Designing virus-like nanoparticles as T 1-enhanced MRI contrast agents

Abstract

The field of nanotechnology is a rapidly growing field. In the past few decades, nanoparticles have been utilized for use in biomedical applications with a huge impact in enhancing diagnostic techniques. Protein cages and virus-like particles are biological examples of nanoparticles. They are highly symmetric, well-defined architectures made from multiple protein subunits and can be genetically or chemically engineered to impart desired new functionalities and have been used for design of nanomaterials for improving current diagnostic techniques, as discussed in this thesis. One of the main techniques for diagnosis used today is magnetic resonance imaging (MRI) as it provides good spatial resolution of soft tissues without using harmful ionizing radiation. However, due to poor sensitivity of this technique, contrast agents are often utilized by clinicians to aid in diagnosis of diseased tissues. The main MRI contrast agents used in T1-enhanced imaging are small Gd-containing molecules. Due to the toxicity of free Gd ions, these agents are administered in a tightly chelated form. Even in this form, high doses increase the risk of toxicity. Thus, it is important to reduce overall dosage of these contrast agents. In this thesis, we discuss design principles for virus-like particle based MRI contrast agents as next generation diagnostics which can overcome the above mentioned barriers. Conjugating clinically approved contrast agents to nano-sized virus-like particles changes the intrinsic properties of the contrast agent, directly impacting and increasing MRI contrast. Modifying the interior surface of these cage-like containers to grow functionalizable polymers provides multiple sites for conjugation of small molecule contrast agents, resulting in high payload of these agents. Modifying the exterior surface of these cage-like containers to present targeting ligands and enable them to localize at desired tissues of interest. All three of these design considerations contribute to higher contrast, significantly lower clinical dose requirements, and allow for safe administration of Gd (III) ions for enhanced imaging. As gadolinium-based contrast agents are directly linked with nephrogenic systemic fibrosis, a rare but deadly disease that causes hardening of tissues and organs, an alternate low-risk metal-complex, Mn (III) porphyrins, has also been explored for bioconjugation to virus-like particles.