Early cancer diagnosis, in combination with efficacious cancer therapies, is critical for achieving the ultimate goal of totally eradicating the disease . Cancer diagnosis is done by taking a biopsy, but if the tumor is inaccessible for biopsy, one has to rely upon the existing imaging techniques, such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single-photon emission CT (SPECT), and ultrasonography (US). These imaging modalities have their strengths and limitations, and most of the times, two or more modalities are used to acquire complementary information. Whichever imaging modality is used, sufficient intensity of a corresponding signal from an area of interest must be achieved in order to differentiate the diseased area from the surrounding tissues. Usually, the imaging of different organs and tissues for early detection and localization of numerous pathologies cannot be successfully achieved without appropriate contrast agents. As in the case involving tumor imaging, only selected agents are expected to have the potential of being useful. An ideal cancer imaging agent, therefore, has to meet the prerequisites of (i) selective accumulation in the diseased sites, (ii) low toxicity, (iii) low immunogenicity, (iv) excretability, and (v) high number of reporter groups. Over the last two decades, synthetic polymers are increasingly studied as a novel Nanoimaging Edited by Beth Goins and William Phillips Copyright © 2011 by Pan Stanford Publishing Pte. Ltd. www.panstanford.com
class of contrast agents. Modern polymer chemistry has led to the generation of a number of biocompatible polymer structures, including branched, graft, multivalent polymers, and dendrimers. Polymeric imaging agents have prolonged plasma half-lives, enhanced stability, reduced toxicity, improved targeting, and a reduced nonspecific binding, thereby allowing for more specific and amplified imaging probes that can significantly differentiate target areas from background. Additionally, multiple reporters and/or homing ligands can be attached to the polymers, allowing multifunctional and multimodality cancer imaging. Common features of this class of contrast agents include (i) prolonged blood circulation time (thus they can serve as blood pool imaging agents), (ii) ability to provide more accurate estimates of the tumor vascular permeability and blood volume using dynamic imaging protocols, and (iii) capability to offer multimodal imaging and combining multiple functions (diagnostic and therapeutic functions) in a single setting.This chapter examines the application of some key synthetic polymers in cancer imaging. We describe the structure and preparation of these polymers, as well as summarize the in vitro and in vivo data published in literature. Finally, we discuss the prospects of polymers in the diagnosis and treatment of cancer. The applications of synthetic polymers as drug carriers have been extensively reviewed by many authors [14, 26, 40, 50]. The use of polymeric MR contrast agents for assessing tumor vascular pharmacokinetic parameters (i.e., vascular permeability product, blood volume, transit time) have also been reviewed [8, 19, 38, 39]. 8.2 POLY(l-GLUTAMIC ACID) (PG)
8.2.1 PG for MRIMRI is a noninvasive imaging modality that can provide three-dimensional imaging with high spatial resolution. MRI with blood pool contrast agents can be used to perform noninvasive angiography, assess angiogenesis, quantify and measure the spacing of blood vessels, and measure blood volume and flow [5, 22]. Blood pool contrast agents are generally conjugates of paramagnetic gadolinium chelated to high-molecular-weight polymers that show prolonged blood circulation time and are largely retained within the intravascular space during MR imaging. Polymeric contrast agents can also passively accumulate within solid tumor tissues owing to the enhanced permeability and retention (EPR) effect . However, the clinical applications of many current macromolecular contrast agents are limited by their slow excretion from the body and the potential toxicity of free gadolinium released by the metabolism of the contrast agents [6, 12, 41]. The ideal polymeric contrast agent is degraded and cleared from the body after completion of MR imaging. Poly (l-glutamic acid) (PG) is a polymeric carrier widely used for diagnosis and therapeutics because of its biocompatibility, biodegradability, and water solubility .