2.2.2. In Vivo Imaging of CD-Based MRI Contrast Agents Based on the Direct Labeling of CD Cavity

In vitro studies have paved the way for a number of groups to demonstrate CD-based MRI contrast agents in vivo. Vascular imaging has long been a molecular imaging goal allowing investigators the ability to image the vasculature with high contrast. The G2/MOP–DTPA–Gd contrast agents synthesized from polyester dendrimers with β-CD core have been demonstrated with high yield and fast synthesis while providing for 2.7 times the relaxivity of Magnevist (DTPA-Gd) [24]. This contrast agent is rapidly hydrolyzed at the pH of 7.4 in the presence of esterase and slowly hydrolyzed at an acidic pH. The superior signal enhancement in vivo was observed following 0.1 mM Gd/kg injection (Figure 5a) and was significantly higher compared to Magnevist (Figure 5b) Furthermore, the G2/MOP–DTPA–Gd contrast agent (Figure 5c) did not show tissue retention, making the ideal blood pool and kidney imaging agent.

Zhou et al. synthesized Gd(III)-1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic-2-hydroxypropyl-β-CD/Pluronic polyrotaxane contrast agent [73]. Interestingly, Gd-DO3A-HPCD/Pluronic polyrotaxane construct circulated for more than 30 min in the living mouse and caused about 100-fold vascular enhancement when compared to the monomeric form (Figure 6a). Furthermore, the polyrotaxane derivative showed a much higher signal enhancement after 5 min in the heart than the monomeric form but underwent rapid elimination by renal filtration, preventing blood enhancement. Thus, the Gd(III)-DO3A-HPCD/Pluronic polyrotaxane (Figure 6b) is a promising contrast agent, which enables higher anatomic detail of blood vessel organization.

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**Figure 5.** Representative T1 weighted multislice image of the mice heart after 0.1 mM Gd/kg injection of G2/MOP–DTPA–Gd contrast (**a**) and Magnevist (**b**). The superior contrast-to-noise ratio was observed from the heart after the G2/MOP–DTPA–Gd injection. The images (**a**) and (**b**) are reprinted with permission from publisher [24]. (**c**) The molecular structure of the developed G2/MOP-DTPA-Gd CD-based contrast agent. **Figure 5.** Representative T1 weighted multislice image of the mice heart after 0.1 mM Gd/kg injection of G2/MOP–DTPA–Gd contrast (**a**) and Magnevist (**b**). The superior contrast-to-noise ratio was observed from the heart after the G2/MOP–DTPA–Gd injection. The images (**a**) and (**b**) are reprinted with permission from publisher [24]. (**c**) The molecular structure of the developed G2/MOP-DTPA-Gd CD-based contrast agent. **Figure 5.** Representative T1 weighted multislice image of the mice heart after 0.1 mM Gd/kg injection of G2/MOP–DTPA–Gd contrast (**a**) and Magnevist (**b**). The superior contrast-to-noise ratio was observed from the heart after the G2/MOP–DTPA–Gd injection. The images (**a**) and (**b**) are reprinted with permission from publisher [24]. (**c**) The molecular structure of the developed G2/MOP-DTPA-Gd CD-based contrast agent.

**Figure 6.** (**a**) T1 weighted 3D maximum intensity projection images of Balb/c mice. Mice were injected with Gd(III)-DO3A-HPCD (top row) or Gd(III) -DO3A-HPCD/Pluronic polirotaxane (bottom row) at a 0.03 mM-Gd/kg dose. Contrast agent distribution is shown in the images for pre injection and 5, 15, and 30 min after injection in to the tail vein with Gd3+ complexes. Images have been re-printed with permission from publisher [73]. (**b**) Molecular structure of the Gd(III)-DO3A-HPCD/Pluronic polirotaxane developed by Zhou et al. **Figure 6.** (**a**) T1 weighted 3D maximum intensity projection images of Balb/c mice. Mice were injected with Gd(III)-DO3A-HPCD (top row) or Gd(III) -DO3A-HPCD/Pluronic polirotaxane (bottom row) at a 0.03 mM-Gd/kg dose. Contrast agent distribution is shown in the images for pre injection and 5, 15, and 30 min after injection in to the tail vein with Gd3+ complexes. Images have been re-printed with permission from publisher [73]. (**b**) Molecular structure of the Gd(III)-DO3A-HPCD/Pluronic polirotaxane developed by Zhou et al. **Figure 6.** (**a**) T1 weighted 3D maximum intensity projection images of Balb/c mice. Mice were injected with Gd(III)-DO3A-HPCD (top row) or Gd(III) -DO3A-HPCD/Pluronic polirotaxane (bottom row) at a 0.03 mM-Gd/kg dose. Contrast agent distribution is shown in the images for pre injection and 5, 15, and 30 min after injection in to the tail vein with Gd3+ complexes. Images have been re-printed with permission from publisher [73]. (**b**) Molecular structure of the Gd(III)-DO3A-HPCD/Pluronic polirotaxane developed by Zhou et al.
