Highly ordered supramolecular nanoassemblies of paramagnetic amphiphilic chelates as potential MRI contrast agents

Supramolecular self-assembled nanoparticles, hereafter referred to as nanoassemblies, made of lipid-based amphiphiles have been extensively studied for drug delivery[1–3] and diagnostic magnetic resonance imaging (MRI)[4–6] applications. Nanoassemblies of paramagnetic amphiphilic chelates, in particular, have many properties deemed necessary for an ideal MRI contrast agent. These include significantly improved contrast enhancement efficiency due to slow molecular reorientation, ability to deliver high payloads of paramagnetic metal ions, ease of altering their sizes by extruding them through polycarbonate filters, ability to passively target tumours through enhanced permeation and retention, and the ability to incorporate (active) targeting moieties or therapeutic drugs, or both, within their framework to form combined therapeutic and diagnostic (theranostic) nanomedicines.[5,7] Most previous studies on the nanoassemblies of paramagnetic amphiphilic chelates have reported on micelles[8–10] or liposomes[6,11–15] obtained by the self-assembly of either sole paramagnetic amphiphilic chelates or mixtures of paramagnetic amphiphilic chelates, commercial phospholipids, and targeting moieties. Compared with liposomes or micelles, nanoassemblies of highly ordered interior nanostructures such as inverse cubosomes and hexosomes can provide a much higher payload of paramagnetic metal ions, especially if they are obtained by the self-assembly of sole paramagnetic amphiphiles. In addition, their intricate water channels may allow the coordinated paramagnetic metal ions a better access to interact with water molecules, thus resulting in improved efficiency. However, usually it is challenging to design paramagnetic molecules to obtain such nanoassemblies, primarily due to the large hydrophilic head group (paramagnetic chelate) which inherently results in amphiphiles with a small critical packing parameter (CPP < 1) (Fig. 1).[16] Some recent examples of obtaining stable nanoassemblies of paramagnetic amphiphilic chelates with highly ordered interior nanostructures are discussed below along with recent reports on the design, synthesis, and characterisation of paramagnetic amphiphilic chelates offering a high CPP (≥1), which thus far has been deemed to be difficult.