Short all-out isokinetic cycling exercises of 90 and 15 s unlock exercise-induced hypoalgesia.

BACKGROUND: Acute physical activity leads to exercise-induced hypoalgesia (EIH). However, to what degree it can be induced by very short but highly intensive exercise is largely unknown. This study aims to investigate the effects of two different short all-out isokinetic exercise sessions on EIH. METHODS: Twenty young male participants underwent three different interventions (90, 15 s all-out isokinetic cycling, respectively, and control) after an individualized low-intensity warm-up in a randomized-controlled-crossover design. Before (pre), after warm-up (post 1) as well as immediately post-intervention (post 2) pain sensitivity was measured employing pressure pain thresholds (PPT; in N) at the elbow, knee and ankle joints as well as the sternum and forehead. Performance parameters (e.g. lactate, perceived exertion, heart rate) were documented. RESULTS: A 'time' × 'intervention' × 'body site' interaction effect (p < 0.001, η2 partial = 0.110) was observed for PPT. Both isokinetic interventions resulted in EIH at all body sites, even after ruling out any warm-up effects, while effects were larger for 90 s (maximum increase of 25.7 ± 11.7 N) compared to 15 s (maximum increase of 19.3 ± 18.9 N), and control (maximum increase of 8.0 ± 6.1 N). Compared to control, 15 s also resulted in hypoalgesic effects and differences were not observed at all sites. In this study, 90 s resulted in higher lactate, subjective exhaustion and heart rate levels compared to 15 s and control (p < 0.001), while higher values were also observed for 15 s compared to control. CONCLUSION: Global EIH assessed immediately after exercise can be induced by short highly intensive exercises. The effects are greater when the subjective and the objective exertion are higher as induced by the 90 s intervention. SIGNIFICANCE STATEMENT: This study investigates the potential for brief, highly intensive exercise sessions to induce exercise-induced hypoalgesia (EIH). The research demonstrates that EIH can indeed be triggered by such short workouts, with greater effects observed during a 90 s session compared to a 15 s one, most likely due to higher subjective and objective exertion. These findings offer insights into the potential for extremely brief but intense exercises to alleviate pain, impacting exercise recommendations and pain management strategies.

Calculation of Oxygen Uptake during Ambulatory Cardiac Rehabilitation.

Background: Cardiopulmonary exercise testing is not used routinely. The goal of this study was to determine whether accurate estimates of VO2 values can be made at the beginning and at the end of a rehabilitation program. Methods: A total of 91 cardiac rehabilitation patients were included. Each participant had to complete cardiopulmonary exercise testing at the beginning and at the end of a rehabilitation program. Measured VO2 values were compared with estimates based on three different equations. Results: Analyses of the means of the differences in the peak values showed very good agreement between the results obtained with the FRIEND equation or those obtained with a combination of rules of thumb and the results of the measurements. This agreement was confirmed with the ICCs and with the standard errors of the measurements. The ACSM equation performed worse. The same tendency was seen when considering the VO2 values at percentage-derived work rates. Conclusions: The FRIEND equation and the more easily applicable combination of rules of thumb are suitable for estimating the peak VO2 and the VO2 at a percentage-derived work rate in cardiac patients both at the beginning and at the end of a cardiac rehabilitation program.

64Cu tumor labeling with hexadentate picolinic acid-based bispidine immunoconjugates.

Discussed are two picolinate appended bispidine ligands (3,7-diazabicyclo[3.3.1]nonane derivatives) in comparison with an earlier described bis-pyridine derivative, which are all known to strongly bind CuII. The radiopharmacological characterization of the two isomeric bispidine complexes includes quantitative labeling with 64CuII at ambient conditions with high radiochemical purities and yields (molar activities >200 MBq/nmol). Challenge experiments in presence of EDTA, cyclam, human serum and SOD demonstrate high stability and inertness of the 64Cu-bispidine complexes. Biodistribution studies performed in Wistar rats indicate a rapid renal elimination for both 64Cu-labeled chelates. The bispidine ligand with the picolinate group in N7 position was selected for further biological experiments, and its backbone was therefore substituted with a benzyl-NCS group at C9. Two tumor target modules (TMs), targeting prostate stem cell antigen (PSCA), overexpressed in prostate cancer, and the fibroblast activation protein (FAP) in fibrosarcoma, were selected for thiourea coupling with the NCS-functionalized ligand and lysine residues of TMs. Small animal PET experiments on tumor-bearing mice showed specific accumulation of the 64Cu-labeled TMs in PSCA- and FAP-overexpressing tumors (standardized uptake value (SUV) for PC3: 2.7±0.6 and HT1080: 7.2±1.25) with almost no uptake in wild type tumors.

Exploring the Potential of Nanogels: From Drug Carriers to Radiopharmaceutical Agents.

Nanogels open up access to a wide range of applications and offer among others hopeful approaches for use in the field of biomedicine. This review provides a brief overview of current developments of nanogels in general, particularly in the fields of drug delivery, therapeutic applications, tissue engineering, and sensor systems. Specifically, cyclodextrin (CD)-based nanogels are important because they have exceptional complexation properties and are highly biocompatible. Nanogels as a whole and CD-based nanogels in particular can be customized in a wide range of sizes and equipped with a desired surface charge as well as containing additional molecules inside and outside, such as dyes, solubility-mediating groups or even biological vector molecules for pharmaceutical targeting. Currently, biological investigations are mainly carried out in vitro, but more and more in vivo applications are gaining importance. Modern molecular imaging methods are increasingly being used for the latter. Due to an extremely high sensitivity and the possibility of obtaining quantitative data on pharmacokinetic and pharmacodynamic properties, nuclear methods such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) using radiolabeled compounds are particularly suitable here. The use of radiolabeled nanogels for imaging, but also for therapy, is being discussed.

Immunotheranostic target modules for imaging and navigation of UniCAR T-cells to strike FAP-expressing cells and the tumor microenvironment.

BACKGROUND: Chimeric antigen receptor (CAR) T-cells are a promising approach in cancer immunotherapy, particularly for treating hematologic malignancies. Yet, their effectiveness is limited when tackling solid tumors, where immune cell infiltration and immunosuppressive tumor microenvironments (TME) are major hurdles. Fibroblast activation protein (FAP) is highly expressed on cancer-associated fibroblasts (CAFs) and various tumor cells, playing an important role in tumor growth and immunosuppression. Aiming to modulate the TME with increased clinical safety and effectiveness, we developed novel small and size-extended immunotheranostic UniCAR target modules (TMs) targeting FAP. METHODS: The specific binding and functionality of the αFAP-scFv TM and the size-extended αFAP-IgG4 TM were assessed using 2D and 3D in vitro models as well as in vivo. Their specific tumor accumulation and diagnostic potential were evaluated using PET studies after functionalization with a chelator and suitable radionuclide. RESULTS: The αFAP-scFv and -IgG4 TMs effectively and specifically redirected UniCAR T-cells using 2D, 3D, and in vivo models. Moreover, a remarkably high and specific accumulation of radiolabeled FAP-targeting TMs at the tumor site of xenograft mouse models was observed. CONCLUSIONS: These findings demonstrate that the novel αFAP TMs are promising immunotheranostic tools to foster cancer imaging and treatment, paving the way for a more convenient, individualized, and safer treatment of cancer patients.

Bispidine Chelators for Radiopharmaceutical Applications with Lanthanide, Actinide, and Main Group Metal Ions.

Octadentate and specifically nonadentate ligands with a bispidine scaffold (3,7-diazabicyclo[3.3.1]nonane) are known to be efficiently coordinated to a range of metal ions of interest in radiopharmaceutical chemistry and lead to exceedingly stable and inert complexes. Nonadentate bispidine L2 (with a tridentate bipyridine acetate appended to N3 and a picolinate at N7) has been shown before to be an ideal chelator for 111In3+, 177Lu3+, and 225Ac3+, nuclides of interest for diagnosis and therapy, and a proof-of-principle study with an SSTR2-specific octreotate has shown potential for theranostic applications. We now have extended these studies in two directions. First, we present ligand derivative L3, in which the bipyridine acetate is substituted with terpyridine, a softer donor for metal ions with a preference for more covalency. L3 did not fulfill the hopes because complexation is much less efficient. While for Bi3+ and Pb2+ the ligand is an excellent chelator with properties similar to those of L2, Lu3+ and La3+ show very slow and inefficient complexation with L3 in contrast to L2, and 225Ac3+ is not fully coordinated, even at an increased temperature (92% radiochemical yield at 80 °C, 60 min, [L3] = 10-4 M). These observations have led to a hypothesis for the complexation pathway that is in line with all of the experimental data and supported by a preliminary density functional theory analysis, which is important for the design of further optimized bispidine chelators. Second, the coordination chemistry of L2 has been extended to Bi3+, La3+, and Pb2+, including solid state and solution structural work, complex stabilities, radiolabeling, and radiostability studies. All complexes of this ligand (La3+, Ac3+, Lu3+, Bi3+, In3+, and Pb2+), including nuclides for targeted α therapy (TAT), single-photon emission computed tomography, and positron emission tomography, are formed efficiently under physiological conditions, i.e., suitable for the labeling of delicate biological vectors such as antibodies, and the complexes are very stable and inert. Importantly, for TAT with 225Ac, the daughter nuclides 213Bi and 209Pb also form stable complexes, and this is important for reducing damage to healthy tissue.

Additional Active Movements Are Not Required for Strength Gains in the Untrained during Short-Term Whole-Body Electromyostimulation Training.

Recommendations for conventional strength training are well described, and the volume of research on whole-body electromyostimulation training (WB-EMS) is growing. The aim of the present study was to investigate whether active exercise movements during stimulation have a positive effect on strength gains. A total of 30 inactive subjects (28 completed the study) were randomly allocated into two training groups, the upper body group (UBG) and the lower body group (LBG). In the UBG (n = 15; age: 32 (25-36); body mass: 78.3 kg (53.1-114.3 kg)), WB-EMS was accompanied by exercise movements of the upper body and in the LBG (n = 13; age: 26 (20-35); body mass: 67.2 kg (47.4-100.3 kg)) by exercise movements of the lower body. Therefore, UBG served as a control when lower body strength was considered, and LBG served as a control when upper body strength was considered. Trunk exercises were performed under the same conditions in both groups. During the 20-min sessions, 12 repetitions were performed per exercise. In both groups, stimulation was performed with 350 µs wide square pulses at 85 Hz in biphasic mode, and stimulation intensity was 6-8 (scale 1-10). Isometric maximum strength was measured before and after the training (6 weeks set; one session/week) on 6 exercises for the upper body and 4 for the lower body. Isometric maximum strength was significantly higher after the EMS training in both groups in most test positions (UBG p < 0.001-0.031, r = 0.88-0.56; LBG p = 0.001-0.039, r = 0.88-0.57). Only for the left leg extension in the UBG (p = 0.100, r = 0.43) and for the biceps curl in the LBG (p = 0.221, r = 0.34) no changes were observed. Both groups showed similar absolute strength changes after EMS training. Body mass adjusted strength for the left arm pull increased more in the LBG group (p = 0.040, r = 0.39). Based on our results we conclude that concurring exercise movements during a short-term WB-EMS training period have no substantial influence on strength gains. People with health restrictions, beginners with no experience in strength training and people returning to training might be particularly suitable target groups, due to the low training effort. Supposedly, exercise movements become more relevant when initial adaptations to training are exhausted.

Toward Personalized Medicine: One Chelator for Imaging and Therapy with Lutetium-177 and Actinium-225.

We report a nonadentate bispidine (3,7-diazabicyclo[3.3.1]nonane) that unveils the potential to bind theranostically relevant radionuclides, including indium-111, lutetium-177, and actinium-225 under mild labeling conditions. This radiopharmaceutical candidate allows the simultaneous application of imaging and treatment (radionuclide theranostics) without changing the type of the bioconjugate; that is, it allows the strong binding to an imaging and a therapeutic radionuclide by the same chelator. Since sophisticated coordination chemistry is required to achieve high thermodynamic and kinetic stability (inertness), it is not surprising that only a few chelators have been reported that are able to strongly bind several radionuclides to a satisfactory extent. Bispidine-derived ligands have proven to be ideal for di- and trivalent metal ions with generally fast complexation kinetics and high in vitro and in vivo stabilities. The presented (radio)complexes are formed under mild conditions (pH 6, <40 °C) and exhibit thermodynamic stability and inertness in human serum comparable to the corresponding DOTA complexes. The bispidine-based complexing agent was conjugated to a peptide, targeting somatostatin type 2 receptors (SSTR2), overexpressed on neuroendocrine tumors. The 177Lu- and 225Ac-labeled conjugates were investigated, considering their binding to two different SSTR2-positive cell lines, including the human pancreatic carcinoid tumor (BON-SSTR2+) and the murine pheochromocytoma cell line (MPC). The biodistribution and accumulation pattern in MPC tumor-bearing mice was also evaluated. The LuIII and AcIII complexes studied show how ligand structures can be optimized in general by extending the denticity and varying the donor set in order to allow for fast complex formation and medically relevant inertness.

Acute Effect of Electromyostimulation Superimposed on Running on Maximal Velocity, Metabolism, and Perceived Exertion.

Electromyostimulation has been shown to intensify exercise when superimposed on cycling. However, little is known about the application during running, which might help to prevent injuries linked to high running volumes, as intensification of running allows for a reduction in training volume. Therefore, the purpose of the study was to examine the effects of electromyostimulation superimposed on running. Men who were no younger than 18 and no older than 35 were eligible for inclusion in the study. Exclusion criteria were previous experience with electromyostimulation training, the presence of a contraindication according to the manufacturer, or a contraindication to physical activity. A sample of 22 healthy males with an ordinary performance capability accomplished three similar cardiopulmonary treadmill tests until exhaustion in a crossover study design that included lactate measurements and interrogations of perceived exertion. The first test was conducted without electromyostimulation and was followed in a randomized order by the second and the third test condition with 30 or 85 Hz stimulation, respectively, of the lower body. Superimposed electromyostimulation significantly reduced the maximal achieved velocity (control 15.6 ± 1.1 vs. 30 Hz 15.1 ± 1.2, p = 0.002; vs. 85 Hz 14.9 ± 1.1 km/h, p < 0.001), increased the perceived exertion at 10, 12 and 14 km/h (85 Hz + 0.7, p = 0.036; +0.9, p = 0.007; +1.3, p < 0.001; 30 Hz + 0.7, p = 0.025; +1.0, p = 0.002; +1.2, p < 0.001), and induced a significantly higher oxygen uptake at 8 km/h (85 Hz + 1.1, p = 0.006; 30 Hz + 0.9 mL·min−1·kg−1, p = 0.042), 10 km/h (30 Hz + 0.9 mL·min−1·kg−1, p = 0.032), and 14 km/h (85 Hz + 1.0 mL·min−1·kg−1, p = 0.011). Both electromyostimulation conditions significantly limited the maximal lactate level (30 Hz p = 0.046; 85 Hz p < 0.001) and 85 Hz also the recovery lactate level (p < 0.001). Superimposed electromyostimulation is feasible and intensifies running. Coaches and athletes could benefit from the increased training stimulus by reducing running velocity or volume, by combining endurance and strength training, and also by inducing better adaptations while maintaining the same velocity or volume. Therefore, electromyostimulation superimposed on running could be an interesting training tool for runners.

Dual-Labelling Strategies for Nuclear and Fluorescence Molecular Imaging: Current Status and Future Perspectives.

Molecular imaging offers the possibility to investigate biological and biochemical processes non-invasively and to obtain information on both anatomy and dysfunctions. Based on the data obtained, a fundamental understanding of various disease processes can be derived and treatment strategies can be planned. In this context, methods that combine several modalities in one probe are increasingly being used. Due to the comparably high sensitivity and provided complementary information, the combination of nuclear and optical probes has taken on a special significance. In this review article, dual-labelled systems for bimodal nuclear and optical imaging based on both modular ligands and nanomaterials are discussed. Particular attention is paid to radiometal-labelled molecules for single-photon emission computed tomography (SPECT) and positron emission tomography (PET) and metal complexes combined with fluorescent dyes for optical imaging. The clinical potential of such probes, especially for fluorescence-guided surgery, is assessed.

Bis(amido)bis(oxinate)diamine Ligands for theranostic radiometals.

With the interest in radiometal-containing diagnostic and therapeutic pharmaceuticals increasing rapidly, appropriate ligands to coordinate completely and stably said radiometals is essential. Reported here are two novel, bis(amido)bis(oxinate)diamine ligands, H2amidohox (2,2'-(ethane-1,2-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide) and H2amidoC3hox (2,2'-(propane-1,3-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide), that combine two 8-hydroxyquinoline and amide donor groups and differ by one carbon in their 1,2-ethylenediamine vs. 1,3-diaminopropane backbones, respectively. Both ligands have been thoroughly studied via metal complexation, solution thermodynamics and radiolabeling with three radiometal ions: [nat/64Cu]Cu2+, [nat/111In]In3+, and [nat/203Pb]Pb2+. X-ray crystallography determined the structures of the hexacoordinated Cu2+-ligand complexes, indicating a better fit of Cu2+ to the H2amidohox binding pocket. Concentration dependent radiolabeling with [64Cu]Cu2+ was successfully quantitative as low as 1 µM with H2amidohox and 10 µM with H2amidoC3hox within 5 min at room temperature. However, [64Cu][Cu(amidohox)] maintained higher kinetic inertness against a superoxide dismutase enzyme-challenge assay and ligand challenges compared to the [64Cu][Cu(amidoC3hox)] counterpart. Similarly, H2amidohox had significantly higher radiochemical conversion with both [111In]In3+ (97% at 1 µM) and [203Pb]Pb2+ (97% at 100 µM) under mild conditions compared to H2amidoC3hox (76% with [111In]In3+ at 1 µM and 0% with [203Pb]Pb2+). By studying non-radioactive and radioactive complexation with both ligands, a comprehensive understanding of the coordination differences between two- and three­carbon diamine backbones is discussed. Overall, the ethylenediamine backbone of H2amidohox proves to be superior in rapid, mild radiolabeling and kinetic inertness towards competing ligands and proteins.

[nat/89Zr][Zr(pypa)]: Thermodynamically Stable and Kinetically Inert Binary Nonadentate Complex for Radiopharmaceutical Applications.

H4pypa is a nonadentate nonmacrocyclic chelator, which previously demonstrated high affinity for scandium-44, lutetium-177, and indium-111. Herein, we report the highly stable binary [Zr(pypa)] complex; the nonradioactive complex was synthesized and characterized in detail using high-resolution electrospray-ionization mass spectroscopy (HR-ESI-MS) and various nuclear magnetic resonance spectroscopies (NMR), which revealed C2v symmetry of the complex. The geometry of [Zr(pypa)] was further detailed via X-ray crystallography and compared with the structure of [Fe(Hpypa)]. Despite a slow complexation rate with an association half-life of 31.4 h at pH 2 and room temperature, the [Zr(pypa)] complex is thermodynamically stable (log KML = 38.92, pZr = 39.4). Radiochemical studies demonstrated quantitative radiolabeling achieved at 10 µM chelator concentration within 2 h at 40 °C and pH = 7, antibody-compatible conditions. Of the utmost importance, [89Zr][Zr(pypa)] is highly kinetically inert upon challenge with excess EDTA and DFO ligands, superior to [89Zr][Zr(DFO)]+, and maintains inertness toward human serum.

Chelators for Treatment of Iron and Copper Overload: Shift from Low-Molecular-Weight Compounds to Polymers.

Iron and copper are essential micronutrients needed for the proper function of every cell. However, in excessive amounts, these elements are toxic, as they may cause oxidative stress, resulting in damage to the liver and other organs. This may happen due to poisoning, as a side effect of thalassemia infusion therapy or due to hereditary diseases hemochromatosis or Wilson's disease. The current golden standard of therapy of iron and copper overload is the use of low-molecular-weight chelators of these elements. However, these agents suffer from severe side effects, are often expensive and possess unfavorable pharmacokinetics, thus limiting the usability of such therapy. The emerging concepts are polymer-supported iron- and copper-chelating therapeutics, either for parenteral or oral use, which shows vivid potential to keep the therapeutic efficacy of low-molecular-weight agents, while avoiding their drawbacks, especially their side effects. Critical evaluation of this new perspective polymer approach is the purpose of this review article.

H2pyhox - Octadentate Bis(pyridyloxine).

A new versatile chelating ligand for intermediate size and softness radiometals [64Cu]Cu2+ and [111In]In3+, H2pyhox, was synthesized by introducing pyridine as a new donor moiety to complement 8-hydroxyquinoline on an ethylenediamine backbone. The combination of pyridine and oxine as donor sets was explored through structural analysis, and crystals of the three metal complexes with Cu2+, La3+, and In3+ demonstrate how the ligand adapts to accommodate metal ions of different sizes and charge. Exhaustive in-batch UV solution studies characterized the protonation constants of the free ligand as well as the formation constants of the metal complexes with Cu2+, In3+, and La3+. Preliminary concentration-dependent radiolabeling studies with [111In]In3+ and [64Cu]Cu2+ show the robustness of H2pyhox to successfully coordinate both radiometals under mild conditions (<15 min, room temperature, pH 6). H2pyhox is the first oxinate ligand to successfully radiolabel [225Ac]Ac3+, albeit only at high concentrations (0.1-1 mM) with gentle heating to 37 °C. Whole serum, protein, and ligand challenge assays further demonstrate the kinetic inertness of the [111In]In3+ and [64Cu]Cu2+ radiometal-ligand complexes, confirming H2pyhox to be a promising versatile radiopharmaceutical chelator.

High denticity oxinate-linear-backbone chelating ligand for diagnostic radiometal ions [111In]In3+ and [89Zr]Zr4.

Advances in nuclear medicine depend on chelating ligands that form highly stable and kinetically inert complexes with relevant radiometal ions for use in diagnosis or therapy. A new potentially decadentate ligand, H5decaox, was synthesised to incorporate two 8-hydroxyquinoline moieties on either end of a diethylenetriamine backbone decorated with three carboxylic acids, one at each N atom of the backbone. Metal complexation was assessed using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS) with In3+, Zr4+ and La3+. Solution thermodynamic studies provided the stepwise protonation constants and metal formation constants, indicating a high affinity for both In3+ and Zr4+ (pIn = 32.3 and pZr = 34.7), and density functional theory (DFT) calculations provided insight into the coordination environments with either metal ion. Concentration dependent radiolabeling experiments with [111In]InCl3 and [89Zr]ZrCl4 showed promise as quantitative radiolabeling (>95%) occurred at micromolar concentrations, under mild, near-physiological conditions of pH 7 and room temperature for 30 minutes. Serum stability of both radiometal complexes was investigated and the [111In]In(decaox) complex remained 91% intact after 24 hours while the [89Zr]Zr(decaox) complex was 86% intact over the same time, comparable to other chelating ligands previously assessed with the same methods. The high radiolabeling yields, limited serum protein transchelation and structural insight of the [89Zr]Zr(decaox) complex suggest a promising fit between the oxinate-containing ligand and the Zr4+ ion, setting the stage for further investigations with a functionalised version of the chelator for its potential in PET imaging.

Metal ion size profoundly affects H3glyox chelate chemistry.

The bisoxine hexadentate chelating ligand, H3glyox was investigated for its affinity for Mn2+, Cu2+ and Lu3+ ions; all three metal ions are relevant with applications in nuclear medicine and medicinal inorganic chemistry. The aqueous coordination chemistry and thermodynamic stability of all three metal complexes were thoroughly investigated by detailed DFT structure calculations and stability constant determination, by employing UV in-batch spectrophotometric titrations, giving pM values (pM = -log[M n+]free when [M n+] = 1 µM, [L] = 10 µM at pH 7.4 and 25 °C) - pCu (25.2) > pLu (18.1) > pMn (12.0). DFT calculated structures revealed different geometries and coordination preferences of the three metal ions; notable was an inner sphere water molecule in the Mn2+ complex. H3glyox labels [52gMn]Mn2+, [64Cu]Cu2+ and [177Lu]Lu3+ at ambient conditions with apparent molar activities of 40 MBq µmol-1, 500 MBq µmol-1 and 25 GBq µmol-1, respectively. Collectively, these initial investigations provide insight into the effects of metal ion size and charge on the chelation with the hexadentate H3glyox and indicate that further investigations of the Mn2+-H3glyox complex in 52g/55Mn-based bimodal imaging might be worthwhile.

Cation Exchange Protocols to Radiolabel Aqueous Stabilized ZnS, ZnSe, and CuFeS2 Nanocrystals with 64Cu for Dual Radio- and Photo-Thermal Therapy.

Here, cation exchange (CE) reactions are exploited to radiolabel ZnSe, ZnS, and CuFeS2 metal chalcogenide nanocrystals (NCs) with 64Cu. The CE protocol requires one simple step, to mix the water-soluble NCs with a 64Cu solution, in the presence of vitamin C used to reduce Cu(II) to Cu(I). Given the quantitative cation replacement on the NCs, a high radiochemical yield, up to 99%, is reached. Also, provided that there is no free 64Cu, no purification step is needed, making the protocol easily translatable to the clinic. A unique aspect of the approach is the achievement of an unprecedentedly high specific activity: by exploiting a volumetric CE, the strategy enables to concentrate a large dose of 64Cu (18.5 MBq) in a small NC dose (0.18 µg), reaching a specific activity of 103 TBq g-1. Finally, the characteristic dielectric resonance peak, still present for the radiolabeled 64Cu:CuFeS2 NCs after the partial-CE reaction, enables the generation of heat under clinical laser exposure (1 W cm-2). The synergic toxicity of photo-ablation and 64Cu ionization is here proven on glioblastoma and epidermoid carcinoma tumor cells, while no intrinsic cytotoxicity is seen from the NC dose employed for these dual experiments.

Light-Activated Carbon Monoxide Prodrugs Based on Bipyridyl Dicarbonyl Ruthenium(II) Complexes.

Two photoactivatable dicarbonyl ruthenium(II) complexes based on an amide-functionalised bipyridine scaffold (4-position) equipped with an alkyne functionality or a green-fluorescent BODIPY (boron-dipyrromethene) dye have been prepared and used to investigate their light-induced decarbonylation. UV/Vis, FTIR and 13 C NMR spectroscopies as well as gas chromatography and multivariate curve resolution alternating least-squares analysis (MCR-ALS) were used to elucidate the mechanism of the decarbonylation process. Release of the first CO molecule occurs very quickly, while release of the second CO molecule proceeds more slowly. In vitro studies using two cell lines A431 (human squamous carcinoma) and HEK293 (human embryonic kidney cells) have been carried out in order to characterise the anti-proliferative and anti-apoptotic activities. The BODIPY-labelled compound allows for monitoring the cellular uptake, showing fast internalisation kinetics and accumulation at the endoplasmic reticulum and mitochondria.

Contemporary Synthesis of Ultrasmall (sub-10 nm) Upconverting Nanomaterials.

Due to their unique photophysical properties, upconverting nanoparticles (UCNPs), i. e. particles capable of converting near-infrared (NIR) photons into tunable emissions in the range of ultraviolet (UV) to NIR, have great potential for use in various biomedical fields such as bioimaging, photodynamic therapy and bioanalytical applications. As far as biomedical applications are concerned, these materials have a number of advantageous properties such as brilliant luminescence and exceptional photostability. Very small "stealth" particles (sub-10 nm), which can circulate in the body largely undetected by the immune system, are particularly important for in vivo use. The fabrication of such particles, which simultaneously have a defined (ultrasmall) size and the required optical properties, is a great challenge and an area that is in its infancy. This minireview provides a concise overview of recent developments on appropriate synthetic methodologies to produce such UCNPs. Particular attention was given to the influence of both surfactants and dopants used to precisely adjust size, crystalline phase and optical properties of UCNPs.