Triply Loaded Nitroxide Brush-Arm Star Polymers Enable Metal-Free Millimetric Tumor Detection by Magnetic Resonance Imaging

Abstract

Nitroxides occupy a privileged position among plausible metal-free magnetic resonance imaging (MRI) contrast agents (CAs) due to their inherently low-toxicity profiles; nevertheless, their translational development has been hindered by a lack of appropriate contrast sensitivity. Nanostructured materials with high nitroxide densities, where each individual nitroxide within a macromolecular construct contributes to the image contrast, could address this limitation, but the synthesis of such materials remains challenging. Here, we report a modular and scalable synthetic

Supramolecular and biomacromolecular enhancement of metal-free magnetic resonance imaging contrast agents

“…Most importantly, the ORCA can survive in the presence of ascorbate for periods of time that exceed-to the best of our knowledge (Table S1 †)-currently known aminoxylbased ORCAs by 20-fold. 24,[40][41][42][43][44][45] Our results indicate that with the combined approach of (i) utilizing macrocycles for steric shielding to inhibit reduction in vivo along with (ii) enhancing T 1 relaxivity by conjugating these supramolecular agents to biomacromolecular scaffolds, ORCAs are moving closer to clinically viable contrast agents.…”

“…24,25 However, two major issues prevent aminoxyl-based ORCAs from replacing traditional contrast agents based on Gd: (i) their single unpaired electron provides weaker contrast compared to the seven unpaired electrons of Gd and (ii) they are reduced rapidly to MRI-silent hydroxylamines in physiological conditions by compounds including ascorbate, saccharides, and cysteine-rich proteins. 24 Contrast issues in ORCAs have improved greatly in recent years by attaching them to polymeric or biomacromolecular nanoparticle systems [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] that both create high local concentrations of aminoxyl moieties and decrease the diffusional and rotational motion of the attached ORCAs. Because rotational correlation time is inversely proportional to relaxivity, attaching contrast agents onto large macromolecules will-in generalimprove their performance.…”

Human Serum Albumin Labelled with Sterically-Hindered Nitroxides as Potential MRI Contrast Agents

“…Positive and negative contrast enhancements are clearly observed in T1 and T2 images, respectively. The r2/r1 values of 10.4-14.3 obtained in a 7 T magnetic field suggest that at high field strengths the conjugates may work most effectively as T2 contrast agents [15,19]. The r2/r1 values per nitroxide exceed those of most other nitroxide-based ORCAs [15,20,23] and the r1 relaxivities are similar to values at 7 T for other ORCAs.…”

Peptide-functionalized NaGdF4 nanoparticles for tumor-targeted magnetic resonance imaging and effective therapy

“…10 The tumor delivery efficiency of nanomaterials is strongly determined by their own physicochemical properties including size, surface modication, and stimuliresponsiveness to tumor microenvironment. [11][12][13][14][15][16] Therefore, there is a strong desire for the development of new modication strategies for generating nanomaterials with improved diagnostic and therapeutic capabilities through increasing their tumor accumulating amounts.…”