An Extracellular MRI Polymeric Contrast Agent That Degrades at Physiological pH

Abstract

Macromolecular contrast agents have the potential to assist magnetic resonance imaging (MRI) due to their high relaxivity, but are not clinically useful because of toxicity due to poor clearance. We have prepared a biodegradable ketal-based polymer contrast agent which is designed to degrade rapidly at physiological pH by hydrolysis, facilitating renal clearance. In vitro, the agent degraded more rapidly at lower pH, with complete fragmentation after 24 h at pH 7.4. In vitro relaxivity measurements showed a direct correlation between molecular weight and relaxivity. We compared our polymer contrast agent with commercially available Magnevist in vivo by MRI imaging, as well as measuring the Gd concentration in blood. Our results show that our polymer contrast agent gives a higher contrast and intensity in the same organs and areas as Magnevist and is cleared from the blood at a similar rate. We aim to improve our polymer contrast agent design to develop it for use as a MRI contrast agent, and explore its use as a platform for other imaging modalities.

Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release

“…547,557,558 For instance, pH-labile acetal or ketal linkages have been introduced into the polymer backbone (linear or branched) and at the junction between hydrophilic and hydrophobic block copolymers. 559–565 Recently, Ni and colleagues reported a three-armed star-block copolymer architecture constituted by poly(ethylene glycol) methoxy (mPEG) and poly( ε -caprolactone) (PCL) that are linked via acetal groups (Figure 35). 413 The star polymer was shown to self-assemble into spherical or rod-shaped micelles, the morphology of which could be controlled by varying the polymer concentration.…”

Environmentally responsive MRI contrast agents

“…Nanoparticulate MRI probes can be designed to exhibit significant contrast response to physiological or pathological pH change in the region of interest. 124 Most typically, this is through the incorporation of pH-responsive Gd 3+ -chelates, 125 acid labile linkers such as ketals 126 or pH-responsive groups into a nanoparticle scaffold, 127 whose pH-responsiveness triggers a global response across the particle, such as a change in hydration state (leading to swelling/collapse), propensity to degrade/dissolve, hydrophilic/hydrophobic change, hydrodynamic diameter, conformational change (globular/linear), micellisation, or change in water permeability. These changes can result in marked changes in F 2 , 112 q , 128 or τ m , 68 and thus T 1 contrast.…”

Advances in gadolinium-based MRI contrast agent designs for monitoring biological processes in vivo

“…The enhanced permeation and retention (EPR) effect of nanoparticle constructs plus facile targeting of a nanoparticle payload through surface modification add to the benefits of using nanoparticles to deliver MRI contrast agent to specific tissues. Gadolinium chelates have been attached via chemical or physical binding (electrostatic or encapsulation) to a variety of nanoparticles, including dendrimers [16–19], micelles [20,21], liposomes [22,23], polymeric [24–26] or inorganic nanoparticles [27,28], and nanogels [29–32]. Among those examples, the use of nanogels is particularly well suited for MRI as they are stable in aqueous media and allow facile access of water molecules throughout the particle.…”