Technology
The Fenestra technology is comprised of iodinated lipids that provide contrast enhancement integrated into a novel oil-in-water lipid emulsion that selectively localizes the lipids to various sites within the body. The Fenestra product family represents the first agents designed and optimized for use in microCT imaging. The technology was developed following more than five years of research at the University of Michigan and an investment of over U.S.$ 10 million. Initial customers include leading pharmaceutical and biotech companies and the National Institutes of Health.
A miniaturized version of traditional clinical CT imaging systems, known as microCT, has been developed in recent years that provides images of exceedingly high resolution. Though initially used almost exclusively ex vivo, recent advances in imaging hardware and computing power have made the technique available to use on living animals. In fact, current microCT systems can provide images in live animals with isotropic spatial resolution approaching 5-10 µm.
However, two key problems hinder the widespread adoption of the method: the relative lack of soft tissue contrast complicates interpretation of anatomical features; and the long acquisition time necessary to overcome motion artefacts preclude the use of standard water-soluble iodinated contrast media that might otherwise overcome the problem of soft tissue contrast.
Because of its comparatively long in vivo residence time (up to several hours), Fenestra is ideally suited for a wide range of microCT imaging procedures and provides unique visualization of hepatobiliary and vascular anatomy and disease. Based on the initial evaluation of the technology, two formulations of Fenestra have been developed to provide contrast enhancement in two distinct applications. Fenestra LC provides extended hepatobiliary contrast useful for visualization of abdominal anatomy and function. Fenestra VC provides prolonged vascular contrast for visualization of cerebral, cardiac, abdominal and peripheral vasculature.
Preclinical imaging
Fenestra LC and Fenestra VC
Fenestra LC provides visualization of the entire hepatobiliary system by exploiting the endogenous lipid metabolism pathways present in the body. Chylomicron remnants (CMR) represent a class of naturally-occurring plasma lipoproteins that selectively shuttle lipids to hepatocytes in the liver. Fenestra LC mimics CMR particles and thereby localizes the contrast-producing lipids it contains to the hepatic parenchyma following intravenous administration. Because the metabolic status of extracellular and intracellular liver lipases determines the uptake and clearance profiles of the lipid molecules, Fenestra LC provides the ability to assess hepatobiliary anatomy and liver function with CT imaging.
Fenestra VC is a refined version of Fenestra LC, in which the surface of the lipid emulsion particle is modified to slow the recognition of the particle by the receptors on hepatocytes that are responsible for its uptake into the liver. With Fenestra VC, the delayed uptake by liver cells produces an agent with prolonged blood pool imaging properties that provides superior contrast enhancement of the entire vasculature for up to several hours after injection. Moreover, the agent remains truly intravascular as long as the endothelial integrity of the vessel is maintained, opening the door to conduct specialized studies characterizing vascular function and vessel permeability.
Examples of initial applications of Fenestra in a variety of mouse models of normal and disease conditions are shown in the following figures. Fenestra’s benefits play an instrumental role in facilitating the implementation of microCT imaging as an increasingly important and popular component of basic research and commercial drug development.
MicroCT imaging of abdomen in a normal mouse. It is not possible to distinguish soft tissues before administration of contrast (left image). Fenestra LC (middle and right images) provides significant hepatic enhancement that simplifies anatomical differentiation and margin definition. Images courtesy of Dr. Jamey Weichert, University of Wisconsin
MicroCT imaging using Fenestra LC in a mouse with CT-26 colon carcinoma (left image, arrow) implanted into the liver and a TGF-a transgenic mouse with hepatoma (right image, T=tumour). Images courtesy of Dr. Jamey Weichert, University of Wisconsin
MicroCT imaging of abdominal vasculature using Fenestra VC in a normal mouse. Visualization of vessels well below 1 mm in diameter is possible. Images courtesy of Dr. Jamey Weichert, University of Wisconsin
MicroCT imaging of cardiac anatomy using Fenestra VC in a normal mouse. Visualization of cardiac chambers and neighbouring vasculature is possible. Images courtesy of Dr. Michael Paulus, Siemens (formerly known as CTI-Concorde and ImTek, Inc.) and Dr. Jamey Weichert, University of Wisconsin
Confirmation of cell implantation using Fenestra LC-enhanced microCT in a mouse. Visualization of successful injection of cells into a lobe of the liver is possible within minutes after injection (arrow on right image) using animals administered with Fenestra LC before injection of cells. Images courtesy of Dr. Jamey Weichert, University of Wisconsin.
Potential therapeutic drug delivery applications
ART’s proprietary oil-in-water lipid emulsions can serve as generalized hepatic drug delivery vehicles for amphipathic or lipophilic compounds. For example, a lipophilic anti-viral drug that is effective in treating hepatitis B or C could be incorporated into the lipid emulsion formulation and delivered selectively to the liver The receptor-mediated uptake system exploited by the technology is a very selective, high capacity intracellular localization pathway that allows significant quantity of drug to be delivered to the affected cells while simultaneously minimizing or eliminating side effects resulting from systemic exposure to the drug.
It is important to emphasize that the uptake of the Lipid Emulsion (LE) particle is virtually independent of the payload it carries as long as the distribution profile of the particle size and surface composition of the particle are not appreciably modified by incorporating the drug to be delivered. Because of this feature, the LE technology has many applications for delivering lipophilic drugs (or lipophilic prodrugs of water-soluble drugs) to hepatocytes. While the therapeutic application of the technology has not yet been tested in preclinical models, the emulsion has been shown in numerous preclinical efficacy and GLP toxicology studies to localize effectively to hepatocytes (up to 96 percent of the dose) without introducing hepatotoxicity. As such, the LE technology holds great promise as a hepatoselective therapeutic delivery system. In addition, by minimally modifying the delivery vehicle, the uptake kinetics can be optimized to suit the features of the target. The LE can conceivably be coated to different degrees to customize the rate of hepatic uptake from hours to days.
ART anticipates that a range of products can be developed from the LE technology that provides localized delivery of therapeutic agents to treat hepatic pathology. Based on the initial assessment of the technology, potential products might include:
- therapeutic delivery systems to treat or control parenchymal liver diseases such as hepatitis, cirrhosis, steatosis and cholesterol metabolism. Drug payloads could include lipophilic anti-viral drugs or prodrugs, lipophilic analogs of RNAi, lipophilic anti-sense oligonucleotides or antibiotics;
- delivery systems for gene therapies against hepatic disorders such as familial hypercholesterolemia, HMG-CoA Reductase or p53 defects or deficiencies;
- delivery of hepatoprotectants used to spare healthy liver tissue in radiation oncology, ablation therapy, chemotherapy or other therapeutic interventions;
- localized delivery of organ transplant rejection drugs or antibiotics.