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.

Design and synthesis of chiral DOTA-based MRI contrast agents with remarkable relaxivities.

Due to the adverse effects of de-metallation in past concerning FDA-approved gadolinium-based contrast agents (GBCAs), researchers have been focusing on developing safer and more efficient alternatives that could avoid toxicity caused by free gadolinium ions. Herein, two chiral GBCAs, Gd-LS with sulfonate groups and Gd-T with hydroxyl groups, are reported as potential candidates for magnetic reasonance imaging (MRI). The r1 relaxivities of TSAP, SAP isomers of Gd-LS and SAP isomer of Gd-T at 1.4 T, 37 °C in water are 7.4 mM-1s-1, 14.5 mM-1s-1 and 5.2 mM-1s-1, respectively. Results show that the hydrophilic functional groups introduced to the chiral macrocyclic scaffold of Gd-T and Gd-LS both give constructive influences on the second-sphere relaxivity and enhance the overall r1 value. Both cases indicate that the design of GBCAs should also focus on the optimal window in Solomon-Bloembergen-Morgan (SBM) theory and the effects caused by the second-sphere and outer-sphere relaxivity.

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.

Stereoselective Construction of Unsymmetrically Linked Heterocycles via Palladium-Catalyzed Alkyne Insertion/Cycloimidoylation Cascade.

A novel strategy to access unsymmetrically linked heterocycles via palladium-catalyzed acylcycloimidoylation of alkyne-tethered carbamoyl chlorides with isocyanides has been developed. Functionalized isocyanides were successfully applied as imine-containing heterocycle precursors to capture the vinyl-PdII intermediate, which was generated from a syn-carbopalladation of alkyne, followed by subsequent intramolecular C-H bond activation/imidoylative Heck reactions. Methylene oxindoles within Z-tetrasubstituted olefins were obtained in high yields with excellent stereoselectivities. Broad functional groups were well tolerated under mild reaction conditions.

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.

A Vehicle-Free Antimicrobial Polymer Hybrid Gold Nanoparticle as Synergistically Therapeutic Platforms for Staphylococcus aureus Infected Wound Healing.

Pathogenic bacteria infection is a serious threat to human public health due to the high morbidity and mortality rates. Nano delivery system for delivering antibiotics provides an alternative option to improve the efficiency compared to conventional therapeutic agents. In addition to the drug loading capacity of nanocarriers, which is typically around 10%, further lowers the drug dose that pathological bacteria are exposed to. Moreover, nanocarriers that are not eliminated from the body may cause side effects. These limitations have motivated the development of self-delivery systems that are formed by the self-assembly of different therapeutic agents. In this study, a vehicle-free antimicrobial polymer polyhexamethylene biguanide (PHMB, with bactericidal and anti-biofilm functions) hybrid gold nanoparticle (Au NPs, with photothermal therapy (PTT)) platform (PHMB@Au NPs) is developed. This platform exhibits an excellent synergistic effect to enhance the photothermal bactericidal effect for Staphylococcus aureus under near-infrared irradiation. Furthermore, the results showed that PHMB@Au NPs inhibit the formation of biofilms, quickly remove bacteria to promote wound healing through PTT in infection model in vivo, and even mediate the transition of macrophages from M1 to M2 type, and accelerate tissue angiogenesis. PHMB@Au NPs will have promising value as highly effective antimicrobial agents for patient management.

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.

Reaction-based chemosensor as dual-channel indicator for visualizing and bioimaging of exogenous hypochlorite concentrations in living cells, Pseudomonas aeruginosa, and zebrafish.

Tracking and quantifying hypochlorite (ClO-) in biological systems and environments remain challenging tasks, and many efforts have been made to improve ClO- recognition performance by modifying the sensor structure. In this study, a pre-designed coumarin/furanohydrazide-based sensor (CMFH) with the coumarin moiety as the building block (fluorogen) was rationally prepared as a ratiometric and colorimetric chemosensor for ClO- recognition. As expected, CMFH demonstrated excellent sensitivity and selectivity for ClO- detection. The fluorescence signal ratio (F466/F556) showed strong ClO- dependency, and the sensor exhibited ultrafast detection (within 60 s) and a low detection limit of 563 nM. Due to its low cytotoxicity and good tissue permeability, CMFH was demonstrated as a dual-channel sensor for ClO- bioimaging and visualization in cells, zebrafish, and even bacteria. Furthermore, CMFH-loaded paper strips were successfully applied to the colorimetric and fluorescent visualization of ClO-. The results demonstrate that CMFH has potential application value for tracking ClO- in various biosystems and environments.

Design of Functional Chiral Cyclen-Based Radiometal Chelators for Theranostics.

A series of water-soluble chiral cyclen-based chelators with chemical handles for selective targeting have been synthesized (cyclen = 1,4,7,10-Tetraazacyclododecane). Optical studies, relaxivity measurements, and competitive titrations were performed to show the versatility of these chiral chelators. The complexations of L3, L4, and L5 with Lu3+, Y3+, Sc3+, and Cu2+ were successfully demonstrated in around 90% to 100% yields. Efficient and rapid radiolabeling of L5 with 177Lu was achieved under mild conditions with 96% yield. The chelators exhibit near quantitative labeling efficiencies with a wide range of radiometal ions, which are promising for the development of targeting specific radiopharmaceutical and molecular magnetic resonance imaging contrast agents.

Unusual Magnetic Field Responsive Circularly Polarized Luminescence Probes with Highly Emissive Chiral Europium(III) Complexes.

Chirality is ubiquitous within biological systems where many of the roles and functions are still undetermined. Given this, there is a clear need to design and develop sensitive chiral optical probes that can function within a biological setting. Here we report the design and synthesis of magnetically responsive Circularly Polarized Luminescence (CPL) complexes displaying exceptional photophysical properties (quantum yield up to 31 % and |glum | up to 0.240) by introducing chiral substituents onto the macrocyclic scaffolds. Magnetic CPL responses are observed in these chiral EuIII complexes, promoting an exciting development to the field of magneto-optics. The |glum | of the 5 D0 → 7 F1 transition increases by 20 % from 0.222 (0 T) to 0.266 (1.4 T) displaying a linear relationship between the Δglum and the magnetic field strength. These EuIII complexes with magnetic CPL responses, provides potential development to be used in CPL imaging applications due to improved sensitivity and resolution.

Synthesis of Water-Soluble Chiral DOTA Lanthanide Complexes with Predominantly Twisted Square Antiprism Isomers and Circularly Polarized Luminescence.

One-step cyclization of a tetraazamacrocycle 5 with 70% yield in a 25-g scale was performed. Its chiral DOTA derivatives, L4, has ∼93% of TSAP coordination isomer in its Eu(III) and Yb(III) complexes in aqueous solution. [GdL4]5- exhibits a high relaxivity, making it a promising and efficient MRI contrast agent. High luminescence dissymmetry factor (glum) values of 0.285 (ΔJ = 1) for [TbL3]- and 0.241 (ΔJ = 1) for [TbL4]5- in buffer solutions were recorded.

Breaking the 1,2-HOPO barrier with a cyclen backbone for more efficient sensitization of Eu(iii) luminescence and unprecedented two-photon excitation properties.

A cyclen backbone was utilized to study the effect of backbone rigidity on Eu(iii) luminescence sensitization using a 1,2-HOPO derivative and 2-thenoyltrifluoroacetonate (TTA) as chromophores. The restriction of molecular movement of Eu-Cy-HOPO brought about by the increased rigidity provided a tightly packed coordination environment for the octadentate Eu(iii) center which resulted in the highest overall quantum yield (30.2%) and sensitization efficiency (64.6%) among 1,2-HOPO sensitized Eu(iii) complexes. Eu-Cy-HOPO is also the first 1,2-HOPO-based lanthanide complex to emit Eu(iii) luminescence under two-photon excitation.

Chiral DOTA chelators as an improved platform for biomedical imaging and therapy applications.

Despite established clinical utilisation, there is an increasing need for safer, more inert gadolinium-based contrast agents, and for chelators that react rapidly with radiometals. Here we report the syntheses of a series of chiral DOTA chelators and their corresponding metal complexes and reveal properties that transcend the parent DOTA compound. We incorporated symmetrical chiral substituents around the tetraaza ring, imparting enhanced rigidity to the DOTA cavity, enabling control over the range of stereoisomers of the lanthanide complexes. The Gd chiral DOTA complexes are shown to be orders of magnitude more inert to Gd release than [GdDOTA]-. These compounds also exhibit very-fast water exchange rates in an optimal range for high field imaging. Radiolabeling studies with (Cu-64/Lu-177) also demonstrate faster labelling properties. These chiral DOTA chelators are alternative general platforms for the development of stable, high relaxivity contrast agents, and for radiometal complexes used for imaging and/or therapy.

New Class of Bright and Highly Stable Chiral Cyclen Europium Complexes for Circularly Polarized Luminescence Applications.

High glum values of +0.30 (ΔJ = 1, 591 nm, in DMSO) and -0.23 (ΔJ = 1, 589 nm, in H2O) were recorded in our series of newly designed macrocyclic europium(III) complexes. A sterically locking approach involving a bidentate chromophore is adopted to control the formation of one stereoisomer, giving rise to extreme rigidity, high stability, and high emission intensity. The combination of a chiral substituent on a macrocyclic chelate for lanthanide ions opens up new perspectives for the further development of circulary polarized luminescent chiral tags in optical and bioapplications.

A smart "off-on" gate for the in situ detection of hydrogen sulphide with Cu(ii)-assisted europium emission.

A water-soluble and emissive Eu-complex (EuL1) bearing a DO3A(Eu3+)-pyridine-aza-crown motif has been prepared and its Cu2+ complex has been demonstrated to be a smart luminescence "off-on" gate for H2S detection in water with a nano-molar detection limit (60 nM). EuL1 binds to Cu2+ ions selectively (KB = 1.2 × 105 M-1) inducing 17-fold luminescence quenching and forming a 1 : 1 stoichiometric complex (EuL1-Cu2+), which responds to H2S selectively with restoration of the original Eu emission of EuL1 followed by a further 40-fold luminescence enhancement, forming a 1 : 1 stoichiometric complex (EuL1-Na2S, KB = 1.5 × 104 M-1). Without Cu2+ ions, EuL1 showed non-specific binding towards H2S with only a 5-fold luminescence enhancement.

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.