Gd³⁺:DOTA-Modified 2-Hydroxypropyl-β-Cyclodextrin/4-Sulfobutyl Ether-β-Cyclodextrin-Based Polyrotaxanes as Long Circulating High Relaxivity MRI Contrast Agents

Abstract

A family of five water-soluble Gd 3+ :1,4,7,10-tetraazacyclododecane-1,4,7-tetraacetic acid-modified polyrotaxane (PR) magnetic resonance contrast agents bearing mixtures of 2-hydroxypropyl-β-cyclodextrin and 4-sulfobutylether-β-cyclodextrin macrocycles threaded onto Pluronic cores were developed as long circulating magnetic resonance contrast agents. Short diethylene glycol diamine spacers were utilized for linking the macrocyclic chelator to the PR scaffold prior to Gd 3+ chelation. The PR products were characterized by 1 H NMR, gel permeation chromatography/ multiangle light scattering, dynamic light scattering, and analytical ultracentrifugation. Nuclear magnetic relaxation dispersion and molar relaxivity measurements at 23 °C revealed that all the PR contrast agents displayed high spin−spin T 1 relaxation and spin−lattice T 2 relaxation rates relative to a DOTAREM control. When injected at 0.05 mmol Gd/kg body weight in BALB/c mice, the PR contrast agents increased the T 1 -weighted MR image intensities with longer circulation times in the blood pool than DOTAREM. Excretion of the agents occurred predominantly via the renal or biliary routes depending on the polyrotaxane structure, with the longest circulating L81 Pluronic-based agent showing the highest liver uptake. Proteomic analysis of PR bearing different β-cyclodextrin moieties indicated that lipoproteins were the predominant component associated with these materials after serum exposure, comprising as much as 40% of the total protein corona. We infer from these findings that Gd(III)-modified PR contrast agents are promising long-circulating candidates for blood pool analysis by MRI.

Lanthanide‐Containing Rotaxanes, Catenanes, and Knots

“…Separately, Thompson and co-workers have produced and studied a family of five water soluble CD polyrotaxanes, where the CD macrocycles have also been appended with Gd-DOTA derivatives (Figure 20). [40] When injected into mice, the polyrotaxanes exhibited increased T 1 -weighted MRI intensities compared to Gd-DOTA -consistent with less rapid solution "tumbling" of the larger polyrotaxanes.…”

“…Arguably, this is provided by work that involves incorporation of kinetically stable Gd(III) complexes into (poly)rotaxane structures for magnetic resonance imaging (MRI). [38][39][40] For example, Vives, Hasenknopf and co-workers prepared cyclodextrin (CD) polyrotaxanes where each CD threaded upon a polymeric alkylammonium axle component is functionalized with either a Gd-DOTA derivative or fluorescent bodipy fragment to generate a target bimodal imaging agent (Figure 18). [38] The measured molar relaxivities for all the polyrotaxane samples prepared were greater than for the widely used Gd-DOTA, consistent with less rapid "tumbling" of the larger polyrotaxanes in solution.…”

Gd3+ Complexes Conjugated to Cyclodextrins: Hydroxyl Functions Influence the Relaxation Properties

“…Thus, a large number of bulkier ligands coordinating the Gd 3+ ion was developed to create more efficient MRI contrast agents. Gd 3+ complexes were therefore incorporated into macromolecular systems such as proteins [12][13][14][15], dendrimers [16], cyclodextrins [17], polyrotaxanes [18][19][20], etc. However, the relaxivity enhancements has been often less than those expected, due to the flexibility of the macromolecule which implies faster local motion for Gd 3+ than the overall slow motion of the entire macromolecule.…”

“…In the first two approaches, dimers, trimers [23], polymers [29], and polyrotaxanes [18][19][20] of CDs were developed in order to maximize the number of Gd 3+ complexes per molecule. For the development of platform for Ln 3+ complexation, CDs were modified, for instance, into per-3,6-anhydro derivatives, which affected their structure leading to a hydrophilic cavity capable of metal binding.…”

Threading Different Rings on X-Shaped Block Copolymers: Hybrid Pseudopolyrotaxanes of Cyclodextrins and Tetronics

“…[22][23][24] These constructs show promise, for instance for the treatment of Niemann-Pick Type C disease, [25][26][27] where 2-hydroxypropyl--cyclodextrin (HP--CD), delivered in the form of PRs, leads to improved pharmacokinetic profiles, bioavailability and larger reduction in the cholesterol pool, due to the longer circulating in blood of HP--CD threaded on a PR compared to CDs alone. 28 In comparison to Pluronics, there have been fewer studies on PPRs of poloxamines (or Tetronics), [29][30][31][32][33] a related family of blockcopolymers where the PEO and PPO blocks are arranged in a cross-shape. Poloxamines display a rich phase behaviour, determined by block length and PEO:PPO ratio, a temperature-dependent micellisation and gelation, [34][35][36][37][38] as well as pH-responsiveness due to the central diamine group.…”