reticulo-endothelial system (liver, spleen, kidneys, lungs). Second, a new class of multifunctional nanoconstructs will be described offering superior contrast enhancement for MR imaging and thermal ablation potential under non invasive electromagnetic fields.

The integrated approach for the rational design of nanoconstructs combines together the in-silico mathematical modeling for the vascular transport and adhesion of blood-borne nanoparticles, in-vitro microfluidic-based assays and in-vivo intravital microscopy analysis in small animals. The multifunctional nanoconstructs are based on mesoporous silicon and hydrogel-based particles exhibiting a variety of size and shape combinations, loaded with Gd-based contrast agents (Magnevist®; Gd-nanotubes and Gd-fullerenes) for T1-based MRI and SuperParamagnetic iron oxide (SPIOs) for T2-based MRI. In the presence of non-invasive electromagnetic fields, these nanoconstructs could also generate thermal toxicity for tissue ablation and/or triggered drug release.

MR is often not considered suitable for molecular imaging. However, with a judicious choice of molecular target, discrete low molecular weight MR probes can be designed to provide positive image contrast of specific pathologies. Here we provide preclinical examples of probes designed to target type I collagen for the imaging of fibrosis (hepatic, pulmonary, cardiac) as well as probes targeted to fibrin for the imaging of thrombus. The advent of simultaneous MR-PET has opened many new avenues in molecular imaging and here, we also describe our experiences with MR-PET in terms of developing new PET tracers and also in utilizing the synergies of MR-PET to develop quantitative activatable MR probes.

MR is often not considered suitable for molecular imaging. However, with a judicious choice of molecular target, discrete low molecular weight MR probes can be designed to provide positive image contrast of specific pathologies. Here we provide preclinical examples of probes designed to target type I collagen for the imaging of fibrosis (hepatic, pulmonary, cardiac) as well as probes targeted to fibrin for the imaging of thrombus. The advent of simultaneous MR-PET has opened many new avenues in molecular imaging and here, we also describe our experiences with MR-PET in terms of developing new PET tracers and also in utilizing the synergies of MR-PET to develop quantitative activatable MR probes.

Magnetic Particle Imaging (MPI) is a new imaging modality that re-uses FDA-approved iron oxide nanoparticle contrast agents in a new imaging scanner (i.e., we do not use an MRI scanner). The MPI method has ideal SNR, penetration, linearity and contrast, and it is completely non-invasive. Moreover, compared to iodine and gadolinum, the iron oxide MPI contrast agents are much safer for patients with Chronic Kidney Disease (CKD). Nearly half of Americans over the age of 70 have CKD. Iodine poses significant risk for renal failure in CKD patients, and gadolinium is contra-indicated for CKD patients due to the risk of Nephrogenic Systemic Fibrosis. Fortunately, iron oxide nanoparticle agents have been shown safe for CKD patients. One iron oxide nanoparticle agent (Faraheme) has even been approved as a treatment for anemia in CKD patients. My lab has built all seven MPI scanners in North America. I will share some of our recent imagine studies. We are exploring numerous MPI applications including safe angiography, targeted cancer imaging, quantitative cell therapy tracking, molecular biosensors, and inflammation imaging.