Project 4 - Nanomaterials for imaging and treatment of cardiovascular diseases
Project Leader - Pamela K. Woodard, M.D.
The goal of this project is to develop and screen nano-constructs for targeting of NPR-C for imaging atherosclerosis, with the most promising compound to undergo full toxicity testing, exploratory investigational new drug (xIND) application and feasibility testing in human subjects.
The Problem. Atherosclerosis is the leading cause of death in Western societies. It impacts the public broadly, affecting an estimated 80 million people in the United States alone. It is a chronic, progressive disease with a long asymptomatic phase. Atherosclerosis may begin as early as the second decade and often progresses untreated until mid-to-late life, when either a physician recognizes a patient’s risk factors, or a patient suffers an acute cardiovascular event or death. Although there are many imaging tools to detect and characterize the extent and severity of atherosclerosis, there are no means to identify early active disease to better risk stratify patents, affect management at an earlier more amenable stage, and monitor treatment progress. Imaging agents are also needed to provide surrogate endpoints that are valuable for the evaluation of new interventions directed at the management of vascular disease.
Why Natriuretic Peptide Receptor-C (NPR-C)? During the five years of our initial PEN grant, Naturic Peptide Receptors (NPR) were identified as a potential target for atherosclerotic imaging and treatment agents. NPR-C is known to be upregulated in atherosclerosis suggesting a potential for early disease detection. The natriuretic peptide family consists of three members: atrial, brain and C-type Natriuretic Peptides (CNP). CNP is the most highly conserved of the three and induces its biological effects through its interaction with NPR-C. These effects include a direct effect on immune cell recruitment in vivo and potent inhibition of VSM cell migration and proliferation. Moreover, NPR-C plays a key role in vascular remodeling, a physiological phenomenon that prevents stenoses early in the atherosclerotic disease process, and in the prevention of neo-intimal proliferation, the cause of angioplasty and stent restenosis. In addition, NPR-C is the only NPR that recognizes all natriuretic peptides and fragments containing five conserved amino acids (Arg-Ile-Asp-Arg-Ile). We have shown that a radiolabeled fragment of CNP (CANF) has the potential as an imaging agent ["Natriuretic peptide-mediated imaging of atherosclerotic plaque”, US Provisional Patent# 61/130681, filed 06/01/09 (Woodard P., Rossin R., Woodard G., Welch M.)].
Recently, we have shown that attaching CANF to a NP (Figure 1) gives longer blood circulation, higher SUV’s, and higher target to non-target ratios when compared to CANF alone (Figure 2). We plan to further assess this agent as well as other nanoparticle-based CANF agents in two animal models, the rabbit model of atherosclerosis/neo-intimal hyperplasia and the mouse model of angiogenesis. By evaluating the agents in both of these models, we can compare their uptake with each other and with the unsupported molecule. The in vivo uptake will also be compared with the binding affinities of the multivalent nanoparticle based targeting agent, measured in vitro. In year 3, we will obtain human use approval (through the IND mechanism) to carry out a clinical trial. This trial is particularly important because we will be able to compare the imaging data with the in vivo pathology in a relevant human model of atherosclerosis.
Our specific aims are:
- Assess the biodistribution and binding of select nanoconstructs targeting NPR-C synthesized in Project 1 and the Nanomaterials Production Core;
- Validate these nanoconstructs for imaging in rabbit and mouse models of atherosclerosis, neointimal proliferation and angiogenesis;
- Perform full toxicity testing and xIND submission with the CANF-comb, or the most promising compound targeting NPR-C;
- Perform two human study feasibility trials with the selected CANF nanoconstruct.