Synthesis of Gadolinium-Labeled Shell-Crosslinked Nanoparticles for Magnetic Resonance Imaging Applications

Abstract

Shell‐crosslinked knedel‐like nanoparticles (SCKs; “knedel” is a Polish term for dumplings) were derivatized with gadolinium chelates and studied as robust magnetic‐resonance‐imaging‐active structures with hydrodynamic diameters of 40 ± 3 nm. SCKs possessing an amphiphilic core–shell morphology were produced from the aqueous assembly of diblock copolymers of poly‐(acrylic acid) (PAA) and poly(methyl acrylate) (PMA), PAA52–b–PMA128, and subsequent covalent crosslinking by amidation upon reaction with 2,2′‐(ethylenedioxy)bis(ethylamine) throughout the shell layer. The properties of these materials, including non‐toxicity towards mammalian cells, non‐immunogenicity within mice, and capability for polyvalent targeting, make them ideal candidates for utilization within biological systems. The synthesis of SCKs derivatized with GdIII and designed for potential use as a unique nanometer‐scale contrast agent for MRI applications is described herein. Utilization of an amino‐functionalized diethylenetriaminepentaacetic acid–Gd analogue allowed for direct covalent conjugation throughout the hydrophilic shell layer of the SCKs and served to increase the rotational correlation lifetime of the Gd. In addition, the highly hydrated nature of the shell layer in which the Gd was located allowed for rapid water exchange; thus, the resulting material demonstrated large ionic relaxivities (39 s–1 mM–1) in an applied magnetic field of 0.47 T at 40 °C and, as a result of the large loading capacity of the material, also demonstrated high molecular relaxivities (20 000 s–1 mM–1).

Enhancement of Relaxivity Rates of Gd–DTPA Complexes by Intercalation into Layered Double Hydroxide Nanoparticles

“…[1,6,7] Some macromolecular ligands have been designed to contain many Gd III atoms and to have a relatively long molecular tumbling time and an optimal exchange rate of the coordinated water molecule (see Figure 1), leading to higher proton relaxivities. [1,7,9,10] Recently, new efforts involving the incorporation of Gd …”

“…The improvement can be achieved by elongating the rotational correlation lifetime of the nuclear ions [1,7] and optimizing the water exchange rate. [8][9][10][11][12][13][14] Currently, considerable effort is being dedicated to designing new ligand structures, including macrocyclic, polymeric and dendritic frameworks with various functional groups, such as carboxylates, aminos/iminos, phosphates, to increase the rotational correlation lifetime. [1,6,7] Some macromolecular ligands have been designed to contain many Gd III atoms and to have a relatively long molecular tumbling time and an optimal exchange rate of the coordinated water molecule (see Figure 1), leading to higher proton relaxivities.…”

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents1

“…The first two parameters have been optimized successfully in Gd hydroxypyridonate (HOPO) based contrast agents, and when attached to macromolecules relaxivities as high as 200 mM -1 s -1 per Gd (peaking between 20-100 MHz, with q = 2, r Gd-H = 3.1 and electronic relaxation times T 1e = 15 ns, T 2e = 0.3 ns) can theoretically be obtained for these complexes. 7 For HOPO based and other complexes, relaxivity enhancement has been demonstrated through the attachment of contrast agents to proteins, [8][9][10] polypeptides, 11 dendrimers, 12,13 nanospheres, 14 and micellar nanoparticles. [15][16][17] Nanometer scale contrast agents also offer the potential to differentiate non-nervous-system tissue.…”

State of Art on Bioimaging by Nanoparticles in Hyperthermia and Thermometry: Visualization of Tissue Protein Targeting

“…However, saturation magnetization of the particles was decreased with increased Gd proportion. The initial increase in the saturation magnetization can be speculated that the Gd 3+ ions have a large spin magnetic moment per atom (7 B) as compared to that of Fe 3+ ion (5 B) [93][94][95].…”