Magnetic resonance imaging (MRI) has become a powerful clinical modality in diagnostic medicine. It is non-invasive and offers high spatial and temporal resolution. The goal of molecular imaging is to reveal the pathophysiology underlying the observed anatomy and diagnose diseases. The detection of pathological biomarkers can lead to early recognition of diseases and improved monitoring for recurrence. Clinically available contrast agents are limited in their discrimination of contrast between tissues and they tend to have very high detection limits. Because biomarkers are very low in concentration there is a need for high payload deposition of contrast agent (CA) and targeted imaging. Encapsulating discrete Gd3+ chelates in nano assembled capsules (NACs) is a simple and effective method of preparing an MRI contrast agent capable of delivering a large payload of high relaxivity imaging agent. The preparation of contrast agent containing NACs had previously focused on preparations incorporating GdDOTP5- into the internal aggregate. In this report we demonstrate that other Gd3+ chelates bearing overall charges as low as 2- can also be used to prepare NACs. This discovery opens up the possibility of using Gd3+ chelates that have inner-sphere water molecules that could further increase the relaxivity enhancement associated with the long rotational correlation time (TR) that arises from encapsulation. However, encapsulation of the q = 1 chelate GdDTPA2- afforded the same increase in relaxivity as the outer-sphere chelate GdTTHA3-. This leads us to the conclusion that in the NAC interior proton transport is not mediated by movement of whole water molecules and the enhanced relaxivity of Gd3+ chelate encapsulated within NACs arises primarily from second sphere effects. The nano assembled capsule platform has been further expanded by an alternative coating method, a new cross linked peptidic shell reported in this work affords robust capsules and exceptionally high per Gd3+ relaxivities (70.7 mM-1s-1). The availability of free amines on the surface of these capsules can be exploited to attach targeting moieties. This was demonstrated through the reaction of fluorescein isothiocyanate (FITC), an intense green emitting dye, with these amines. Green emission from the capsules indicated that surface amines were accessible to FITC. Unlike T1-shortening contrast agents, paraCEST agents can be switched on and off by the imaging scientist by turning on and off a pre-saturation pulse. This affords the ability to acquire both pre- and post-contrast images even after administration of a paraCEST contrast agent. This could potentially eliminate problems co-registering pre- and post-contrast images. A reverse NAC may allow a cationic paraCEST contrast agent to be incorporated in a high payload NAC. We were successful in synthesizing a reverse capsule using DyDOTAM3+, a paraCEST agent, and the negatively charged polymer polyacrylate and encapsulated with SiO2 nanoparticles. These initial preparations of reverse NACs were not able to generate CEST contrast however.
Identifer | oai:union.ndltd.org:pdx.edu/oai:pdxscholar.library.pdx.edu:open_access_etds-4095 |
Date | 21 July 2016 |
Creators | Farashishiko, Annah |
Publisher | PDXScholar |
Source Sets | Portland State University |
Detected Language | English |
Type | text |
Format | application/pdf |
Source | Dissertations and Theses |
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