Department of Chemistry

Abstract:

Part I. Molecules:

Srinivasan Mukundan, Jr. PhD, MD
Assistant Professor of Radiology (Neuroradiology) and Biomedical Engineering

Active targeting of cellular constituents with specific biochemical agents capable of being detected external to the organism is the basis of the so-called “molecular imaging” (MI). The existing paradigm in MI is the attachment of a reporter molecule (radionuclide, fluorophore, paramagnetic agent, etc.) to a ligand capable of binding to a molecular target. The complex biochemical constructs of these agents along with the limited signal from the usual 1:1 molecular ratio between ligand and reporter, has resulted in the absence of computed tomography (CT) from the MI arena. Recently, the superior anatomic resolution of CT has been combined with the exquisite signal to noise ratio of positron emission tomography (PET) or single photon emission computed tomography (SPECT). Our goal is to demonstrate the potential of CT as a MI modality, through the use of a novel platform technology.

To help overcome these shortcomings, we are developing a “platform” technology approach that uses liposomal nanoparticles into which a variety of imaging agents (readout molecules) can be incorporated (Figure 1). Signal amplification results from the ability to package a large number of readout molecules (106) into a single particle.

Moreover, target specificity can be engineered by modifying the construct of the liposomal nanoparticles (i.e. size and/or surface-molecules). These agents offer great flexibility in modality while retaining target-specificity. Further, they offer the intriguing possibility of co-encapsulation of imaging agents along with therapeutic agents to facilitate imaging guidance of therapy. In recent work, we have demonstrated (1) The encapsulation of extremely high levels of Iodine in the nanoparticles, enabling CT imaging of very small (<0.1mm) soft tissue and blood vessel features (2) the ability to maintain high concentration of iodine in the bloodpool so that it is possible to achieve more than 500 Hounsfield units (HU) of CT enhancement within the bloodpool for over four hours following intravenous administration.

Part II: Medical Imaging
James M. Provenzale, MD
Professor of Radiology, Section Head Neuroradiology

Despite advances in the surgical, chemotherapeutic and radiotherapeutic treatment of malignant gliomas over the last two decades, the prognosis for individuals with these tumors remains extremely poor. In order to maintain viability beyond a few millimeters in diameter, a tumor must develop its own vascular supply (which is referred to as angiogenesis). This vascular network is comprised of immature and hyperpermeable vessels that rely on both angiogenesis-promoting and antiangiogenic factors for their development. This network of blood vessels is also felt to be partly responsible for metastatic spread. Tumor neovascularity has a number of features that are almost pathognomonic for malignancy including large endothelial cell gaps (or fenestrae), incomplete basement membranes, relative lack of smooth muscle association with endothelial cells, and high vascular tortuosity.

Much of the progress in knowledge regarding the molecular biology of tumors has implicated tumor neovascularity and angiogenesis as a potential therapeutic target. As such, there has been increasing interest in the use of therapies to decrease formation of abnormal tumor vasculature. In order to monitor the efficacy of these novel therapies, modern imaging techniques are needed that go beyond the classical anatomic based methods to include a physiologic assessment as well. Perfusion imaging, using computed tomography (CT), magnetic resonance (MR), or positron emission tomography (PET) is one such approach (Figure 2). Specifically, two parameters, relative cerebral blood volume (rCBV) and permeability appear to be particularly suited to evaluate tumor vascularity. Moreover, these parameters may be a means of showing whether early response of a tumor to antioangiogenesis therapy has occurred.

Host: David Beratan

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