High Apparent Activity Research Articles

Development and First-in-Human evaluation of a Site-Specific [18F]-Labeled PD-L1 nanobody PET radiotracer for noninvasive imaging in NSCLC.

Immunohistochemistry (IHC) for PD-L1 detection is limited by its invasiveness and heterogeneity of tumors. To address these challenges, a new PD-L1-targeted nanobody-based immune-PET radiotracer [18F]AlF-APN09 was developed using the site-specific radiolabeling method with the complexing agent (Mal-RESCA) under mild conditions. [18F]AlF-APN09 was prepared at room temperature (pH 4.6-4.8) within 20min with satisfactory radiochemical yields (45.8±4.48%, non-decay corrected), high radiochemical purity (>98%) and moderate apparent molar activity (15-35GBq/μmol), and remained stable in both PBS and 5% HSA after 4h (>90%). Cell uptake studies indicated variable levels of surface PD-L1 expression in the following order: A549PD-L1>H1975>A549. In micro-PET/CT imaging, A549PD-L1 and H1975 tumors were distinctly visualized in a 6.0:1 and 3.2:1 ratios over PD-L1-negative A549 tumors in vivo. Ex vivo biodistribution studies showed tumor uptake values of 6.47±1.06%ID/g (A549PD-L1) and 2.27±0.19%ID/g (H1975), significantly higher than 0.90±0.28%ID/g in A549 tumors. The estimated effective radiation dose in humans was 8.65E-03mSv/MBq, lower than that of conventional [18F]FDG. First-in-human imaging was conducted on a single resectable non-small cell lung cancer (NSCLC) subject without any adverse reactions. The radiotracer exhibited renal excretion with minimal hepatobiliary clearance. Tumor uptake reached SUVmax 4.20 at 2h post-injection, demonstrating high contrast and rapid clearance. After PD-1 inhibitor immunotherapy and chemotherapy, the subject showed a therapeutic response and postoperative pathological specimens confirmed a major pathological response (MPR). These results suggest that we have successfully developed a new PD-L1-targeted nanobody PET tracer using the site-specific labeling method with the complexing agent (Mal-RESCA) within 20min under mild conditions and [18F]AlF-APN09 is a promising noninvasive PET radiotracer for visualizing PD-L1 expression in tumors, offering rapid tumor targeting, excellent signal-to-noise ratios, and favorable clearance properties.

Phosphonate-Based Aza-Macrocycle Ligands for Low-Temperature, Stable Chelation of Medicinally Relevant Rare Earth Radiometals and Radiofluorination.

Radioisotopes of fluorine (18F), scandium (43/44Sc, 47Sc), lutetium (177Lu), and yttrium (86Y, 90Y) have decay properties ideally suited for targeted nuclear imaging and therapy with small biologics, such as peptides and antibody fragments. However, a single-molecule strategy to introduce these radionuclides into radiopharmaceuticals under mild conditions to afford inert in vivo complexes is critically lacking. Here, we introduce H4L2 and H4L3, two small-cavity macrocyclic chelator structural isomers bearing a single phosphonate functional group. Potentiometry and spectrophotometry were employed to determine H4L2 and H4L3's ability to form a single [M(L)]- species with metals of different sizes (Sc3+, Lu3+, and Y3+) under physiologically relevant conditions. NMR spectroscopy and density functional theory (DFT) calculations suggest modulation of H4L2 and H4L3's inner-sphere hydration across the Sc3+/Lu3+/Y3+ series. Radiochemical labeling experiments with 18F, 44Sc, 177Lu, and 86Y reveal that H4L2 selectively chelates radioscandium at room temperature with high apparent molar activity (AMA, 462 mCi/μmol), while radiofluorination remains inaccessible. In contrast, H4L3 enables room temperature radiochelation 44Sc, 177Lu, and 86Y (AMA: 96-275 mCi/μmol) and incorporates 18F via the Sc-18F methodology to form [18F][ScF(L3)]2-. In vivo biodistribution analysis at 1 h postinjection confirms the broad utility of H4L3: all four radiochemical complexes clear off-target organs and remain >98% intact in urine metabolite analyses. The scope of room temperature radiochemical labeling, paired with facile 18F incorporation, to afford in vivo compatible complexes exceeds the clinical gold standard chelator DOTA and previously reported acyclic chelators, rendering H4L3 promising for prospective radiopharmaceutical applications.

Rapid Concentration of Ga-68 and Proof-of-Concept Microscale Labeling of [68Ga]Ga-PSMA-11 in a Droplet Reactor.

The radiometal gallium-68 (Ga-68) has garnered significant interest due to its convenient production via compact and widely available generators and the high performance of 68Ga-labeled compounds for positron-emission tomography (PET) imaging for cancer diagnosis and management of patients undergoing targeted radionuclide therapy. Given the short half life of Ga-68 (68 min), microfluidic-based radiosynthesis is a promising avenue to establish very rapid, efficient, and routine radiolabeling with Ga-68; however, the typical elution volume of Ga-68 from a generator (4-10 mL) is incompatible with the microliter reaction volumes of microfluidic devices. To bridge this gap, we developed a microscale cartridge-based approach to concentrate Ga-68. By optimizing cartridge design, resin type, resin mass, and eluent composition, Ga-68 was reliably concentrated from ~6 mL to ~80 µL with high recovery efficiency (>97%, n = 14). Furthermore, this method is suitable for both single- and dual-generator setups. To demonstrate suitability of the concentrated radiometal for radiolabeling, we performed microdroplet synthesis of [68Ga]Ga-PSMA-11, achieving high radiochemical yield (83 ± 11%, n = 3), excellent radiochemical purity (>99%), and high apparent specific activity (255-320 MBq/μg). The entire process, including Ga-68 concentration, radiosynthesis, purification, and formulation, was completed in 12 min. Starting with activity of 0.81-0.84 GBq, 0.51-0.64 GBq of product was produced, sufficient for multiple patient doses. This work paves the way to clinical-scale production of other 68Ga-labeled compounds using droplet microreactor methods, or high-throughput labeling optimization or compound screening of 68Ga-labeled probes using droplet reaction arrays.

The production and separation of 161Tb with high specific activity at the University of Utah

Targeted radiotherapy (TRT) is an increasingly prominent area of research in nuclear medicine, particularly in the context of treating cancerous tumors. One radionuclide of considerable interest for TRT is terbium-161 (t1/2 = 6.95 days), which undergoes beta emission and shares similar decay properties as 177Lu (FDA-approved as LUTATHERA® and PLUVICTO®). Besides beta emission, 161Tb also emits a significant number of conversion and Auger electrons further enhancing its therapeutic potential. Terbium-161 can be produced using nuclear reactors through an indirect neutron capture reaction, G64160dn,γG64161d→3.66min,β−T65161b, from 160Gd targets. However, a key challenge in utilizing 161Tb for TRT lies in effectively separating target and product materials to attain high specific activity for radiolabeling. Here, we detail the production of no-carrier added 161Tb using low flux research reactors (mean thermal (<0.625 eV) neutron flux: 1.356×1012n∙cm−2∙s−1) like the University of Utah TRIGA Reactor, using enriched 160Gd2O3 targets (1.5 ± 0.3 μCi of 161Tb per mg of 160Gd target per hour of irradiation). We also developed a separation technique based on cation exchange and extraction chromatography, suitable for mCi level irradiations with targets exceeding 200 mg. In a simulated full-scale irradiation, 161Tb was successfully isolated from large mass targets using cation exchange (AG 50W-X8, with 2-hydroxyisobutyric acid at 70 mM, pH 4.75) and extraction chromatography (LN Resin, 0.5–0.75 M HNO3) methods. This resulted in high apparent molar activities of [161Tb]Tb-DOTA (113 ± 3 MBq/nmol), demonstrating high purity 161Tb relevant for potential future preclinical applications.

Scalability study on [133La]LaCl3 production with a focus on potential clinical applications

BackgroundIn recent years, targeted alpha therapy has gained importance in the clinics, and in particular, the alpha-emitter 225Ac plays a fundamental role in this clinical development. Nevertheless, depending on the chelating system no real diagnostic alternative has been established which shares similar chemical properties with this alpha-emitting radionuclide. In fact, the race to launch a diagnostic radionuclide to form a matched pair with 225Ac is still open, and 133La features attractive radiation properties to claim this place. However, in order to enable its translation into clinical use, upscaling of the production of this PET radionuclide is needed.ResultsA study on optimal irradiation parameters, separation conditions and an exhaustive product characterization was carried out. In this framework, a proton irradiation of 2 h, 60 µA and 18.7 MeV produced 133La activities of up to 10.7 GBq at end of bombardment. In addition, the performance of four different chromatographic resins were tested and two optimized purification methods presented, taking approximately 20 min with a 133La recovery efficiencies of over 98%, decay corrected. High radionuclide purity and apparent molar activity was proved, of over 99.5% and 120 GBq/µmol, respectively, at end of purification. Furthermore, quantitative complexation of PSMA-617 and mcp-M-PSMA were obtained with molar activities up to 80 GBq/µmol. In addition, both 133La-radioconjugates offered high stability in serum, of over (98.5 ± 0.3)% and (99.20 ± 0.08)%, respectively, for up to 24 h. A first dosimetry estimation was also performed and it was calculated that an 133La application for imaging with between 350 and 750 MBq would only have an effective dose of 2.1–4.4 mSv, which is comparable to that of 18F and 68Ga based radiopharmaceuticals.ConclusionsIn this article we present an overarching study on 133La production, from the radiation parameters optimization to a clinical dose estimation. Lanthanum-133 activities in the GBq range could be produced, formulated as [133La]LaCl3 with high quality regarding radiolabeling and radionuclide purity. We believe that increasing the 133La availability will further promote the development of radiopharmaceuticals based on macropa or other chelators suitable for 225Ac.Graphical abstract

[89Zr]ZrCl4 for direct radiolabeling of DOTA-based precursors

IntroductionZirconium-89 (89Zr) is a positron emitter with several advantages over other shorter-lived positron emission tomography (PET) compatible radiometals such as gallium-68 or copper-64. These include practically unlimited availability, extremely low cost, greatly facilitated distribution logistics, positron energy fit for medical PET imaging, and sufficiently long physical half-life to enable PET imaging at later time points for patient-specific dosimetry estimations. Despite these apparent benefits, the reception of 89Zr in the nuclear medicine community has been tepid. The driving factor for the absence of broader adaptation is mostly routed in its final formulation — [89Zr]zirconium oxalate. While serving as a suitable precursor solution for the gold standard chelator deferoxamine (DFO), [89Zr]Zr-oxalate is inaccessible for the most commonly used chelators, such as the macrocyclic DOTA, due to its pre-chelated state.Consequently, pioneering work has been conducted by multiple research groups to create oxalate-free forms of [89Zr]Zr4+, either via chemical conversion of oxalate into other counterion forms or via direct radiochemical isolation of [89Zr]ZrCl4, showing that [89Zr]Zr-DOTA complexes are possible and stable. However, this success was accompanied by challenges, including complex and labor-intensive radiochemical processing and radiolabeling procedures as well as the relatively minuscule conversion rates. Here, we report on the direct production of [89Zr]ZrCl4 avoiding oxalate and metal contaminants to enable efficient radiolabeling of DOTA constructs. MethodsWe based our direct production of [89Zr]ZrCl4 on previously reported methods and further optimized its quality by including an additional iron-removing step using the TK400 Resin. Here, we avoided using oxalic acid and effectively minimized the content of trace metal contaminants. Our two-step purification procedure was automated, and we confirmed excellent radionuclide purity, minimal trace metals content, great reactivity over time, and high specific molar activity. In addition, DOTA-based PSMA-617 and DOTAGA-based PSMA-I&T were radiolabeled to demonstrate the feasibility of direct radiolabeling and to estimate the maximum apparent specific activities. Lastly, the biodistribution of [89Zr]Zr-PSMA-617 was assessed in mice bearing PC3-PIP xenografts, and the results were compared to the previously published data. ResultsA total of 18 batches, ranging from 6.9 to 20 GBq (186 to 541 mCi), were produced. The specific molar activity for [89Zr]ZrCl4 exceeded 0.96 GBq (26 mCi) per nanomole of zirconium. The radionuclidic purity was >99 %, and the trace metals content was in the <1 ppm range. The [89Zr]ZrCl4 remained in its reactive chemical form for at least five days when stored in cyclic olefin polymer (COP) vials. Batches of 11.1 GBq (300 mCi) of [89Zr]Zr-PSMA-617 and 14.4 GBq (390 mCi) of [89Zr]Zr-PSMA-I&T, corresponding to specific activities of 11.1 MBq/μg (0.3 mCi/μg), and 14.4 MBq/μg (0.39 mCi/μg), respectively, were produced. [89Zr]Zr-PSMA-617 animal PET imaging results were in agreement with the previously published data. ConclusionIn this work, we report on a suitable application of TK400 Resin to remove iron during [89Zr]ZrCl4 radiochemical isolation. The breakthrough allows for direct radiolabeling of DOTA-based constructs with [89Zr]ZrCl4, leading to high apparent molar activities and excellent conversion rates.

Improved titanium-44 purification process for establishing a high apparent molar activity titanium-44/scandium-44 generator

44Sc-radiopharmaceuticals are gaining more interest but still lack availability. The proof of principle of a44Ti/44Sc generator, which can produce 44Sc daily, has been established but with some limitations and drawbacks. Despite recent advances, separation of 44Ti from massive quantities of scandium target material is still cumbersome. In this work, the improved radiochemical separation of 44Ti from residual scandium target material was carried out by precipitation of Sc with fluoride ions. Furthermore, two approaches were used to set up a high apparent molar activity small-scale generator. The first method relied on extraction chromatography for fine purification using a DGA resin, followed by loading of the purified 44Ti onto a ZR resin column. In the second method, 44Ti was loaded on the ZR resin directly after the precipitation step. This second method was used to set up a generator of 370 kBq and evaluate by radiolabeling. An apparent molar activity of 2 MBq/nmol was obtained for the radiolabeling with DOTA, the most common and suitable chelate for scandium. This result is comparable with previously published data on 44 m/44Sc.

Unraveling the Role of Particle Size and Nanostructuring on the Oxygen Evolution Activity of Fe-Doped NiO.

Nickel-based oxides and oxyhydroxide catalysts exhibit state-of-the-art activity for the sluggish oxygen evolution reaction (OER) under alkaline conditions. A widely employed strategy to increase the gravimetric activity of the catalyst is to increase the active surface area via nanostructuring or decrease the particle size. However, the fundamental understanding about how tuning these parameters influences the density of oxidized species and their reaction kinetics remains unclear. Here, we use solution combustion synthesis, a low-cost and scalable approach, to synthesize a series of Fe0.1Ni0.9O samples from different precursor salts. Based on the precursor salt, the nanoparticle size can be changed significantly from ∼2.5 to ∼37 nm. The OER activity at pH 13 trends inversely with the particle size. Using operando time-resolved optical spectroscopy, we quantify the density of oxidized species as a function of potential and demonstrate that the OER kinetics exhibits a second-order dependence on the density of these species, suggesting that the OER mechanism relies on O-O coupling between neighboring oxidized species. With the decreasing particle size, the density of species accumulated is found to increase, and their intrinsic reactivity for the OER is found to decrease, attributed to the stronger binding of *O species (i.e., a cathodic shift of species energetics). This signifies that the high apparent OER activity per geometric area of the smaller nanoparticles is driven by their ability to accumulate a larger density of oxidized species. This study not only experimentally disentangles the influence of the density of oxidized species and intrinsic kinetics on the overall rate of the OER but also highlights the importance of tuning these parameters independently to develop more active OER catalysts.

IrO2-ZrO2-SiO2 ternary oxide composites- based DSAs: Activity toward oxygen evolution reaction with long-term stability

BackgroundHigher purity of copper is produced by Electrowinning (EW) in the cathode. A major challenge in this technique is the anodic structure that causes in the energy consumption, corrosion resistance, and contamination of the copper produced in the cathode. MethodsTernary metallic oxide (IrO2-ZrO2-SiO2) composites with the different molar percentages of IrO2: SiO2 (10:60, 15:55, and 20:50%) were prepared on titanium substrate by the sol-gel technique, and then thermal decomposition to study the impact of IrO2 and SiO2 contents on the electrocatalyst performances of the dimensionally stable anodes (DSAs). The physicochemical properties of the DSAs were determined by X-ray diffraction (XRD), Field emission scanning electron microscope (FE-SEM), Atomic force microscopy (AFM), and electrochemical measurements. Significant findingsFE-SEM and AFM images display the impact of SiO2 on the crystallization and crystal growth of IrO2, leading to the formation of finer oxide particles and the porous morphology of the ternary oxide coatings. The DSA composed of 50 % SiO2 and 20 % IrO2 (IZS (20–30–50)) with a more porous surface area represented high apparent electrocatalytic activity toward the oxygen evolution reaction with long-term stability as analyzed under cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and accelerated lifetime (ALT) plots.

Construction of catalase@hollow silica nanosphere: Catalase with immobilized but not rigid state for improving catalytic performances

Enzyme immobilization usually make use of nanomaterials to hold up biocatalysis stability in various unamiable reaction conditions, but also lead large discount on enzyme activity. Thus, there are abundant researches focus on how to deal with the relation of enzyme molecules and supports. In this work, a new state of highly active enzymes has been established through facile and novel in situ immobilization and soft template removal method to construct enzyme contained hollow silica nanosphere (catalase@HSN) biocatalysts where enzymes in the cavity exhibit “immobilized but not rigid state”. The obtained catalase@HSN was characterized by transmission electron microscopy, scanning electron microscopy and confocal laser scanning microscopy et al. Catalase@HSN exhibits excellent activity (about 80 % activity recovery rate) and stability suffers from extreme pH, temperature, and organic solvents. Moreover, the reusability and storage stability of catalase@HSN also are satisfactory. This proposed strategy provides a facile method for preparing biocatalysts under mild conditions, facilitating the applications of immobilized enzyme in the fields of real biocatalytic industry with high apparent activity and passable stability.

Is Smaller Better? Cu2+/Cu+ Coordination Chemistry and Copper-64 Radiochemical Investigation of a 1,4,7-Triazacyclononane-Based Sulfur-Rich Chelator.

The biologically triggered reduction of Cu2+ to Cu+ has been postulated as a possible in vivo decomplexation pathway in 64/67Cu-based radiopharmaceuticals. In an attempt to hinder this phenomenon, we have previously developed a family of S-containing polyazamacrocycles based on 12-, 13-, or 14-membered tetraaza rings able to stabilize both oxidation states. However, despite the high thermodynamic stability of the resulting Cu2+/+ complexes, a marked [64Cu]Cu2+ release was detected in human serum, likely as a result of the partially saturated coordination sphere around the copper center. In the present work, a new hexadentate macrocyclic ligand, 1,4,7-tris[2-(methylsulfanyl)ethyl)]-1,4,7-triazacyclononane (NO3S), was synthesized by hypothesizing that a smaller macrocyclic backbone could thwart the observed demetalation by fully encapsulating the copper ion. To unveil the role of the S donors in the metal binding, the corresponding alkyl analogue 1,4,7-tris-n-butyl-1,4,7-triazacyclononane (TACN-n-Bu) was considered as comparison. The acid-base properties of the free ligands and the kinetic, thermodynamic, and structural properties of their Cu2+ and Cu+ complexes were investigated in solution and solid (crystal) states through a combination of spectroscopic and electrochemical techniques. The formation of two stable mononuclear species was detected in aqueous solution for both ligands. The pCu2+ value for NO3S at physiological pH was 6 orders of magnitude higher than that computed for TACN-n-Bu, pointing out the significant stabilizing contribution arising from the Cu2+-S interactions. In both the solid state and solution, Cu2+ was fully embedded in the ligand cleft in a hexacoordinated N3S3 environment. Furthermore, NO3S exhibited a remarkable ability to form a stable complex with Cu+ through the involvement of all of the donors in the coordination sphere. Radiolabeling studies evidenced an excellent affinity of NO3S toward [64Cu]Cu2+, as quantitative incorporation was achieved at high apparent molar activity (∼10 MBq/nmol) and under mild conditions (ambient temperature, neutral pH, 10 min reaction time). Human serum stability assays revealed an increased stability of [64Cu][Cu(NO3S)]2+ when compared to the corresponding complexes formed by 12-, 13-, or 14-membered tetraaza rings.

Cyclotron Production of Gallium-68 Radiopharmaceuticals Using the 68Zn(p,n)68Ga Reaction and Their Regulatory Aspects.

Designing and implementing various radionuclide production methods guarantees a sustainable supply, which is important for medical use. The use of medical cyclotrons for radiometal production can increase the availability of gallium-68 (68Ga) radiopharmaceuticals. Although generators have greatly influenced the demand for 68Ga radiopharmaceuticals, the use of medical cyclotrons is currently being explored. The resulting 68Ga production is several times higher than obtained from a generator. Moreover, the use of solid targets yields end of purification and end of synthesis (EOS) of up to 194 GBq and 72 GBq, respectively. Furthermore, experiments employing liquid targets have provided promising results, with an EOS of 3 GBq for [68Ga]Ga-PSMA-11. However, some processes can be further optimized, specifically purification, to achieve high 68Ga recovery and apparent molar activity. In the future, 68Ga will probably remain one of the most in-demand radionuclides; however, careful consideration is needed regarding how to reduce the production costs. Thus, this review aimed to discuss the production of 68Ga radiopharmaceuticals using Advanced Cyclotron Systems, Inc. (ACSI, Richmond, BC, Canada) Richmond, Canada and GE Healthcare, Wisconsin, USA cyclotrons, its related factors, and regulatory concerns.

Limited carbon cycling due to high-pressure effects on the deep-sea microbiome

Deep-sea microbial communities are exposed to high-pressure conditions, which has a variable impact on prokaryotes depending on whether they are piezophilic (that is, pressure-loving), piezotolerant or piezosensitive. While it has been suggested that elevated pressures lead to higher community-level metabolic rates, the response of these deep-sea microbial communities to the high-pressure conditions of the deep sea is poorly understood. Based on microbial activity measurements in the major oceanic basins using an in situ microbial incubator, we show that the bulk heterotrophic activity of prokaryotic communities becomes increasingly inhibited at higher hydrostatic pressure. At 4,000 m depth, the bulk heterotrophic prokaryotic activity under in situ hydrostatic pressure was about one-third of that measured in the same community at atmospheric pressure conditions. In the bathypelagic zone—between 1,000 and 4,000 m depth—~85% of the prokaryotic community was piezotolerant and ~5% of the prokaryotic community was piezophilic. Despite piezosensitive-like prokaryotes comprising only ~10% (mainly members of Bacteroidetes, Alteromonas) of the deep-sea prokaryotic community, the more than 100-fold metabolic activity increase of these piezosensitive prokaryotes upon depressurization leads to high apparent bulk metabolic activity. Overall, the heterotrophic prokaryotic activity in the deep sea is likely to be substantially lower than hitherto assumed, with major impacts on the oceanic carbon cycling.

68Ga-DOTATATE Prepared from Cyclotron-Produced 68Ga: An Integrated Solution from Cyclotron Vault to Safety Assessment and Diagnostic Efficacy in Neuroendocrine Cancer Patients.

Cyclotron production of 68Ga is a promising approach to supply 68Ga radiopharmaceuticals. To validate this capability, an integrated solution for a robust synthesis of 68Ga-DOTATATE prepared from cyclotron-produced 68Ga was achieved. A retrospective comparison analysis was performed on patients who underwent PET/CT imaging after injection of DOTATATE labeled with 68Ga produced by a cyclotron or eluted from a generator to demonstrate the clinical safety and diagnostic efficacy of the radiopharmaceutical as a routine standard-of-care diagnostic tool in the clinic. Methods: An enriched pressed 68Zn target was irradiated by a cyclotron with a proton beam set at 12.7 MeV for 100 min. The fully automated process uses an in-vault dissolution system in which a liquid distribution system transfers the dissolved target to a dedicated hot cell for the purification of 68GaCl3 and radiolabeling of DOTATATE using a cassette-based automated module. Quality control tests were performed on the resulting tracer solution. The internal radiation dose for 68Ga-DOTATATE was based on extrapolation from rat biodistribution experiments. A retrospective comparison analysis was performed on patients who underwent PET/CT imaging after injection of DOTATATE labeled with cyclotron- or generator-produced 68Ga. Results: The synthesis of 68Ga-DOTATATE (20.7 ± 1.3 GBq) with high apparent molar activity (518 ± 32 GBq/μmol at the end of synthesis) was completed in 65 min, and the radiopharmaceutical met the requirements specified in the European Pharmacopoeia monograph on 68Ga-chloride (accelerator-produced) solution for radiolabeling. 68Ga-DOTATATE was stable for at least 5 h after formulation. The dosimetry calculated with OLINDA for cyclotron- and generator-produced 68Ga-DOTATATE was roughly equivalent. The SUVmean or SUVmax of tumoral lesions with cyclotron-produced 68Ga-DOTATATE was equivalent to that with generator-produced 68Ga. Among physiologic uptake levels, a significant difference was found in kidneys, spleen, and stomach wall, with lower values in cyclotron-produced 68Ga-DOTATATE in all cases. Conclusion: Integrated cyclotron production achieves reliable high yields of clinical-grade 68Ga-DOTATATE. The clinical safety and imaging efficacy of cyclotron-produced 68Ga-DOTATATE in humans provide supporting evidence for its use in routine clinical practice.

Evaluation of MxOy/fucoidan hybrid system and their application in lipase immobilization process

In this work, new MxOy/fucoidan hybrid systems were fabricated and applied in lipase immobilization. Magnesium (MgO) and zirconium (ZrO2) oxides were used as MxOy inorganic matrices. In the first step, the proposed oxides were functionalized with fucoidan from Fucus vesiculosus (Fuc). The obtained MgO/Fuc and ZrO2/Fuc hybrids were characterized by means of spectroscopic analyses, including Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and nuclear magnetic resonance. Additionally, thermogravimetric analysis was performed to determine the thermal stability of the hybrids. Based on the results, the mechanism of interaction between the oxide supports and fucoidan was also determined. Furthermore, the fabricated MxOy/fucoidan hybrid materials were used as supports for the immobilization of lipase from Aspergillus niger, and a model reaction (transformation of p-nitrophenyl palmitate to p-nitrophenol) was performed to determine the catalytic activity of the proposed biocatalytic system. In that reaction, the immobilized lipase exhibited high apparent and specific activity (145.5 U/gcatalyst and 1.58 U/mgenzyme for lipase immobilized on MgO/Fuc; 144.0 U/gcatalyst and 2.03 U/mgenzyme for lipase immobilized on ZrO2/Fuc). The immobilization efficiency was also confirmed using spectroscopic analyses (FTIR and XPS) and confocal microscopy.

Defect engineering of enzyme-embedded metal–organic frameworks for smart cargo release

A biological system that can efficiently respond to external signals to release its cargo is promising in many areas. Here, we report a method of engineering defects in enzyme-embedded metal–organic frameworks (MOFs) which brings advantageous properties for drug delivery, showing that defects sometimes can bring out miraculous performances. The glucose oxidase (GOx) encapsulated in MOFs with defects displayed much higher apparent activity than that in normal MOFs. By the combination of Fourier transformation of extended X-ray absorption fine structures and molecular simulations, we proved that the defects generated mesopores and thus enhanced the enzyme substrate transportation. Based on this defect engineering approach, a drug delivery system was constructed by co-encapsulating GOx and insulin in defected MOFs. The insulin in defected MOFs can be efficiently released in response to a high glucose concentration while scarcely released with a low glucose concentration, providing a new possible route for intelligent insulin delivery.

New Fully Automated Preparation of High Apparent Molar Activity 68Ga-FAPI-46 on a Trasis AiO Platform.

A large number of applications for fibroblast activation protein inhibitors (FAPI)-based PET agents have been evaluated in conditions ranging from cancer to non-malignant diseases such as myocardial infarction. In particular, 68Ga-FAPI-46 was reported to have a high specificity and affinity for FAP-expressing cells, a fast and high accumulation in tumor lesions/injuries together with a fast body clearance when investigated in vivo. Due to the increasing interest in the use of the agent both preclinically and clinically, we developed an automated synthesis for the production of 68Ga-FAPI-46 on a Trasis AiO platform. The new synthetic procedure, which included the processing of the generator eluate using a strong cation exchange resin and a final purification step through an HLB followed by a QMA cartridge, yielded 68Ga-FAPI-46 with high radiochemical purity (>98%) and apparent molar activity (271.1 ± 105.6 MBq/nmol). Additionally, the in vitro and in vivo properties of the product were assessed on glioblastoma cells and mouse model. Although developed for the preparation of 68Ga-FAPI-46 for preclinical use, our method can be adapted for clinical production as a reliable alternative to the manual (i.e., cold kit) or modular systems preparations already described in the literature.

Spatial confinement of partially oxidized RuCo alloys in N-doped carbon frameworks for highly efficient oxygen evolution electrocatalysis under acidic conditions

The acidic oxygen evolution reaction (OER) is currently one of the main bottlenecks limiting the practical applications of proton exchange membrane (PEM) water electrolysis technology, which is due to the lack of highly reactive, stable and cost-effective electrocatalysts. Herein, the interfacial CoRu-based metal–metal oxide heterostructures embedded in nitrogen-doped carbon nanosheets (RuCoOx-RuCo-NC) were rationally designed and synthesized by using a cobalt-based metal–organic framework (MIL-L-Co) as an effective synthetic platform. RuCoOx-RuCo-NC exhibited superior electrocatalytic OER performance in acidic environments by taking advantage of spatial confinement effect and metal–semiconductor interface. The optimal catalysts afforded a quite small overpotential of only 228 mV to achieve a current density of 10 mA cm−2 and showed excellent long-term durability within 12 h of operation. Specifically, RuCo-RuCoOx@NC enabled a mass activity as high as 0.933 A mgRu-1 at an overpotential of 300 mV, significantly outperforming the benchmark RuO2 catalyst. RuCoOx-RuCo-NC is expected to be one of the best acidic OER electrocatalysts with high apparent and mass activities among Ru/Ir-based catalysts reported.

High Cytotoxic Effect by Combining Copper-64 with a NOTA-Terpyridine Platinum Conjugate.

Terpyridine platinum (TP)-based chemotherapeutic agents target three-dimensional structures on DNA known as G-quadruplexes. We report the rational design and synthesis of a TP conjugate combined with copper-64 (64Cu), the decay characteristics of which include emission of β- and Auger electrons for radiotherapy and β+ particles for positron emission tomography (PET) imaging. The present experimental studies show that the novel [64Cu]Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-TP is stable, permitting selective killing of cancer cells. The antitumor activity of [64Cu]Cu-NOTA-TP at high apparent molar activity is in the low nanomolar range and 27,800-fold greater than that of natCu-NOTA-TP at 24 h post treatment. These results suggest that this combination of a cytotoxic TP agent with 64Cu has considerable potential for cancer treatment and PET imaging.

Paper-Based Enzymatic Colorimetric Assay for Rapid Malathion Detection.

Due to their unique properties, paper-based biosensors have attracted attention as inexpensive devices for on-site analysis. To achieve fast and sensitive detection of analytes, immobilization of enzymes with high apparent activities on paper is highly desirable; however, this is challenging. Herein, we report an improved approach to attach a malathion degrading enzyme, PoOPHM9, on paper via an interlocking network of Pluronic F127 (PF127)-poly(acrylic acid)-enzyme conjugates. The addition of PF127 improved retention of enzymatic activity as the apparent kinetic constant Vmax of the immobilized enzyme increased two-fold compared with the paper prepared without PF127. The PF127-poly(acrylic acid)-PoOPHM9 papers provided rapid colorimetric detection of malathion at 0.1-50 mM. The detection was completed within 5 min using a smartphone and image analysis software. As a proof-of-concept, malathion-contaminated water, plant, and apple samples were analyzed with the papers successfully. This material is promising for on-site rapid analysis of malathion-contaminated samples.