PEGylated liposome co-encapsulating iohexol and gadoteridol for multimodal CT and MR imaging

Excerpt

Noninvasive imaging techniques such as x-ray/computed tomography (x-ray/CT) and magnetic resonance imaging (MRI) are often used to investigate and characterize anatomical differences and biological processes, detect and diagnose diseases, and assist in the planning and delivery of therapeutic interventions for various disorders (1-5). Although the different imaging techniques can detect inherent contrast in biological systems, conventional diagnostic contrast agents (CAs) such as iohexol (an iodine-based CA for use with CT) and gadoteridol (a gadolinium (Gd)-based CA for use with MRI; is known to increase the risk of nephrogenic systemic fibrosis) are often used to enhance soft tissue contrast generated with CT and MRI techniques (6, 7). These CAs are typically low molecular weight molecules that are rapidly cleared from circulation and have to be administered multiple times during the procedure to obtain images that are suitable for interpretation (e.g., for angiography). The development of a CA with a prolonged circulation time would benefit patients who cannot tolerate the administration of a CA multiple times or if persistent signal enhancement is required for the imaging procedure. For example, before the radiation therapy of a patient is initiated, volumetric CT and MRI data sets have to be acquired and registered to calculate the radiation dose and to define the target (8). Subsequently, cone-beam CT or MR is used to guide the delivery of radiation at each treatment session (9-11). In this application, the contrast agent provides a prolonged signal enhancement to plan (CT and MRI) and visualize the target during the process of cone-beam CT or MR-guided radiation therapy. Thus, an agent with an in vivo circulation half-life of several days (or even weeks) is ideal to use with these techniques.

A viable strategy to achieve prolonged signal enhancement in vivo is to use a colloidal vehicle that can compactly package and transport conventional CAs through the circulatory system without degradation to the target site. To achieve this, nano-sized colloidal carriers have been engineered using nanoparticles such as liposomes, lipid micelles, proteins, etc (12, 13), and some of these carriers are designed to generate simultaneous contrast enhancement with multiple imaging modalities (14, 15). However, none of the colloidal systems reported to date have been demonstrated to provide satisfactory simultaneous signal enhancement in CT and MRI. In addition, these colloids have a limited in vivo stability and circulation half-life, which prevents their use throughout the planning phase and during radiation therapy (12, 16). This report describes the development and biodistribution of a pegylated liposome-based colloidal carrier that co-encapsulates iohexol and gadoteridol (PEGlipo-IG-1) in mice, and CT and MRI imaging in rabbits (17-19).