Theranostic and Contrast Agent Development Lab

The UW Theranostic and Contrast Agent Development Lab is involved in the design, synthesis, and evaluation of novel targeted molecular imaging agents for computed tomography, magnetic resonance, and nuclear medicine including PET and SPECT as well as therapeutic radiopharmaceuticals. Our design strategy is based on a biochemical approach, whereby naturally occurring compounds known to be stored and or metabolized in the organ or tissue of interest serve as carriers for the radiologic moiety.

Our pan-cancer phospholipid tumor delivery platform has afforded a variety of new imaging and therapy agents active in multiple modalities including MRI (Gd-NM600), nuclear medicine (NM404/600), visible and near infrared optical, and a new tumor selective CT contrast agent under development. Radioiodinated (I-124/131) NM404 has been examined in over 6 clinical trials in multiple tumor types and radiometal labeled NM600 is expected to begin a clinical phase 1 trial in in advanced cancer patients in Q2, 2025. Our current NIH P01 grant was the first ever, large P01 grant funded by the NCI in the field of theranostics. Based on early findings in our collaborative laboratories, the premise of this work is to define the role of low dose targeted radionuclide therapies to stimulate the immune system against cancer cells and to induce immune memory to prevent recurrence of cancers once they are treated.

We have also discovered that low-dose TRT can prime the tumor immune microenvironment and significantly expand the scope and efficacy of current immunotherapies including checkpoint inhibitors. Our technologies are covered by over 50 US and international patents and licensed to two theranostic companies founded by Dr. Weichert.

The lab is unique in that we perform all synthesis, analysis, formulation, and pharmacokinetic evaluation as well as multimodality imaging totally within our group. Moreover, we work very closely with clinical and preclinical collaborators in immunology, radiobiology, and dosimetry here at UW. We are fortunate to have an extremely strong and cooperative association with cancer biologists on campus who have developed a variety of relevant cancer models. Dr. Weichert also founded the UWCCC Small Animal Imaging and Radiotherapy facility which is one of the strongest such facilities in the US. This facility allows us to seamlessly translate agents to clinical status.

Research

Targeted Design and Delivery of Cell Selective Imaging Agents for Computed Tomography (CT), Nuclear Medicine, PET, and Magnetic Resonance (MR)

CT and MRI Contrast Agents: CT projects include the development of polyiodinated lipophilic agents for hepatocytes-selective imaging as well as blood pool agents for CTA (angiography) and lymphography. MR interests utilize the same lipoprotein-like vehicle to deliver gadolinium chelates to hepatocytes for tumor imaging and a blood pool version may prove useful for detecting and characterizing atheroschlerotic plaques and other vascular anomalies. Utilizing a targeted delivery approach coupled with design and development of appropriate agents represents a significant enhancement over currently available imaging agents in all diagnostic modalities. We can now easily detect sub-300 micron liver tumors in live mice using the ImTek microCT scanner. Finally, combining the hepatocyte-selective ITG with a long acting radiopaque blood pool agent to temporarily enhance the vessels affords ultra-high-resolution liver tumor images. As a result of these studies, the surface of the chylomicron remnant-like carrier was modified in order to delay hepatocyte uptake thus resulting in prolonged blood pool activity (up to three hours). Combining these two versions of the ITG emulsion has eliminated the need to administer a subsequent small dose of urographic agent to get the highest contrast images of the tumor margins. An MRI blood pool agent is also under development. Such blood pool-selective agents may have widespread clinical use in CTA, MRA, cardiac, and atheroschlerotic conditions. Installation of a research MicroCT scanners has been vital toward further development of the hepatocyte-selective CT as well as CT and MR blood pool agents. Many of the initial CT imaging experiments in rodent models have been completed on these scanners at ultra high resolutions less than 20 micrometers. Moreover, ultra-high resolution blood pool imaging studies coupled with 3D reconstruction of the data may lead to very early detection and or characterization of atheroma or other vascular abnormalities. Such ultra high-resolution studies in rodents are not currently possible on large gantry clinical scanners. Results obtained on the MicroCT scanners may, however, provide a window to the future capabilities of our new agents as the resolution of commercial scanners continues to improve.

Tumor Selective Nuclear Medicine/PET Agents

Radioiodinated phospholipid analogs have proven useful in gamma camera imaging of a variety of human tumor xenografts and spontaneous tumor models in rodents. A promising second-generation analog, NM404, is currently undergoing clinical evaluation in lung cancer patients. The agent, which has shown remarkable tumor cells retention in 25/25 tumor models, can be defined as a diapeuticTM agent (Cellectar, LLC., Madison, WI) since it affords both tumor diagnostic and therapeutic potential. We are currently examining the tumor selectively of this agent in hyperplasia and neoplasia mouse models, and are initiating studies to evaluate its potential to predict tumor response to a variety of treatment modalities including external beam radiotherapy, chemotherapy, radio-frequency ablation, and surgical resection. We will soon be labeling this exciting compound with iodine-124, a new PET isotope with a 4 day half-life.

Facilities

Located on the 6^th floor of the UWCCC tower, this new state-of-the-art lab totals 1800 gsf and includes complete synthetic organic, radiochemical, and analytical capabilities. High field structural NMR studies are performed at the National NMR center facility located in the new biochemistry building. The isotope lab includes a dedicated hot cell, Capintec dose calibrator, gamma-counter, Bioscan AR-2000 plate imaging radioTLC-scanner, and Gilson Unipoint HPLC system with both diode array and Bicron radio-detectors. Moreover, for formulation of lipophilic agents, the facility is equipped with a Microfluidics model-110S microfluidizer capable of attaining 23,000 psi and generating sub 100-nanometer diameter emulsions. Particle size analyses are performed with a Particle Sizing Systems (Nicomp) Model 380 sub-micron particle sizer with zeta potential capability. A portion of the lab is also set up for performing small animal surgery as well as tissue distribution and metabolism studies. The lab contains multiple state-of-the-art Pentium 3/4 computers as well as AccuImage and Amira (TGS, Inc., San Diego, CA) image processing software which, via 100 Mbs ethernet connections with departmental scanners, allows advanced 3-dimensional image processing to be performed directly within the lab itself.

The University of Wisconsin Medical School in conjunction with the Comprehensive Cancer Center and several departments including Radiology and Medical Physics is currently formalizing a state of the art small animal imaging facility. A new 1050 GSF small animal imaging suite is currently under construction in the K4 animal facility in the Clinical Science Center and is slated for occupancy in the fall of 2005. This lab will have its own isolated animal holding room for rodents undergoing serial long-term imaging studies. Our current first generation MicroCAT-1 (ImTek, Inc, Knoxville, TN) scanner is located in the Radiology Department Contrast Agent Development Lab (K4/649 CSC) located on the 6th floor of the UW Comprehensive Cancer Center. The commercial scanner was acquired in March of 2001 and was the 6th such commercial unit at the time which was capable of imaging live mice and small rats at spatial resolutions exceeding 40 mm. The unit is based on cone beam architecture and acquires volumetric CT data sets. Coupled with sophisticated Amira and Accuimage image processing software, the unit is capable of simultaneous multiplanar as well as 3-dimensional reconstruction, thus affording exquisite anatomic details. The unit is controlled by a Dell-620 workstation with twin 1GHz P3 Xeon processors, 2GB of PC 600 RAM, and 4-36GB RAID-stacked, 10,000 RPM, SCSY hard disks for data storage. Moreover, a stand-alone workstation, was recently established which allows simultaneous data acquisition and processing. This system includes twin 2.2 GHz P4 Xeon processors, 4 GB of PC800 RAM, and 4-72 GB RAID-stacked, 10,000 rpm SCSY hard disks as well as a 9.4 GB DVD/RW drive for principle investigator data file archiving. The highlight of this system includes a VolPro-1000 true real-time 3D-volume rendering card with 512 MB of on-board memory capable of real-time volume rendering of 1024x1024x1024 3-D data sets. Stereo imaging capability will be added in the fall of 2005. We recently (1/05) received separate NCRR Shared Instrumentation grants to acquire both a Varian 4.7T high field magnetic resonance imaging scanner as well as a second-generation large field of view MicroCAT-2 microCT scanner capable of 18 micron spatial resolution. We were able to leverage our extramural scanner acquisitions to secure institutional funds to purchase the world’s first microCT/microPET Hybrid scanner which will be built exclusively for us by CTI (Knoxville, TN). This system will be unique in that it will combine CTI/Siemen’s next generation QS microPET and MicroCAT-3 large field of view scanner technologies. Having the scanners linked together will alleviate the common problem of image coregistration associated with fusing data sets from two separate modalities and will also significantly enhance the quantitation of PET images due to build in attenuation correction afforded by the CT scanner. This significant infusion of high-resolution microscanning technology will complement our current small field of view microCT and medium field of view Concorde R4 microPET (located in the Waisman center) imaging systems, the latter of which is capable of scanning small primates.

Conventional CT contrast agents are not suitable for microCT scanning due to relatively long data acquisition times (currently ranging from 8-20 minutes) in live rodents. The UW contrast agent development lab has developed two long-acting microCT-compatible agents, including hepatocyte and vascular selective agents. Currently these are the only contrast agents which are suitable for microCT scanning and very recently have been made available to the preclinical research community via Alerion Biomedical, Inc. (San Diego, CA). These agents enhance the soft tissue capabilities of microCT significantly.

This lab has also developed a new diapeutic tumor agent, NM404 which is capable of both detection and treatment via radiotherapy a wide variety of tumors. Based on membrane enzyme deficiencies of tumor cells, these radioiodinated phospholipid ether analogs undergo selective tumor cell uptake and prolonged retention in 27/27 tumor models it has been evaluated in. Moreover, this agent is unique in that it does not localize in benign or hyperplastic cells or in inflammatory sites. Due to its avidity for such a wide variety of xenograft and spontaneous malignant animal and human tumors in rodent models, this agent is currently being evaluated as a diagnostic agent in lung cancer patients under a physician sponsored IND at the University of Wisconsin Comprehensive Cancer Center. Due to apparent therapeutic responses observed in mouse tumor models, this agent is entering formal therapy studies in mice and rats. Therapy responses following administration of a single imaging dose of 125I-labled NM404 are thought to be due to its extremely long retention time in malignant cells. This agent is currently being converted to a PET imaging agent labeled with a relatively new positron emitter, iodine-124. Unlike most short-lived PET isotopes, iodine-124 has a 4 day half-life which matched perfectly with the pharmacokinetic profile of NM404.

By the end of 2005, we expect to have a fully functional small animal imaging lab (1200 gsf) located within the medical school animal facility as well as add three new microscanners including a state-of-the-art large field of view microCT scanner (ImTek MicroCAT-3, CTI/Siemens, Knoxville, TN), 4.7T microMRI scanner, as well as the world’s first commercial next generation microCT/microPET hybrid scanner (CTI/Siemens) capable of 1 mm microPET resolution and 18-micron microCT resolution. Institutional fund raising efforts are underway to acquire a bioacoustic microscope as well as a bioluminescence scanner. The small animal imaging lab outlined here will be moved to the new IRC complex when it is completed in 2008. This new building will house 50,000 square feet of interdisciplinary imaging space on the lower two floors. The small animal imaging lab will move into an entire suite of microimaging labs that will be located next to an adjacent animal vivarium in this complex. This facility, coupled with all new multimodal scanner technology and our proprietary contrast and imaging agents, will become one of the premier microimaging facilities in the country.

Collaborations

Other Collaborators

Behnam Badie, MD, Brain Model, Neurological Surgery
Pupa De Stasio, Synchrotron Spectro Microscopy, Synchrotron Radiation Center
William Dove, PhD, Intestinal Model, McArdle Laboratories
Michael Gould, PhD, Transgenic Rat Models, McArdle Laboratories
Paul Harari, MD, Squamous Cell Carcinoma Model, Human Oncology
Paul Lambert, PhD, Cervical Model, McArdle Laboratories
R. Jerry Nickles, PET Physics/Chemistry, Medical Physics
Amy Moser, PhD, Mammary Model, Human Oncology
Sharon Weber, MD, Liver/HCC Models, Surgical Oncology
George Wilding, MD, Prostate Model, UW Carbone Cancer Center

Partners