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. 2018 Nov 21;29(11):3550-3560.
doi: 10.1021/acs.bioconjchem.8b00525. Epub 2018 Nov 7.

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

Yawo A Mondjinou, Bradley P Loren, Christopher J Collins, Seok-Hee Hyun, Asher Demoret, Joseph Skulsky, Cheyenne Chaplain, Vivek Badwaik, David H Thompson

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

Yawo A Mondjinou et al. Bioconjug Chem. .

Abstract

A family of five water-soluble Gd3+: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 Gd3+ chelation. The PR products were characterized by 1H 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 T1 relaxation and spin-lattice T2 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 T1-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.

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Figures

Figure 1.
Figure 1.
Structure of Gd:DOTA-HPβCD/SBEβCD Pluronic-based polyrotaxane contrast agents with cholesteryl endcaps. Blue conical structure = HPβCD. Yellow conical structure = SBEβCD. Pluronic cores = F127 (m = 200, n = 65); F68 (m = 151, n = 29); L35 (m = 21, n = 16); L64 (m = 26, n = 30); L81 (m = 6, n = 43).
Figure 2.
Figure 2.
1H NMRD spectra of Gd:DOTA-HPβCD/SBEβCD Pluronic F127, F68, L35, and L81 polyrotaxanes.
Figure 3.
Figure 3.
Relaxivity determinations (A, r1; B, r2) of Gd:DOTA-HPβCD/SBEβCD Pluronic polyrotaxanes and DOTAREM at 7 T, 25 °C. Blue: F127; Red, L81; Purple: F68; Yellow: L35; Aqua: L64; Green: DOTAREM.
Figure 4.
Figure 4.
3D Maximum intensity projections of Balb/c mice recorded at 7 T before and after tail vein injection of 0.05 mmol Gd/kg body weight of DOTAREM and Gd:DOTA-HPβCD/SBEβCD PR MR contrast agents. Images were recorded using a T1-weighted 3D gradient echo sequence.
Figure 4.
Figure 4.
3D Maximum intensity projections of Balb/c mice recorded at 7 T before and after tail vein injection of 0.05 mmol Gd/kg body weight of DOTAREM and Gd:DOTA-HPβCD/SBEβCD PR MR contrast agents. Images were recorded using a T1-weighted 3D gradient echo sequence.
Figure 5.
Figure 5.
Normalized intensities of Gd:DOTA-HPβCD/SBEβCD Pluronic PR contrast agents and DOTAREM control. Aqua diamonds, DOTAREM; Red squares, F127; Green triangles, L35; Purple crosses, L81; Blue crosses, F68.
Figure 6.
Figure 6.
Total protein adsorption onto Gd:DOTA-HPβCD/SBEβCD PR (left) and L81-based PR Containing Different βCD Derivatives (right) as Determined by Total MS Ion Current. Inset: Ordinate expansion to emphasize the differences in protein deposition onto L81-based PR containing different βCD derivatives.
Figure 7.
Figure 7.
Average Percentage of PR Protein Corona as a Function of L81 PR Type.
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