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Recent advances in the use of radiometals for both imaging and therapy has spurred on the development of an original chemistry that endows radionuclide-chelating molecular cages with ever sharper physicochemical properties. Macrocyclic polyamines (MPAs) such as cyclen and DOTA are among the most frequently encountered cages for the design of new radiotracers, owing to their versatile chemistry that makes them customizable molecular tools. The idea of using MPAs for alternative purposes has recently emerged, with an eye towards benefiting from their unique topology, versatility, symmetry and water-solubility. This review summarizes strategies that have been recently implemented in which MPAs are used as multivalent molecular platforms for constructing sophisticated suprastructures that found applications in various fields, from material chemistry to chemical biology. These original approaches are invaluable in that they successfully expand the scope of applications of MPAs far beyond their restricted roles of metal chelating appendages.

Lithium amide [(Me 3 TACD)Li] 2 derived from the NNNN macrocycle (Me 3 TACD)H ((Me 3 TACD)H = 1,4,7-trimethyl-1,4,7,10-tetraazacyclododecane) reacted with DIBAL(H) to give the lithium hydridoaluminate [(Me 3 TACD·AlH i Bu 2 )Li(THF)] ( 1 - THF ). With HBPin, the lithium hydridoborate [(Me 3 TACD·HBPin)Li] ( 2 ) was obtained. Both compounds have been characterized by multinuclear NMR spectroscopy and single crystal X-ray diffraction. The monomeric structure contains a five-coordinate lithium and does not show any interaction between the lithium center and the hydride.

We present a detailed study of the lanthanide(III) complexes with cyclen-based ligands containing phenylacetamide pendants that incorporate CF3 group(s) at different distances from the metal ion. The complexes exhibit square-antiprismatic coordination in solution, as demonstrated by analysis of the Yb3+-induced paramagnetic shifts and the X-ray structure of the [YbL3] complex. Luminescence lifetime measurements and a detailed 1H and 17O relaxometric characterization confirmed the presence of an inner-sphere H2O molecule. The Tm3+ complexes provide chemical-exchange saturation-transfer response upon saturation at the frequency of the amide protons. A 19F relaxation study provided accurate estimates of the Ln···F distances that were used to rationalize the efficiency of the complexes as 19F magnetic resonance imaging (MRI) probes, which was tested in vitro using MRI phantom studies.

A total of 44 bis-aryl-monocyclic polyamines, monoaryl-monocyclic polyamines and their transition metal complexes were prepared, chemically characterized, and screened in vitro against the Leishmania donovani promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells. The IC(50) and/or IC(90) values showed that 10 compounds were similarly active at about 2-fold less potent than known drug pentamidine against promastigotes. The most potent compound had an IC(50) of 2.82 μM (compared to 2.93 μM for pentamidine). Nine compounds were 1.1–13.6-fold more potent than pentamidine against axenic amastigotes, the most potent one being about 2-fold less potent than amphotericin B. Fourteen compounds were about 2–10 fold more potent than pentamidine, the most potent one is about 2-fold less potent than amphotericin B against intracellular amastigotes in THP1 cells. The 2 most promising compounds (FeL7Cl(2) and MnL7Cl(2)), with strong activity against both promastigotes and amastigotes and no observable toxicity against the THP1 cells are the Fe(2+)- and Mn(2+)- complexes of a dibenzyl cyclen derivative. Only 2 of the 44 compounds showed observable cytotoxicity against THP1 cells. Tetraazamacrocyclic monocyclic polyamines represent a new class of antileishmanial lead structures that warrant follow up studies.

We present two novel octadentate cyclen-based ligands bearing one (L1 ) or two (L2 ) phenylacetamide pendants with two CF3 groups either at positions 3 and 5 (L1 ) or 4 (L2 ). The corresponding Gd3+ complexes possess one coordinated water molecule, as confirmed by luminescence lifetime measurements on the EuIII and TbIII analogues. A detailed 1 H and 17 O relaxometric characterization has revealed the parameters that govern the relaxivities of these complexes. The water-exchange rate of the mono-amide derivative GdL1 (kex298 =1.52×106 s-1 ) is faster than that determined for the bis-amide complex GdL2 (kex298 =0.73×106 s-1 ). 1 H and 19 F NMR studies have indicated that the complexes are present in solution almost exclusively as the square-antiprismatic (SAP) isomers. 19 F NMR relaxation studies indicated Gd⋅⋅⋅F distances of 7.4±0.1 and 9.1±0.1 A for GdL1 and GdL2 , respectively. Phantom MRI studies revealed the favorable properties of GdL2 as a dual 1 H/19 F magnetic resonance imaging (MRI) probe, whereas the shorter Gd⋅⋅⋅F distance of GdL1 reduces the signal-to-noise ratio due to the very short transverse relaxation time of the 19 F NMR signal.

The new transition-metal oxothiostannate [Ni(cyclen)(H2O)2]4[Sn10S20O4]·∼13H2O (1) was prepared under hydrothermal conditions using Na4SnS4·14H2O as the precursor in the presence of [Ni(cyclen)(H2O)2](ClO4)2·H2O. Compound 1 comprises the [Sn10S20O4]8– anion constructed by the T3-type supertetrahedron [Sn10S20] and the [Sn10O4] anti-T2 cluster. Channels host the H2O molecules, and the sample can be reversibly dehydrated and rehydrated without significantly affecting the crystallinity of the material. 119Sn NMR spectroscopy of an aqueous solution of Na4SnS4·14H2O evidences that between 25 and 120 °C only [SnS4]4– and [Sn2S6]4– anions are present. In further experiments, hints were found that the formation of tin oxosulfide ions depends on the Ni2+-centered complexes. Compound 1 exhibits promising photocatalytic properties for the visible-light-driven hydrogen evolution reaction, with 18.7 mmol·g–1 H2 being evolved after 3 h.

A cyclen-based hybrid supermolecule crystal, [(FeCl2 )(cyclen)]Cl (1), where cyclen=1,4,7,10-tetraazacyclododecane, was prepared using a liquid-liquid diffusion approach. The variable crystal structures exhibit that compound 1 belongs to an orthorhombic crystal system, Pna21 space group (point group C2V ) in the temperature range of 150-400 K. This hybrid supermolecule shows a dielectric relaxation behavior around room temperature, and the ferroelectric nature of 1 has been directly verified by hysteresis measurements. In addition, the AC (alternating current) conductivity study reveals that the 1 displays a beyond limiting behavior. These interesting findings are for the first time reported in the field of supermolecular ferroelectrics. This study may open a new way to construct supermolecular ferroelectrics and give insights into their conductor behavior.

The pyridinophane molecule L2 (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-trien-13-ol) has shown promise as a therapuetic for neurodegenerative diseases involving oxidative stress and metal ion misregulation. Protonation and metal binding stability constants with Mg(2+), Ca(2+), Cu(2+), and Zn(2+) ions were determined to further explore the therapeutic and pharmacological potential of this water soluble small molecule. These studies show that incorporation of an –OH group in position 4 of the pyridine ring decreases the pI values compared to cyclen and L1 (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-triene). Furthermore, this approach tunes the basicity of the tetra-aza macrocyclic ligand through the enhanced resonance stabilization of the –OH in position 4 and rigidity of the pyridine ring such that L2 has increased basicity compared to previously reported tetra-aza macrocycles. A metal binding preference for Cu(2+), a redox cycling agent known to produce oxidative stress, indicates that this would be the in vivo metal target of L2. However, the binding constant of L2 with Cu(2+) is moderated compared to cyclen due to the rigidity of the ligand and shows how ligand design can be used to tune metal selectivity. An IC(50)=298.0 µM in HT-22 neuronal cells was observed. Low metabolic liability was determined in both Phase I and II in vitro models. Throughout these studies other metal binding systems were used for comparison and as appropriate controls. The reactivity reported to date and pharmacological features described herein warrant further studies in vivo and the pursuit of L2 congeners using the knowledge that pyridine substitution in a pyridinophane can be used to tune the structure of the ligand and retain the positive therapeutic outcomes.

We reported a set of water-soluble transition metal complexes that can serve as both 19F and PARACEST magnetic resonance imaging agents. The high number of equivalent fluorine atoms and the paramagnetic effect of metals offer these complexes high 19F sensitivity as demonstrated by in vitro19F MRI experiments. The complexes contain carboxamide groups appended onto a cyclen macrocycle, which provide 1H CEST peaks well differentiated from bulk water. The Co(ii) agent displays two CEST peaks that can be utilized for ratiometric pH determination and the concept of combining 19F MR and PARACEST as complementary imaging techniques was demonstrated with the Fe(ii) complex.

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.

The first examples of 1,7-orthogonally diprotected cyclen (1,4,7,10-tetraazacyclododecane) derivatives have been prepared through a straightforward and convenient synthetic strategy. These compounds represent useful starting materials for the preparation of several functionalised macrocyclic chelating agents.

The unique properties of 1,4,7,10-tetraazacyclododecane (cyclen) make it not only a suitable polyamine headgroup in cationic lipids for gene delivery, but also a good host molecule for metal coordination. In this study, a series of cyclen-based lipids and their Zn(II)-complexes were synthesized to study the effect of Zn-coordination on the gene transfection. Both the Zn-free and Zn-containing lipids could form nano-sized particles with suitable positive potential to condense and protect DNA from degradation by DNase. More importantly, Zn coordination could significantly reduce the cytotoxicity of the liposomes. Meanwhile, the gene transfection efficiency of the cyclen-based lipids could also be distinctly improved by the Zn-coordination. Mechanistic studies reveal that the Zn-free and Zn-containing liposomes showed similar cellular uptake properties. However, confocal microscopy shows that Zn-containing liposomes may induce more efficient endosomal escape than the Zn-free counterpart, which could be attributed to their much higher pH buffering capacity. This study presents an efficient strategy to enhance the gene transfection efficiency and biocompatibility of cyclen-based cationic lipids.

Molecular robot provides a promising way to receive response signals and make decisions with intelligent information processing at the molecule level. In this work, a molecular robot prototype based on a europium(III)-cyclen complex (EuL) was designed and assembled, consisting of multiplex sensing and information processing in a single system. By utilizing the Eu3+ ion as a central processing unit (CPU) and terpyridine (Terpy) group as an arm of the molecular robot, multiplex detection function of this molecular robot can be accomplished in three test channels: the detection of Fe2+ with UV-vis, Zn2+ using photoluminescence, and Mn2+ using magnetic resonance imaging. The optimized structures revealed that the transition metal ions bound by the arms of two EuL molecules formed a hexacoordination octahedral rigidity structure in the adducts. For the structure of L and EuL, three pyridine rings of Terpy unit were not in a plane, and they were fixed to form a plane when captured the transition metal ions during the formation of the adducts. In addition, three different modes of molecular logic devices (OR, INHIBIT, and YES) were established based on relevant signals in the multiplex detection channels. The sensing of metal ions in human urine using EuL was also carried out, and the result demonstrated the presence of good recoveries and high analytical precision. Such a molecular robot prototype is expected to be used in intelligent medical diagnostics and, in particular, information processing at molecular level.

The cationic ZnII part of aqua(1,4,7,10-tetraazacyclododecane)zinc(II) bis(perchlorate), [Zn(C8H20N4)(H2O)](ClO4)2, exhibits a slightly distorted square-pyramidal coordination environment with a water molecule in the apical position. In the crystal, the macrocyclic ring alternates between two conformations with equal occupancies. Two of the three perchlorate anions are situated about a twofold rotation axis, and one of them shows disorder of the O atoms with occupancies of 0.62 (7) and 0.38 (7). In the crystal, the complexes are connected by intermolecular hydrogen bonding via the perchlorate anions.

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.

An ideal chelator for f-elements features rapid kinetics of complexation, high thermodynamic stability, and slow kinetics of dissociation. Here we present the facile synthesis of a macrocyclic ligand bearing four 1-hydroxy-2-pyridinone units linked to a cyclen scaffold that rapidly forms thermodynamically stable complexes with lanthanides (Sm3+ , Eu3+ , Tb3+ , Dy3+ ) and a representative late actinide (Cm3+ ) in aqueous media and concurrently sensitizes them. Extended X-ray absorption fine structure (EXAFS) spectroscopy revealed an increase in the Ln/An-O bond lengths following the trend Cm>Eu>Tb and EXAFS data were compatible with time-resolved luminescence studies, which indicated one to two water molecules in the inner metal coordination sphere of Eu(III) and two water molecules for the Cm(III) complex. Spectrofluorimetric ligand competition titrations against DTPA confirmed the high thermodynamic stability of DOTHOPO complexes, with pM values between 19.9(1) and 21.9(2).

International audience; The synthesis through click chemistry of triethoxysilylated cyclen derivative-based ligands is described. Different methods were used such as the copper catalyzed Huisgen's reaction, or thiol-ene reaction for the functionalization of the cyclen scaffold with azidopropyltriethoxysilane or mercaptopropyltriethoxysilane, respectively. These ligands were then grafted on magnetic mesoporous silica nanoparticles (MMSN) for extraction and separation of Ni(II) and Co(II) metal ions from model solutions. The bare and ligand-modified MMSN materials revealed high adsorption capacity (1.0-2.13 mmol g À1) and quick adsorption kinetics, achieving over 80% of the total capacity in 1-2 hours.

Background Lead-212 (212Pb, t1/2 = 10.6 h) and lead-203 (203Pb, t1/2 = 51.9 h) are an element-equivalent, or a matched theranostic radioisotope pair that show great potential for application in targeted radionuclide therapy (TRT) and single-photon emission computed tomography (SPECT), respectively. At TRIUMF we have produced both 203Pb and 212Pb using TRIUMF’s TR13 (13 MeV) and 500 MeV cyclotrons, and subsequently purified and evaluated both radioisotopes using a series of pyridine-modified DOTA analogues in comparison to the commercially available chelates DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and TCMC (1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane). Results Proton irradiation (12.8 MeV) of natural and enriched thallium-203 (203Tl) targets gave 203Pb saturation yields of 134 ± 25 and 483 ± 3 MBq/μA, respectively. Thorium-228 (228Th, t1/2 = 1.9 y), a by-product of 232Th proton spallation on TRIUMF’s main 500 MeV beamline (beamline 1A, BL1A), was recovered to build a 228Th/212Pb generator with the ability to deliver up to 9–10 MBq of 212Pb daily. Both lead isotopes were purified via solid phase extraction chromatography (Pb resin), and isolated in an acetate form ([203/212Pb]Pb(OAc)2) suitable for direct radiolabeling of chelators and bioconjugates. A series of cyclen-based chelators (herein referred to as DOTA-1Py, -2Py, and -3Py) along with established chelates DOTA and TCMC were evaluated for their ability to complex both 203Pb and 212Pb. All chelates incorporated 212Pb/203Pb efficiently, with higher radiolabeling yields observed for the 212Pb-complexes. Conclusion The production of 203Pb and 212Pb was established using TRIUMF 13 MeV and 500 MeV cyclotrons, respectively. Both production methods provided radiometals suitable for subsequent radiolabeling reactions using known and novel chelates. Furthermore, the novel chelate DOTA-3Py may be a good candidate for biomolecule conjugation and further theranostic 212Pb/203Pb studies.

The synthesis of a new RuII complex, in which the metal is coordinated by two 1,10-phenanthroline ligands and a 2,2&prime, bipyridyl unit linked, via methylene bridges in its 4 and 4&prime, positions, to two 1,4,7,10-tetraazacyclododecane (cyclen) macrocycles ([Ru(phen)2L]2+) is reported. Protonation and ZnII binding by [Ru(phen)2L]2+ have been analyzed by potentiometric titration, evidencing the formation of mixed hetero-binuclear and hetero-trinuclear ZnII/RuII complexes. These complexes were tested as bis-phenol A (BPA) binders. Only the dizinc complex with [Ru(phen)2L]2+ is able to bind BPA in aqueous solution, affording a remarkably stable {Zn2[Ru(phen)2L]BPA(H&minus, 2)}4+ adduct at neutral pH, in which BPA is bound in its doubly deprotonated form to the two ZnII ions. BPA binding was found to quench the luminescence emission of the RuII(phen)2bipy core. Although the quenching effect is modest, this study demonstrates that appropriately designed dizinc complexes can be used for binding and optical sensing of BPA in water.

A library of ciprofloxacin-nuclease conjugates was designed and synthesized to investigate their potential as catalytic antibiotics. The Cu(II) complexes of the new designer compounds (i) showed excellent in vitro hydrolytic and oxidative DNase activity, (ii) showed good antibacterial activity against both Gram-negative and Gram-positive bacteria, and (iii) proved to be highly potent bacterial DNA gyrase inhibitors via a mechanism that involves stabilization of the fluoroquinolone-topoisomerase-DNA ternary complex. Furthermore, the Cu(II) complexes of two of the new designer compounds were shown to fragment supercoiled plasmid DNA into linear DNA in the presence of DNA gyrase, demonstrating a "proof of concept" in vitro. These ciprofloxacin-nuclease conjugates can therefore serve as models with which to develop next-generation, in vivo functioning catalytic antimicrobials.

Intramolecular magnetic interaction between a localized open-shell 4f-electronic system and a photoexcited macrocyclic π-conjugate system in terbium-phthalocyaninnato (Tb-Pc) 1:1 complex was investigated using variable-temperature variable-field magnetic circular dichroism (VTVH MCD) spectroscopy. The 1:1 complex [Tb(Pc)(cyclen)]Cl (Pc2- = phthalocyaninato dianion, cyclen = 1,4,7,10-tetraazacyclododecane) with the capping ligand providing an exact fourfold symmetry showed a significant temperature dependence and a nonlinear field dependence in the MCD intensity of the Pc-centered highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) π-π* transition, while a diamagnetic congener [Y(Pc)(cyclen)]Cl showed a temperature-independent MCD with a linear-field dependence. This indicates that the (4f)8 system of the Tb ion with a total angular momentum J and the photoexcited π-system of the Pc macrocycle with an orbital angular momentum L are magnetically coupled. By numerical simulation using a model where ground doublet state |Jz⟩ = |±6⟩ and excited quartet state |Jz, Lz⟩ = |±6, ±|Lz|⟩ are included, the J-L interaction magnitude ΔJL and the Pc-centered orbital angular momentum |Lz|ℏ were determined to be 1.1 cm-1 and 2.0 ℏ, respectively. From ab initio restricted active space self-consistent field (RASSCF)-restricted active space state interaction (RASSI) calculations on the π-π* excited states of the Tb complex, the magnitude of the J-L interaction was estimated. The comparison between the calculations on the Y and Tb complexes revealed that the ferromagnetic-type coupling occurs between the orbital component in the J of Tb and the L on Pc, supporting the model that we employed for the analysis of the experimental data.

The proton bond is a paradigmatic quantum molecular interaction and a major driving force of supramolecular chemistry. The ring cavities of crown ethers provide an intriguing environment, promoting competitive proton sharing with multiple coordination anchors. This study shows that protons confined in crown ether cavities form dynamic bonds that migrate to varying pairs of coordinating atoms when allowed by the flexibility of the macrocycle backbone. Prototypic native crown ethers (12-crown-4, 15-crown-5 and 18-crown-6) and aza-crown ethers (cyclen, 1-aza-18-crown-6 and hexacyclen) are investigated. For each system, Infrared action spectroscopy experiments and ab initio Molecular Dynamics computations are employed to elucidate the structural effects associated with proton diffusion and its entanglement with the conformational and vibrational dynamics of the protonated host.

High-sugar-tethered glycodendrimers are a remarkable tool in glycobiology for the investigation of carbohydrate-protein interaction using its multivalency property. An enthralling double-stage convergent synthetic approach was selected to build a novel class of chlorine-containing glucose-coated dendrimers using an efficient click catalyst ‘dinuclear copper(I) thiodiacetate complex.’ In this context, cyclen core was developed through a divergent approach, while the glucodendron was developed via a convergent approach independently. Both azide-alkyne partners were coupled through a modular copper azide-alkyne cycloaddition (CuAAC) strategy to afford a high yield of the desired 36-glucose-coated glycodendrimer. The synthesized glycodendrimer has been elucidated by NMR, gel permeation chromatography (GPC), and IR spectral analysis.

The amyloid cascade is central for the neurodegeneration disease pathology, including Alzheimer’s and Parkinson’s, and remains the focus of much current research. S100A9 protein drives the amyloid-neuroinflammatory cascade in these diseases. DOPA and cyclen-based compounds were used as amyloid modifiers and inhibitors previously, and DOPA is also used as a precursor of dopamine in Parkinson’s treatment. Here, by using fluorescence titration experiments we showed that five selected ligands: DOPA-D-H-DOPA, DOPA-H-H-DOPA, DOPA-D-H, DOPA-cyclen, and H-E-cyclen, bind to S100A9 with apparent Kd in the sub-micromolar range. Ligand docking and molecular dynamic simulation showed that all compounds bind to S100A9 in more than one binding site and with different ligand mobility and H-bonds involved in each site, which all together is consistent with the apparent binding determined in fluorescence experiments. By using amyloid kinetic analysis, monitored by thioflavin-T fluorescence, and AFM imaging, we found that S100A9 co-aggregation with these compounds does not hinder amyloid formation but leads to morphological changes in the amyloid fibrils, manifested in fibril thickening. Thicker fibrils were not observed upon fibrillation of S100A9 alone and may influence the amyloid tissue propagation and modulate S100A9 amyloid assembly as part of the amyloid-neuroinflammatory cascade in neurodegenerative diseases.

A finite chain of thirty-one paramagnetic centers is reported, synthesised by reaction of hydrated chromium fluoride, copper carbonate and pivalic acid in the presence of 1,4,7,10-tetrazacyclododecane (cyclen). Magnetic studies show predominantly anti-ferromagnetic exchange leading to a high density of low-lying spin sites and large saturation fields.. © 2021 Wiley-VCH GmbH.

The development of lanthanide-based luminescent probes with a long emission lifetime has the potential to revolutionize imaging-based diagnostic techniques. By a rational design strategy taking advantage of computational predictions, a novel, water-soluble Eu3+ complex from a cyclen-based ligand bearing 1,3-disubstituted benzo[h]isoquinoline arms was realized. The ligand has been obtained overcoming the lack of reactivity of position 3 of the isoquinoline moiety. Notably, steric hindrance of the heteroaromatic chromophore allowed selective and stoichiometry-controlled insertion of two or three antennas on the cyclen platform without any protection strategy. The complex bears a fourth heptanoic arm for easy conjugation to biomolecules. This new chromophore allowed the sensitization of the metal center either with one or two photons excitation. The suitability as a luminescent bioprobe was validated by imaging BMI1 oncomarker in lung carcinoma cells following an established immunofluorescence approach. The use of a conventional epifluorescence microscope equipped with a linear structured illumination module disclosed a simple and inexpensive way to image confocally Ln-bioprobes by single photon excitation in the 350&ndash, 400 nm window, where ordinary confocal systems have no excitation sources.

Background Lead-212 (212Pb, t1/2 = 10.6 h) and lead-203 (203Pb, t1/2 = 51.9 h) are an element-equivalent, or a matched theranostic radioisotope pair that show great potential for application in targeted radionuclide therapy (TRT) and single-photon emission computed tomography (SPECT), respectively. At TRIUMF we have produced both 203Pb and 212Pb using TRIUMF’s TR13 (13 MeV) and 500 MeV cyclotrons, and subsequently purified and evaluated both radioisotopes using a series of pyridine-modified DOTA analogues in comparison to the commercially available chelates DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and TCMC (1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane). Results Proton irradiation (12.8 MeV) of natural and enriched thallium-203 (203Tl) targets gave 203Pb saturation yields of 134 ± 25 and 483 ± 3 MBq/μA, respectively. Thorium-228 (228Th, t1/2 = 1.9 y), a by-product of 232Th proton spallation on TRIUMF’s main 500 MeV beamline (beamline 1A, BL1A), was recovered to build a 228Th/212Pb generator with the ability to deliver up to 9–10 MBq of 212Pb daily. Both lead isotopes were purified via solid phase extraction chromatography (Pb resin), and isolated in an acetate form ([203/212Pb]Pb(OAc)2) suitable for direct radiolabeling of chelators and bioconjugates. A series of cyclen-based chelators (herein referred to as DOTA-1Py, -2Py, and -3Py) along with established chelates DOTA and TCMC were evaluated for their ability to complex both 203Pb and 212Pb. All chelates incorporated 212Pb/203Pb efficiently, with higher radiolabeling yields observed for the 212Pb-complexes. Conclusion The production of 203Pb and 212Pb was established using TRIUMF 13 MeV and 500 MeV cyclotrons, respectively. Both production methods provided radiometals suitable for subsequent radiolabeling reactions using known and novel chelates. Furthermore, the novel chelate DOTA-3Py may be a good candidate for biomolecule conjugation and further theranostic 212Pb/203Pb studies. Supplementary Information The online version contains supplementary material available at 10.1186/s41181-021-00121-4.

Phosphate triesters are cleaved by gold nanoparticles functionalized with metal complexes (Zn(II), Cu(II), Co(II), Co(III), Eu(III), Yt(III), Zr(IV)) of triazacyclonononane and cyclen ligands with a mononuclear mechanism with impressive rate accelerations with respect to the uncatalyzed processes, constituting a remarkable example of nerve agents hydrolyzing nanoazymes.

The coordination compounds of the trivalent lanthanide ions (Ln(III)) have unique photophysical properties. Ln(III) excitation is usually performed through a light-harvesting antenna. To enable Ln(III)-based emitters to reach their full potential, an understanding of how complex structure affects sensitization and quenching processes is necessary. Here, the role of the linker between the antenna and the metal binding fragment was studied. Four macrocyclic ligands carrying coumarin 2 or 4-methoxymethylcarbostyril sensitizing antennae linked to an octadentate macrocyclic ligand binding site were synthesized. Complexation with Ln(III) (Ln = La, Sm, Eu, Gd, Tb, Yb and Lu) yielded species with overall &minus, 1, 0, or +2 and +3-charge. Paramagnetic 1H NMR spectroscopy indicated subtle differences between the coumarin- and carbostyril-carrying Eu(III) and Yb(III) complexes. Cyclic voltammetry showed that the effect of the linker on the Eu(III)/Eu(II) apparent reduction potential was dependent on the electronic properties of the N-substituent. The Eu(III), Tb(III) and Sm(III) complexes were all luminescent. Coumarin-sensitized complexes were poorly emissive, photoinduced electron transfer was not a major quenching pathway in these species. These results show that seemingly similar emitters can undergo very different photophysical processes, and highlight the crucial role the linker can play.

Fluorescence quenching of carbon dots (CDs) occurs in their aggregated state ascribed to direct π–π interactions or excessive resonance energy transfer (RET). Thus, CDs have been severely restricted for applications requiring phosphors that emit in the solid state, such as the fabrication of white light-emitting diodes (WLEDs). In this report, novel CDs with bright solid-state fluorescence (SSF) were synthesized by simple microwave-assisted synthesis method, using 1,4,7,10-tetraazacyclododecane (cyclen) and citric acid as precursors. Under 365 nm UV light, these CDs emit bright yellow SSF, indicating they successfully overcome the aggregation-induced fluorescence quenching (ACQ) effect. When the excitation wavelength (λex) is fixed at 450 nm, the emission peak of the CDs is centered at 546 nm with the Commission Internationale de l’Eclairage chromaticity (CIE) coordinates of (0.43, 0.55), which means that they can be combined with a blue-emitting chip in order to fabricate WLEDs. More importantly, the absolute quantum yield (QY) of these CDs powder reached 48% at λex of 450 nm, which was much higher than many previously reported SSF-emitting CDs and indicating their high light conversion ability in solid-state. Thanks to the excellent optical property of these CDs powder, they were successfully used in the preparation of high-performance WLEDs. This study not only enriches SSF-emitting CD-based nanomaterials with good prospects for application, but also provides valuable reference for subsequent research on the synthesis of solid-state fluorescent CDs.

Poor nuclear delivery and accumulation are the main reasons for the reduced drug efficacy of many anticancer drugs that target DNA or enzymes in the nucleus, and it is a major obstacle to successful cancer therapy. To address this problem, developing practical drug delivery systems for nuclear delivery is urgently needed. Here we develop a supramolecular hydrogel by conjugating the anticancer agent 10-hydroxycamptothecine (HCPT) and macrocyclic polyamine cyclen to a self-assembling peptide. The cyclen fragment possesses nuclear localization and ATP hydrolysis properties, which can provide a synergistic therapeutic effect for cancer treatment. The HCPT-FFFK-cyclen nanofibers showed improved nuclear accumulation and inhibition capacity in cancer cells including drug-resistant cancer cells in vitro. The nanofibers also exhibited favorable ATP consuming ability in vitro. Moreover, the obtained nanomedicine showed enhanced anticancer efficiency and favorable biocompatibility in vivo when administered to mice via tail vein injection. This constructed self-delivery drug system significantly improved the delivery efficiency of the small molecule agents into the nucleus and showed favorable ATP consuming ability, offering new strategies for developing nanomedicines for cancer combination therapy.

The clinical applications of nitrogen mustard antitumor drugs are limited by their poor aqueous solubility, poor cellular uptake, lack of targeting, and severe side effects. Cyclen could be protonated under physiological conditions, which may be beneficial for increasing cell membrane affinity and cellular uptake. Herein, a novel self-assembling peptide–drug conjugate was developed by conjugating chlorambucil (CRB) and cyclen to a self-assembling peptide. The resultant supramolecular hydrogel was prepared via a heating–cooling process and displayed improved aqueous solubility. Rheology, CD spectra, and transmission electron microscopy measurements indicated that the hydrogel with a β-sheet configuration and a nanofiber structure had favorable rheological properties. A cellular uptake experiment demonstrated that cyclen effectively increases the uptake of the resulting hydrogel by tumor cells. MTT results indicated that the hydrogel exhibited favorable inhibitory activities against A549, HeLa, and MCF-7 cancer cell lines and was less toxic towards 3T3 (normal cells). The results of γ-H2AX experiments showed that the obtained nanomedicine could induce significantly more DNA damage compared with free chlorambucil. Hematology analysis experiments revealed that the obtained nanomedicine has good biocompatibility. Our findings indicate that the self-delivery nanodrug system has clinical potential for cancer treatment.

Considering the special structure of 1,4,7,10-tetraazacyclododecane (cyclen) which is easy to form complexes with ions, it is beneficial to achieve particular selectivity. Cyclen was selected as a precursor to react with triglycidyl isocyanurate (TGIC), and a novel kind of hydrophilic polymeric monolithic material was facilely prepared via epoxy-amine ring-opening reaction in the presence of a binary porogenic system of acetonitrile (ACN) and polyethylene glycol. The resulting poly (TGIC-co-cyclen) monolithic column was used to separate both nonpolar alkylbenzenes using mobile phase of ACN/H2O (35/65, v/v) and polar phenolic compounds and anilines under the mobile phase of ACN/H2O (60/40, v/v) in reversed-phase capillary liquid chromatography (cLC). It should be pointed that the monolith was further used for separation of a mixture of toluene, DMF, acrylamide and thiourea under the mobile phase of ACN/H2O (95/5, v/v) by hydrophilic interaction chromatography (HILIC). These results indicated that the poly (TGIC-co-cyclen) column exhibited mixed-mode retention mechanism. As a result, the prepared monolithic material was employed for enrichment of glycosylated peptides from the tryptic digest of human immunoglobulin G (IgG) and serum protein tryptic digests. A total of 531 N-glycopeptides and 329 N-glycosylation sites, mapped to 166 glycoproteins, were identified from 2 μL human serum digest. The results indicated the prepared monolith had ability for enriching N-glycopeptides from complex biological samples.

1,4,7,10-Tetraazacyclododecane (cyclen) has a unique cyclic structure that endows it with a number of characteristics, including its cationic nature, easy modification and strong coordination ability toward a wide range of cations. Zn2+, which can easily coordinate to cyclen, is an essential metal ion for DNA binding. In this report, Zn(ii)-polycations derived from cyclen were studied as non-viral gene delivery vectors. Polycations were synthesized from diglycidyl ethers and cyclen through ring-opening polymerization, and then Zn(ii)-complexes were obtained by reacting the polycations with Zn(NO3)2·6H2O. UV absorption and circular dichroism spectra revealed that the Zn(ii)-complexes may induce apparent conformational changes of DNA, while polycations could not. Agarose gel retardation assay demonstrated that although the Zn(ii)-polycations exhibited slightly lower DNA binding ability compared to their polycation counterparts, they showed better DNA release, which might favor the gene transfection process. In vitro transfection results revealed that the coordination of Zn(ii) may dramatically increase the transfection efficiency of the polymers. In addition, almost all polycations and their Zn(ii)-complexes exhibited better serum tolerance than polyethylenimine (PEI), especially Zn-cyclen-HD. Flow cytometry and BSA adsorption experiments also demonstrated the good serum tolerance of the Zn(ii)-polycations. Meanwhile, such materials also exhibited acceptable cytotoxicities at transfection dosages. These results may afford us clues for developing novel non-viral gene vectors with high efficiency and biocompatibility.