Chiral Gd-DOTA as a Versatile Platform for Hepatobiliary and Tumor Targeting MRI Contrast Agents

Abstract

The leakage of gadolinium ions (Gd3+) from commercial Gd3+-based contrast agents (GBCAs) in patients is currently the major safety concern in clinical magnetic resonance imaging (MRI) scans, and the lack of task-specific GBCAs limits its usage in the early detection of disease and imaging of specific biological regions. Herein, ultrastable GBCAs were constructed via decorating chiral Gd-DOTA with a phenylic analogue to one of the pendent arms, and the stability constant was determined as high as 27.08, accompanied by negligible decomplexation in 1 M of HCl over 2 years. A hepatic-specific chiral Gd-DOTA was screened out as a potential alternative to commercial Gd-EOB-DTPA, while combination with functional molecules favored chiral Gd-DOTA as tumor targeting probes. Therefore, the novel chiral Gd-DOTA is believed to be an ideal platform for designing the next generation of GBCAs for various clinical purposes due to its outstanding inert nature.

Lipophilic Group-Modified Manganese(II)-Based Contrast Agents for Vascular and Hepatobiliary Magnetic Resonance Imaging

“…Since serum albumin exists at concentrations ranging from 3.5 to 5.0% in plasma, the relaxivities of the contrast agents were measured in a solution of 4.5% bovine serum albumin (BSA) to assess contrast agent binding to BSA . It was shown in Figure that the relaxivity of Gd-EOB-DTPA in the solution of BSA is slightly elevated, with r 1 being approximately 1.2-fold of that in tris buffer, which is consistent with reported literature. , In contrast, the addition of BSA resulted in an obvious increase in the relaxivity of MnL1–11 to about 200–300%. According to the literature, the increase in field strength diminishes the ability to enhance relaxivity due to the prolonged rotational correlation time. ,, For example, the relaxivity of Mn­(PC2A-BP) increases from 3.8 to 35.7 Mn mM –1 s –1 at 0.49 T (20 MHz), 37 °C in the presence of 4.62% human serum albumin, but it decreases to about 15 Mn mM –1 s –1 at 60 MHz (∼1.41 T field strength), whose performance at the higher field strength is similar to that of MnL6 .…”

“…The OATP family includes OATP1B1, OATP1B3, and OATP2B1, as well as Na + -dependent taurocholate transporter polypeptide (NTCP), among which the expression of OATP1B1 and OATP1B3 is relatively high. ,, In order to further understand the pathway by which the OATPs system exerts a transport effect on MnL6 , we performed molecular docking simulations of MnL6 using Autodock 4.2 with MnL2 , MnL3 , and Gd-EOB-DTPA as a control, and the crystal structures of the proteins used were referenced from the previous literature. ,, …”

“…The est. log P of Gd-EOB-DTPA was 0.74, which is consistent with the previous literature, and that of MnLs ranged from −1.02 to 1.04, respectively. ,, The est. log P of MnLs is affected by the lipophilic substituents.…”

“…This method was used for both HPLC purity validation and estimated log P determination, referring to previous literature. ,, Briefly, UV detection was performed at 250 or 279 nm using an Agilent 1100 series HPLC with a UV detector. Welch Xtimate C4 (3 μm, 120 Å, 150 mm × 4.6 mm) was used, and the method was as follows: eluent A, a 10 mM ammonium acetate aqueous solution, and eluent B, a mixture of 90% acetonitrile and 10% of eluent A. Gradient: 5% B from 0 to 1 min, 5 to 50% B from 1 to 10 min, 50–95% B from 10 to 11 min, 95% B from 11 to 12 min, 95 to 5% B from 12 to 13 min, and 5% B from 13 to 15 min.…”

“…Contrast agents (CAs) are indispensable in magnetic resonance imaging (MRI) in order to improve the sensitivity for detecting lesions, and in fact, more than one-third of MRIs are performed with the assistance of CAs . Due to their excellent T1 enhancement effect, gadolinium-based contrast agents (GBCAs) with linear or macrocyclic ligands have been the focus in both preclinical and clinical applications. , However, the extensive usage has revealed potential safety concerns with GBCAs. − The leakage of gadolinium ions from the ligands has caused nephrogenic systemic fibrosis in patients with chronic kidney disease, and the subsequent discovery of gadolinium deposition in the brain and bones led to additional restrictions with strict regulation. , Despite the suspension of several linear GBCAs by the European Medicines Agency, Gd-EOB-DTPA and Gd-BOPTA with linear ligands continue to be used in clinics for hepatobiliary imaging . This makes it increasingly attractive to design novel macrocyclic GBCAs or to find gadolinium-free alternatives with hepatobiliary-specific imaging capabilities. ,− …”