Chiral Pyclen-Based Heptadentate Chelates as Highly Stable MRI Contrast Agents.

In recent years, pyclen-based complexes have attracted a great deal of interest as magnetic resonance imaging (MRI) contrast agents (CAs) and luminescent materials, as well as radiopharmaceuticals. Remarkably, gadopiclenol, a Gd(III) bishydrated complex featuring a pyclen-based heptadentate ligand, received approval as a novel contrast agent for clinical MRI application in 2022. To maximize stability and efficiency, two novel chiral pyclen-based chelators and their complexes were developed in this study. Gd-X-PCTA-2 showed significant enhancements in both thermodynamic and kinetic stabilities compared to those of the achiral parent derivative Gd-PCTA. 1H NMRD profiles reveal that both chiral gadolinium complexes (Gd-X-PCTA-1 and Gd-X-PCTA-2) have a higher relaxivity than Gd-PCTA, while variable-temperature 17O NMR studies show that the two inner-sphere water molecules have distinct residence times τMa and τMb. Furthermore, in vivo imaging demonstrates that Gd-X-PCTA-2 enhances the signal in the heart and kidneys of the mice, and the chiral Gd complexes exhibit the ability to distinguish between tumors and normal tissues in a 4T1 mouse model more efficiently than that of the clinical agent gadobutrol. Biodistribution studies show that Gd-PCTA and Gd-X-PCTA-2 are primarily cleared by a renal pathway, with 24 h residues of Gd-X-PCTA-2 in the liver and kidney being lower than those of Gd-PCTA.

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

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.

A novel Gd3+ DTPA-bisamide complex with high relaxivity as an MRI contrast agent.

A novel Gd(III) complex-based magnetic resonance imaging (MRI) contrast agent GdL has been designed and synthesized, which exhibited a much higher relaxivity (7.8 mM-1 s-1) than the commercially used Magnevist® (3.5 mM-1 s-1), good water solubility (>100 mg mL-1), excellent thermodynamic stability (log KGdL = 17.21 ± 0.27), high biosafety and biocompatibility. In particular, the relaxivity of GdL increased to 26.7 mM-1 s-1 in a 4.5% bovine serum albumin (BSA) solution at 1.5 T, which was not significant in other commercial MRI contrast agents. The interaction sites and interaction types of GdL and BSA were further demonstrated by molecular docking simulations. Furthermore, the in vivo MRI behaviour was evaluated by using a 4T1 tumour-bearing mouse model. These results suggested that GdL is an excellent T1-weighted MRI contrast agent and has the potential to be applied in clinical diagnosis.

Rational Design of Gd-DOTA-Type Contrast Agents for Hepatobiliary Magnetic Resonance Imaging.

The safety risks of gadolinium (Gd3+)-based contrast agents (GBCAs) arise from their inevitable leakage of Gd3+, and the pursuit of more stable GBCAs for magnetic resonance imaging (MRI) has drawn increasing attention. Yet, Gd-EOB-DTPA and Gd-BOPTA are the only two authorized GBCAs for liver diagnosis in spite of their weak stability. In this study, one of the pendent arms of the most inert commercial Gd-DOTA was decorated with phenyl moieties, in which obvious enhancements of both kinetic and thermodynamic stability were achieved. Gd-L4 with a para-substituted OBn group was observed with ready hepatocellular uptake, with significant contrast provided in diagnosing orthotopic hepatocellular carcinoma, and its hepatobiliary secretion accounted for more than 50% of the injection dose in mice. In this study, Gd-L4 was found with comparable performance in liver MRI diagnosis to that of commercial Gd-EOB-DTPA and was thus deemed as an ideal candidate for further clinical applications.

A New OATP-Mediated Hepatobiliary-Specific Mn(II)-Based MRI Contrast Agent for Hepatocellular Carcinoma in Mice: A Comparison With Gd-EOB-DTPA.

BACKGROUND: Growing concerns about the safety of gadolinium (Gd)-based contrast agents have reinforced the need for the development of Gd-free MRI contrast agents (CAs) that are effective in imaging liver tumors. PURPOSE: To evaluate the ability of Mn-BnO-TyEDTA MRI CA to detect hepatocellular carcinoma in a mouse model of implanted liver tumor. STUDY TYPE: Prospective. ANIMAL MODEL: Thirteen orthotopically implanted liver tumor mice. FIELD STRENGTH/SEQUENCE: 3.0 T/precontrast and postcontrast T1-weighted fast spoiled gradient recalled echo and T2-weighted fast recovery fast spin-echo imaging with fat suppression. ASSESSMENT: The relative enhancement ratio was calculated and statistically compared. Lesion detection in postcontrast images was analyzed by calculations of area under the curve (AUC, the increases in liver-to-tumor contrast-to-noise ratio [∆CNR] vs. time curve). Mn or Gd levels were measured in the liver and tumoral tissues by inductively coupled plasma-mass spectrometry. Tumor specimens were stained with hematoxylin and eosin (H&E) and the expression of organic anion transfer peptide (OATP)1B1 was evaluated by immunofluorescence (IF) staining and mean fluorescence intensity (MFI) was calculated. STATISTICAL TESTS: Unpaired t-test and two-tailed paired t-test. P < 0.05 was considered statistical significance. RESULTS: Mn-BnO-TyEDTA and Gd-EOB-DTPA demonstrated nearly identical enhancement patterns in the liver, tumor, and psoas muscle and no difference in lesion detection (AUC10-30, Mn  = 851 ∆CR·min, AUC10-30, Gd  = 823 ∆CR·min). A Significant higher concentration of metal (Mn or Gd) was found in the liver compared to the tumor ([Mn]liver  = 0.88 ± 0.07 µmmol/g, [Mn]tumor  = 0.49 ± 0.05 µmmol/g, [Gd]liver  = 0.65 ± 0.07 µmmol/g, [Gd]tumor  = 0.27 ± 0.04 µmmol/g). IF staining showed significantly decreased expression of OATP1B1 in the tumor core compared to the liver (MFItumor  = 5.28 ± 1.54, MFIliver  = 25.49 ± 3.41). DATA CONCLUSION: Mn-BnO-TyEDTA can provide comparable hepatobiliary tumor contrast enhancement to Gd-EOB-DTPA. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Advances in magnetic resonance imaging contrast agents for glioblastoma-targeting theranostics.

Glioblastoma (GBM) is the most aggressive malignant brain tumour, with a median survival of 3 months without treatment and 15 months with treatment. Early GBM diagnosis can significantly improve patient survival due to early treatment and management procedures. Magnetic resonance imaging (MRI) using contrast agents is the preferred method for the preoperative detection of GBM tumours. However, commercially available clinical contrast agents do not accurately distinguish between GBM, surrounding normal tissue and other cancer types due to their limited ability to cross the blood-brain barrier, their low relaxivity and their potential toxicity. New GBM-specific contrast agents are urgently needed to overcome the limitations of current contrast agents. Recent advances in nanotechnology have produced alternative GBM-targeting contrast agents. The surfaces of nanoparticles (NPs) can be modified with multimodal contrast imaging agents and ligands that can specifically enhance the accumulation of NPs at GBM sites. Using advanced imaging technology, multimodal NP-based contrast agents have been used to obtain accurate GBM diagnoses in addition to an increased amount of clinical diagnostic information. NPs can also serve as drug delivery systems for GBM treatments. This review focuses on the research progress for GBM-targeting MRI contrast agents as well as MRI-guided GBM therapy.

Real-time in situ monitoring via europium emission of the photo-release of antitumor cisplatin from a Eu-Pt complex.

A water-soluble light-responsive antitumor agent, PtEuL, based on a cisplatin-linked europium-cyclen complex has been synthesized and evaluated for controlled cisplatin release by linear/two-photon excitation in vitro with concomitant turn-on and long-lived europium emission as a responsive traceable signal.