Advances in cobalt complexes as anticancer agents Munteanu, Catherine R; Suntharalingam, Kogularamanan
Dalton transactions : an international journal of inorganic chemistry,
01/2015, Letnik:
44, Številka:
31
Journal Article
Recenzirano
The evolution of resistance to traditional platinum-based anticancer drugs has compelled researchers to investigate the cytostatic properties of alternative transition metal-based compounds. The ...anticancer potential of cobalt complexes has been extensively studied over the last three decades, and much time has been devoted to understanding their mechanisms of action. This perspective catalogues the development of antiproliferative cobalt complexes, and provides an in depth analysis of their mode of action. Early studies on simple cobalt coordination complexes, Schiff base complexes, and cobalt-carbonyl clusters will be documented. The physiologically relevant redox properties of cobalt will be highlighted and the role this plays in the preparation of hypoxia selective prodrugs and imaging agents will be discussed. The use of cobalt-containing cobalamin as a cancer specific delivery agent for cytotoxins will also be described. The work summarised in this perspective shows that the biochemical and biophysical properties of cobalt-containing compounds can be fine-tuned to produce new generations of anticancer agents with clinically relevant efficacies.
Gallium-68 (
Ga) is a positron-emitting isotope used for clinical PET imaging of peptide receptor expression.
Ga radiopharmaceuticals used in molecular PET imaging consist of disease-targeting ...biomolecules tethered to chelators that complex
Ga
. Ideally, the chelator will rapidly, quantitatively and stably coordinate
Ga
at room temperature, near neutral pH and low chelator concentration, allowing for simple routine radiopharmaceutical formulation. Identification of chelators that fulfil these requirements will facilitate development of kit-based
Ga radiopharmaceuticals. Herein the reaction of a range of widely used macrocyclic and acyclic chelators with
Ga
is reported. Radiochemical yields have been measured under conditions of varying chelator concentrations, pH (3.5 and 6.5) and temperature (25 and 90 °C). These chelators are: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane macrocycles substituted with phosphonic (NOTP) and phosphinic (TRAP) groups at the amine, bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), a tris(hydroxypyridinone) containing three 1,6-dimethyl-3-hydroxypyridin-4-one groups (THP) and the hexadentate tris(hydroxamate) siderophore desferrioxamine-B (DFO). Competition studies have also been undertaken to assess relative complexation efficiencies of each chelator for
Ga
under different pH and temperature conditions. Performing radiolabelling reactions at pH 6.5, 25 °C and 5-50 μM chelator concentration resulted in near quantitative radiochemical yields for all chelators, except DOTA. Radiochemical yields either decreased or were not substantially improved when the reactions were undertaken at lower pH or at higher temperature, except in the case of DOTA. THP and DFO were the most effective
Ga
chelators at near-neutral pH and 25 °C, rapidly providing near-quantitative radiochemical yields at very low chelator concentrations. NOTP and HBED were only slightly less effective under these conditions. In competition studies with all other chelators, THP demonstrated highest reactivity for
Ga
complexation under all conditions. These data point to THP possessing ideal properties for rapid, one-step kit-based syntheses of
Ga-biomolecules for molecular PET imaging. LC-MS and
H,
C{
H} and
Ga NMR studies of HBED complexes of Ga
showed that under the analytical conditions employed in this study, multiple HBED-bound Ga complexes exist. X-ray diffraction data indicated that crystals isolated from these solutions contained octahedral Ga(HBED)(H
O), with HBED coordinated in a pentadentate N
O
mode, with only one phenolic group coordinated to Ga
, and the remaining coordination site occupied by a water molecule.
Gallium-68 (
68
Ga) is a positron-emitting isotope used for clinical PET imaging of peptide receptor expression.
68
Ga radiopharmaceuticals used in molecular PET imaging consist of disease-targeting ...biomolecules tethered to chelators that complex
68
Ga
3+
. Ideally, the chelator will rapidly, quantitatively and stably coordinate
68
Ga
3+
at room temperature, near neutral pH and low chelator concentration, allowing for simple routine radiopharmaceutical formulation. Identification of chelators that fulfil these requirements will facilitate development of kit-based
68
Ga radiopharmaceuticals. Herein the reaction of a range of widely used macrocyclic and acyclic chelators with
68
Ga
3+
is reported. Radiochemical yields have been measured under conditions of varying chelator concentrations, pH (3.5 and 6.5) and temperature (25 and 90 °C). These chelators are: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane macrocycles substituted with phosphonic (NOTP) and phosphinic (TRAP) groups at the amine, bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), a tris(hydroxypyridinone) containing three 1,6-dimethyl-3-hydroxypyridin-4-one groups (THP) and the hexadentate tris(hydroxamate) siderophore desferrioxamine-B (DFO). Competition studies have also been undertaken to assess relative complexation efficiencies of each chelator for
68
Ga
3+
under different pH and temperature conditions. Performing radiolabelling reactions at pH 6.5, 25 °C and 5-50 μM chelator concentration resulted in near quantitative radiochemical yields for all chelators, except DOTA. Radiochemical yields either decreased or were not substantially improved when the reactions were undertaken at lower pH or at higher temperature, except in the case of DOTA. THP and DFO were the most effective
68
Ga
3+
chelators at near-neutral pH and 25 °C, rapidly providing near-quantitative radiochemical yields at very low chelator concentrations. NOTP and HBED were only slightly less effective under these conditions. In competition studies with all other chelators, THP demonstrated highest reactivity for
68
Ga
3+
complexation under all conditions. These data point to THP possessing ideal properties for rapid, one-step kit-based syntheses of
68
Ga-biomolecules for molecular PET imaging. LC-MS and
1
H,
13
C{
1
H} and
71
Ga NMR studies of HBED complexes of Ga
3+
showed that under the analytical conditions employed in this study, multiple HBED-bound Ga complexes exist. X-ray diffraction data indicated that crystals isolated from these solutions contained octahedral Ga(HBED)(H
2
O), with HBED coordinated in a pentadentate N
2
O
3
mode, with only one phenolic group coordinated to Ga
3+
, and the remaining coordination site occupied by a water molecule.
A range of macrocyclic and acyclic chelators have been reacted with the PET isotope, gallium-68, and their radiolabelling efficiencies have been compared. Structural data for complexes of HBED with Ga
3+
are reported.
A range of macrocyclic and acyclic chelators have been reacted with the PET isotope, gallium-68, and their radiolabelling efficiencies have been compared. Structural data for complexes of HBED with ...Ga
3+
are reported.
Gallium-68 (
68
Ga) is a positron-emitting isotope used for clinical PET imaging of peptide receptor expression.
68
Ga radiopharmaceuticals used in molecular PET imaging consist of disease-targeting biomolecules tethered to chelators that complex
68
Ga
3+
. Ideally, the chelator will rapidly, quantitatively and stably coordinate
68
Ga
3+
at room temperature, near neutral pH and low chelator concentration, allowing for simple routine radiopharmaceutical formulation. Identification of chelators that fulfil these requirements will facilitate development of kit-based
68
Ga radiopharmaceuticals. Herein the reaction of a range of widely used macrocyclic and acyclic chelators with
68
Ga
3+
is reported. Radiochemical yields have been measured under conditions of varying chelator concentrations, pH (3.5 and 6.5) and temperature (25 and 90 °C). These chelators are: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane macrocycles substituted with phosphonic (NOTP) and phosphinic (TRAP) groups at the amine, bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), a tris(hydroxypyridinone) containing three 1,6-dimethyl-3-hydroxypyridin-4-one groups (THP) and the hexadentate tris(hydroxamate) siderophore desferrioxamine-B (DFO). Competition studies have also been undertaken to assess relative complexation efficiencies of each chelator for
68
Ga
3+
under different pH and temperature conditions. Performing radiolabelling reactions at pH 6.5, 25 °C and 5–50 μM chelator concentration resulted in near quantitative radiochemical yields for all chelators, except DOTA. Radiochemical yields either decreased or were not substantially improved when the reactions were undertaken at lower pH or at higher temperature, except in the case of DOTA. THP and DFO were the most effective
68
Ga
3+
chelators at near-neutral pH and 25 °C, rapidly providing near-quantitative radiochemical yields at very low chelator concentrations. NOTP and HBED were only slightly less effective under these conditions. In competition studies with all other chelators, THP demonstrated highest reactivity for
68
Ga
3+
complexation under all conditions. These data point to THP possessing ideal properties for rapid, one-step kit-based syntheses of
68
Ga-biomolecules for molecular PET imaging. LC-MS and
1
H,
13
C{
1
H} and
71
Ga NMR studies of HBED complexes of Ga
3+
showed that under the analytical conditions employed in this study, multiple HBED-bound Ga complexes exist. X-ray diffraction data indicated that crystals isolated from these solutions contained octahedral Ga(HBED)(H
2
O), with HBED coordinated in a pentadentate N
2
O
3
mode, with only one phenolic group coordinated to Ga
3+
, and the remaining coordination site occupied by a water molecule.
Background
Foot and ankle characteristics are associated with patellofemoral pain (PFP) and may also relate to patellofemoral osteoarthritis (PFOA). A greater understanding of these characteristics ...and PFOA, could help to identify effective targeted treatments.
Objectives
To determine whether foot and ankle characteristics are associated with knee symptoms and function in individuals with PFOA.
Methods
For this cross‐sectional study we measured weightbearing ankle dorsiflexion range of motion, foot posture (via the Foot Posture Index FPI), and midfoot mobility (via the Foot Measurement Platform), and obtained patient‐reported outcomes for knee symptoms and function (100 mm visual analogue scales, Anterior Knee Pain Scale AKPS, Knee injury and Osteoarthritis Outcome Score, repeated single step‐ups and double‐leg sit‐to‐stand to knee pain onset). Pearson's r with significance set at p < 0.05 was used to determine the association between foot and ankle charateristics, with knee symptoms and function, adjusting for age.
Results
188 participants (126 67% women, mean SD age of 59.9 7.1 years, BMI 29.3 5.6 kg/m2) with symptomatic PFOA were included in this study. Lower weightbearing ankle dorsiflexion range of motion had a small significant association with higher average knee pain (partial r = − 0.272, p < 0.001) and maximum knee pain during stair ambulation (partial r = − 0.164, p = 0.028), and lower scores on the AKPS (indicative of greater disability; partial r = 0.151, p = 0.042). Higher FPI scores (indicating a more pronated foot posture) and greater midfoot mobility (foot mobility magnitude) were significantly associated with fewer repeated single step‐ups (partial r = − 0.181, p = 0.023 and partial r = − 0.197, p = 0.009, respectively) and double‐leg sit‐to‐stands (partial r = − 0.202, p = 0.022 and partial r = − 0.169, p = 0.045, respectively) to knee pain onset, although the magnitude of these relationships was small. The amount of variance in knee pain and disability explained by the foot and ankle characteristics was small (R2‐squared 2 to 8%).
Conclusions
Lower weightbearing ankle dorsiflexion range of motion, a more pronated foot posture, and greater midfoot mobility demonstrated small associations with worse knee pain and greater disability in individuals with PFOA. Given the small magnitude of these relationships, it is unlikely that interventions aimed solely at addressing foot and ankle mobility will have substantial effects on knee symptoms and function in this population.
Trial registration
The RCT was prospectively registered on 15 March 2017 with the Australia and New Zealand Clinical Trials Registry (ANZCTRN12617000385347).
Introduction
The aim of this study was to determine whether participant characteristics and clinical assessments could identify radiographic osteoarthritis (OA) in individuals with clinically ...diagnosed, symptomatic patellofemoral osteoarthritis (PFOA).
Methods
Participant characteristics and clinical assessments were obtained from 179 individuals aged 50 years and over with clinically diagnosed symptomatic PFOA, who were enrolled in a randomised trial. Anteroposterior, lateral, and skyline X‐rays were taken of the symptomatic knee. The presence of radiographic PFOA was defined as “no or early PFOA” (Kellgren and Lawrence KL grade ≤1 in the PF compartment) or “definite PFOA” (KL grade ≥2). Diagnostic test statistics were applied to ascertain which participant characteristics and clinical assessments could identify the presence of definite radiographic PFOA.
Results
A total of 118 participants (66%) had definite radiographic PFOA. Univariate analysis identified that older age (>61 years), female sex, higher body mass index (BMI) (>29 kg/m2), longer pain duration (>2.75 years), higher maximum knee pain during stair ambulation (>47/100 mm), and fewer repeated single step‐ups to pain onset (<21) were associated with the presence of definite radiographic PFOA. Multivariate logistic regression indicated that BMI, pain duration, and repeated single step‐ups to pain onset were independently associated with radiographic PFOA and identified the presence of definite radiographic PFOA with an overall accuracy of 73%.
Conclusion
In individuals over 50 years of age with a clinical diagnosis of PFOA, higher BMI, longer pain duration, and fewer repeated single step‐ups to pain onset increased the likelihood of radiographic PFOA. However, overall diagnostic accuracy was modest, suggesting that radiographic PFOA cannot be confidently identified using these tests.
Long-term clinical outcomes of catheter ablation (CA) compared to thoracoscopic surgical ablation (SA) to treat patients with long-standing persistent atrial fibrillation (LSPAF) are not known.
The ...purpose of this study was to compare the long-term (36-month) clinical efficacy, quality of life, and cost-effectiveness of SA and CA in LSPAF.
Participants were followed up for 3 years using implantable loop recorders and questionnaires to assess the change in quality of life. Intention-to-treat analyses were used to report the findings.
Of the 115 patients with LSPAF treated, 104 (90.4%) completed 36-month follow-up CA: n = 57 (95%); SA: n = 47 (85%). After a single procedure without antiarrhythmic drugs, 7 patients (12%) in the CA arm and 5 (11%) in the SA arm hazard ratio 1.22; 95% confidence interval (CI) 0.81–1.83; P = .41 were free from atrial fibrillation/tachycardia (AF/AT) ≥30 seconds at 36 months. Thirty-three patients (58%) in the CA arm and 26 (55%) in the SA arm (hazard ratio 1.04; 95% CI 0.57–1.88; P = .91) had their AF/AT burden reduced by ≥75%. The overall impact on health-related quality of life was similar, with mean quality-adjusted life year estimates of 2.45 (95% CI 2.31–2.59) for CA and 2.32 (95% CI 2.13–2.52) for SA. Estimated costs were higher for SA (mean £24,682; 95% CI £21,746–£27,618) than for CA (mean £18,002; 95% CI £15,422–£20,581).
In symptomatic LSPAF, CA and SA were equally effective at achieving arrhythmia outcomes (freedom from AF/AT ≥30 seconds and ≥75% burden reduction) after a single procedure without antiarrhythmic drugs. However, SA is significantly more costly than CA.
ClinicalTrials.gov identifier NCT04280042
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