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 focussed 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 τR that arises from encapsulation. However, encapsulation of the q = 1 chelate GdDTPA2− did not give rise to a significant increase in relaxivity relative to encapsulation of 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.
Nano-assembled capsules can incorporate large payloads of high relaxivity Gd3+, permitting the development of highly detectable molecular imaging agents for MRI. A new encapsulating shell, based upon cross-linked peptides, is found to afford smaller capsules (127 nm average diameter) with exceptionally high per-Gd3+ relaxivities (70.7 s-1mmolal-1).
Although paraCEST is a method with immense scope for generating image contrast in MRI, it suffers from the serious drawback of high detection limits. For a typical discrete paraCEST agent the detection limit is roughly an order of magnitude higher than that of a clinically used relaxation agent. One solution to this problem may be the incorporation of a large payload of paraCEST agents into a single macromolecular agent. Here we report a new synthetic method for accomplishing this goal: incorporating a large payload of the paraCEST agent DyDOTAM3+ into a Reverse Assembled nano-Capsule. An aggregate can be generated between this chelate and polyacrylic acid (PAA) after the addition of ethylene diamine. Subsequent addition of polyallylamine hydrochloride (PAH) followed by silica nanoparticles generated a robust encapsulating shell and afforded capsule with a mean hydrodynamic diameter of 650 ± 250 nm. Unfortunately this encapsulation did not have the effect of amplifying the CEST effect per agent, but quenched the CEST altogether. The quenching effect of encapsulation could be attributed to the effect of slowing molecular tumbling, which is inevitable when the chelate is incorporated into a nano-scale material. This increases the transverse relaxation rate of chelate protons and a theoretical examination using Solomon Bloembergen Morgan theory and the Bloch equations shows that the increase in the transverse relaxation rate constant for the amide protons, in even modestly sized nano-materials, is sufficient to significantly quench CEST.
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 Gd 3+ 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 GdDOTP 5into the internal aggregate. In this report we demonstrate that other Gd 3+ chelates bearing overall charges as low as 2-can also be used to prepare NACs. This discovery opens up the possibility of using Gd 3+ chelates that have inner-sphere water molecules that could further increase the relaxivity enhancement associated with the long rotational correlation time (R) that arises from encapsulation. However, encapsulation of the q = 1 chelate GdDTPA 2afforded the same increase in relaxivity as the outer-sphere chelate GdTTHA 3-. 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 Gd 3+ chelate encapsulated within NACs arises primarily from second sphere effects. The all the support you gave me when my health was on the down side (Dr Benjamin
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