Uniform and Length-Tunable, Paramagnetic Self-Assembled Nitroxide-Based Nanofibers for Magnetic Resonance Imaging

Abstract

Magnetic resonance imaging (MRI) is a widely used non-invasive medical imaging tool. Nanoparticle-based MRI contrast agents have received considerable attention due to their high loading capability for magnetic species, enhanced accumulation in lesions, and versatile surface functionalization. Anisotropic nanoparticles such as nanofibers can exhibit significant advantages over their well-explored spherical counterparts in terms of their pharmacokinetic and biodistribution profiles. Herein, we report the retrosynthetic design, synthesis, and characterization of uniform and length-tunable paramagnetic core-shell nanofibers for MRI through the use of the seeded-growth “living” crystallization-driven self-assembly (CDSA) approach. Triblock copolymer (TriBCP) precursors with a crystallizable polycarbonate core-forming segment, a nitroxide-bearing central region, and a hydrophilic poly(ethylene glycol) (PEG) terminal corona-forming segment were prepared via sequential living organocatalytic ring-opening polymerization (ROP). Low dispersity nanofibers of length ca. 80 nm relevant for biomedical applications were prepared for detailed studies by living CDSA and these possessed an average number of nitroxides per nanofiber of >8000. Subsequent evaluation of the water-proton relaxivities demonstrated that tuning the hydrophilicity of the central segment in the TriBCP allowed access to nanofibers with impressive performance compared to most existing polymer-based nitroxide-based contrast agents. As a result of their 1D morphology, the synthetic nanofibers therefore represent promising organic radical contrast agents (ORCAs) for MRI applications.

Contrast Agents Based on Human Serum Albumin and Nitroxides for 1H-MRI and Overhauser-Enhanced MRI

“…Stable organic radicals are considered an alternative to paramagnetic metal complexes such as CA for MRI [21]. Organic radical CAs (ORCAs) are compatible with standard imaging protocols, biocompatible, and biodegradable [21][22][23][24][25][26][27]. Although low-molecular radicals demonstrate low relaxivity, fast decay in vivo and are rapidly eliminated [22,[28][29][30][31][32][33], the incorporation of multiple radicals into macromolecular or supramolecular structures afforded ORCA, capable of competing with Gd complexes [23][24][25][26]28,[33][34][35].…”

“…Although low-molecular radicals demonstrate low relaxivity, fast decay in vivo and are rapidly eliminated [22,[28][29][30][31][32][33], the incorporation of multiple radicals into macromolecular or supramolecular structures afforded ORCA, capable of competing with Gd complexes [23][24][25][26]28,[33][34][35]. Various nitroxidebased systems, such as encapsulated micelles [36], functionalized polymers [26,27,37], dendrimers [24][25][26][38][39][40][41], and proteins [23], have been developed for 1 H-MRI.…”

Bottom–up on-surface synthesis based on click-functionalized peptide bundles

“…In addition, after the preparation of a rigid rod, its exposed end still has unreacted clickable groups that can be used for additional functional modifications. To illustrate this advantage, PEG, which is a polymer having excellent hydrophilicity, biocompatibility, low/non-toxicity, and broad use in imaging, 33,34 self-assembly [35][36][37] and anticancer 38,39 fields, was selected as the functional group to modify the exposed end of a rigid rod. Using CUAAC click chemistry, linear PEG (PEGalkynyl 10 kDa) with one-terminal click-functional was grafted alone on an azide-modified mica sheet, showing a height of approximately 9 nm (Fig.…”

Length-Dependent Cellular Internalization of Nanobody-Functionalized Poly(2-oxazoline) Nanorods

“…A means to overcoming this drawback was reported by Manners and co-workers who demonstrated that the inclusion of a short hydrophobic block in the polymer architecture results in the formation of an amorphous domain capable of encapsulating drugs at the core−corona interface. 21 In general, studies of crystalline-core polymer nanoparticles have shown them capable of functioning as MRI contrast agents, 22 drug/gene delivery vehicles, 18,21,23,24 antimicrobials, 25,26 and penetrating tumor spheroids, 9 further emphasizing their potential utility. Recently, our group reported the heat-induced living CDSA of poly(2-oxazoline) (POx) block copolymers in water.…”