64CuCl2 PET Imaging of 4T1-Related Allograft of Triple-Negative Breast Cancer in Mice

⁶⁴CuCl₂ is an economic radiotracer for oncologic PET investigations. In the present study, we characterized the uptake of ⁶⁴CuCl₂ in vivo by µPET/CT in an allograft 4T1-related mouse model (BALB/c) of advanced breast cancer. ¹⁸F-FDG was used as a comparator. Twenty-two animals were imaged 7–9 days following 4T1-cell implantation inside mammary glands. Dynamic ⁶⁴CuCl₂ µPET/CT acquisition or iterative static images up to 8 h p.i. were performed. Animal biodistribution and tumor uptake were first evaluated in vivo by µPET analysis and then assessed on tissue specimens. Concerning ¹⁸F-FDG µPET, a static acquisition was performed at 15 min and 60 min p.i. Tumor ⁶⁴CuCl₂ accumulation increased from 5 min to 4 h p.i., reaching a maximum value of 5.0 ± 0.20 %ID/g. Liver, brain, and muscle ⁶⁴CuCl₂ accumulation was stable over time. The tumor-to-muscle ratio remained stable from 1 to 8 h p.i., ranging from 3.0 to 3.7. Ex vivo data were consistent with in vivo estimations. The ¹⁸F-FDG tumor accumulation was 8.82 ± 1.03 %ID/g, and the tumor-to-muscle ratio was 4.54 ± 1.11. ⁶⁴CuCl₂ PET/CT provides good characterization of the 4T1-related breast cancer model and allows for exploration of non-glycolytic cellular pathways potentially of interest for theragnostic strategies.     

Super Early Scan of PSMA PET/CT in Evaluating Primary and Metastatic Lesions of Prostate Cancer

⁶⁸Ga-prostate specific membrane antigen (PSMA)-11 PET/CT has been widely used in the diagnosis of prostate cancer (PCa); however, the urine lead shielding resulting from the urinary metabolism of tracers may obstruct the detection of surrounding metastasis. In this research, the additive value of super early scanning in diagnosing primary lesions and metastasis in the pelvic cavity was evaluated. Firstly, the differentiation efficiency of ⁶⁸Ga-PSMA-11 PET scanned at 3 min post-injection (min P.I.) was measured in PSMA-positive (22rv1 cells) and PSMA-negative (PC3 cells) model mice. Secondly, 106 patients were scanned at 3 min P.I. for the pelvic cavity and then scanned as a standard protocol at 45 min P.I. In the results, the differential diagnosis of PSMA expression was completely reflected as early as 3 min P.I. for mice models. For patients, when correlated with the Gleason score, the quantitative results of the super early scan displayed a comparable correlation coefficient with the routine scan. The target to bladder ratios increased from 1.44 ± 2.40 at 45 min to 10.10 ± 19.10 at 3 min (p < 0.001) for the primary lesions, and it increased from 0.99 ± 1.88 to 9.27 ± 23.03 for metastasis. Meanwhile, the target to background ratios increased from 2.21 ± 2.44 at 3 min to 19.13 ± 23.93 at 45 min (p < 0.001) for the primary lesions, and it increased from 1.68 ± 2.71 to 12.04 ± 18.73 (p < 0.001) for metastasis. In conclusion, super early scanning of ⁶⁸Ga-PSMA-11 PET/CT added referable information for metastasis detection in order to avoid disturbing tracer activity in the urinary system.     

A High Separation Factor for 165Er from Ho for Targeted Radionuclide Therapy

Background: Radionuclides emitting Auger electrons (AEs) with low (0.02–50 keV) energy, short (0.0007–40 µm) range, and high (1–10 keV/µm) linear energy transfer may have an important role in the targeted radionuclide therapy of metastatic and disseminated disease. Erbium-165 is a pure AE-emitting radionuclide that is chemically matched to clinical therapeutic radionuclide ¹⁷⁷Lu, making it a useful tool for fundamental studies on the biological effects of AEs. This work develops new biomedical cyclotron irradiation and radiochemical isolation methods to produce ¹⁶⁵Er suitable for targeted radionuclide therapeutic studies and characterizes a new such agent targeting prostate-specific membrane antigen. Methods: Biomedical cyclotrons proton-irradiated spot-welded Ho_(m) targets to produce ¹⁶⁵Er, which was isolated via cation exchange chromatography (AG 50W-X8, 200–400 mesh, 20 mL) using alpha-hydroxyisobutyrate (70 mM, pH 4.7) followed by LN2 (20–50 µm, 1.3 mL) and bDGA (50–100 µm, 0.2 mL) extraction chromatography. The purified ¹⁶⁵Er was radiolabeled with standard radiometal chelators and used to produce and characterize a new AE-emitting radiopharmaceutical, [¹⁶⁵Er]PSMA-617. Results: Irradiation of 80–180 mg ^natHo targets with 40 µA of 11–12.5 MeV protons produced ¹⁶⁵Er at 20–30 MBq·µA⁻¹·h⁻¹. The 4.9 ± 0.7 h radiochemical isolation yielded ¹⁶⁵Er in 0.01 M HCl (400 µL) with decay-corrected (DC) yield of 64 ± 2% and a Ho/¹⁶⁵Er separation factor of (2.8 ± 1.1) · 10⁵. Radiolabeling experiments synthesized [¹⁶⁵Er]PSMA-617 at DC molar activities of 37–130 GBq·µmol⁻¹. Conclusions: A 2 h biomedical cyclotron irradiation and 5 h radiochemical separation produced GBq-scale ¹⁶⁵Er suitable for producing radiopharmaceuticals at molar activities satisfactory for investigations of targeted radionuclide therapeutics. This will enable fundamental radiation biology experiments of pure AE-emitting therapeutic radiopharmaceuticals such as [¹⁶⁵Er]PSMA-617, which will be used to understand the impact of AEs in PSMA-targeted radionuclide therapy of prostate cancer.     

Glypican-3-Targeted Alpha Particle Therapy for Hepatocellular Carcinoma

Glypican-3 (GPC3) is expressed in 75% of hepatocellular carcinoma (HCC), but not normal liver, making it a promising HCC therapeutic target. GC33 is a full-length humanized monoclonal IgG1 specific to GPC3 that can localize to HCC in vivo. GC33 alone failed to demonstrate therapeutic efficacy when evaluated in patients with HCC; however, we posit that cytotoxic functionalization of the antibody with therapeutic radionuclides, may be warranted. Alpha particles, which are emitted by radioisotopes such as Actinium-225 (Ac-225) exhibit high linear energy transfer and short pathlength that, when targeted to tumors, can effectively kill cancer and limit bystander cytotoxicity. Macropa, an 18-member heterocyclic crown ether, can stably chelate Ac-225 at room temperature. Here, we synthesized and evaluated the efficacy of [²²⁵Ac]Ac–Macropa–GC33 in mice engrafted with the GPC3-expressing human liver cancer cell line HepG2. Following a pilot dose-finding study, mice (n = 10 per group) were treated with (1) PBS, (2) mass-equivalent unmodified GC33, (3) 18.5 kBq [²²⁵Ac]Ac–Macropa–IgG1 (isotype control), (4) 9.25 kBq [²²⁵Ac]Ac–Macropa–GC33, and (5) 18.5 kBq [²²⁵Ac]Ac–Macropa–GC33. While significant toxicity was observed in all groups receiving radioconjugates, the 9.25 kBq [²²⁵Ac]Ac–Macropa–GC33 group demonstrated a modest survival advantage compared to PBS (p = 0.0012) and 18.5 kBq [²²⁵Ac]Ac–IgG1 (p = 0.0412). Hematological analysis demonstrated a marked, rapid reduction in white blood cells in all radioconjugate-treated groups compared to the PBS and unmodified GC33 control groups. Our studies highlight a significant disadvantage of using directly-labeled biomolecules with long blood circulation times for TAT. Strategies to mitigate such treatment toxicity include dose fractionation, pretargeting, and using smaller targeting ligands.     

Preparation and Biological Evaluation of [99mTc]Tc-CNGU as a PSMA-Targeted Radiotracer for the Imaging of Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a well-established biological target that is overexpressed on the surface of prostate cancer lesions. Radionuclide-labeled small-molecule PSMA inhibitors have been shown to be promising PSMA-specific agents for the diagnosis and therapy of prostate cancer. In this study, a glutamate-urea-based PSMA-targeted ligand containing an isonitrile (CNGU) was synthesized and labeled with ^99mTc to prepare [^99mTc]Tc-CNGU with a high radiochemical purity (RCP). The CNGU ligand showed a high affinity toward PSMA (K_i value is 8.79 nM) in LNCaP cells. The [^99mTc]Tc-CNGU exhibited a good stability in vitro and hydrophilicity (log P = −1.97 ± 0.03). In biodistribution studies, BALB/c nude mice bearing LNCaP xenografts showed that the complex had a high tumor uptake with 4.86 ± 1.19% ID/g, which decreased to 1.74 ± 0.90% ID/g after a pre-injection of the selective PSMA inhibitor ZJ-43, suggesting that it was a PSMA-specific agent. Micro-SPECT imaging demonstrated that the [^99mTc]Tc-CNGU had a tumor uptake and that the uptake was reduced in the image after blocking with ZJ-43, further confirming its PSMA specificity. All of the results in this work indicated that [^99mTc]Tc-CNGU is a promising PSMA-specific tracer for the imaging of prostate cancer.     

Analysis of Pros and Cons in Using [68Ga]Ga-PSMA-11 and [18F]PSMA-1007: Production,Costs, and PET/CT Applications in Patients with Prostate Cancer

The aim of this work is to compare [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]PSMA-1007 PET/CT as imaging agents in patients with prostate cancer (PCa). Comparisons were made by evaluating times and costs of the radiolabeling process, imaging features including pharmacokinetics, and impact on patient management. The analysis of advantages and drawbacks of both radioligands might help to make a better choice based on firm data. For [⁶⁸Ga]Ga-PSMA-11, the radiochemical yield (RCY) using a low starting activity (L, average activity of 596.55 ± 37.97 MBq) was of 80.98 ± 0.05%, while using a high one (H, average activity of 1436.27 ± 68.68 MBq), the RCY was 71.48 ± 0.04%. Thus, increased starting activities of [⁶⁸Ga]-chloride negatively influenced the RCY. A similar scenario occurred for [¹⁸F]PSMA-1007. The rate of detection of PCa lesions by Positron Emission Tomography/Computed Tomography (PET/CT) was similar for both radioligands, while their distribution in normal organs significantly differed. Furthermore, similar patterns of biodistribution were found among [¹⁸F]PSMA-1007, [⁶⁸Ga]Ga-PSMA-11, and [¹⁷⁷Lu]Lu-PSMA-617, the most used agent for RLT. Moreover, the analysis of economical aspects for each single batch of production corrected for the number of allowed PET/CT examinations suggested major advantages of [¹⁸F]PSMA-1007 compared with [⁶⁸Ga]Ga-PSMA-11. Data from this study should support the proper choice in the selection of the PSMA PET radioligand to use on the basis of the cases to study.     

Engineered rHDL Nanoparticles as a Suitable Platform for Theranostic Applications

Reconstituted high-density lipoproteins (rHDLs) can transport and specifically release drugs and imaging agents, mediated by the Scavenger Receptor Type B1 (SR-B1) present in a wide variety of tumor cells, providing convenient platforms for developing theranostic systems. Usually, phospholipids or Apo-A1 lipoproteins on the particle surfaces are the motifs used to conjugate molecules for the multifunctional purposes of the rHDL nanoparticles. Cholesterol has been less addressed as a region to bind molecules or functional groups to the rHDL surface. To maximize the efficacy and improve the radiolabeling of rHDL theranostic systems, we synthesized compounds with bifunctional agents covalently linked to cholesterol. This strategy means that the radionuclide was bound to the surface, while the therapeutic agent was encapsulated in the lipophilic core. In this research, HYNIC-S-(CH₂)₃-S-Cholesterol and DOTA-benzene-p-SC-NH-(CH₂)₂-NH-Cholesterol derivatives were synthesized to prepare nanoparticles (NPs) of HYNIC-rHDL and DOTA-rHDL, which can subsequently be linked to radionuclides for SPECT/PET imaging or targeted radiotherapy. HYNIC is used to complexing ^99mTc and DOTA for labeling molecules with ^{111, 113m}In, ^{67, 68}Ga, ¹⁷⁷Lu, ¹⁶¹Tb, ²²⁵Ac, and ⁶⁴Cu, among others. In vitro studies showed that the NPs of HYNIC-rHDL and DOTA-rHDL maintain specific recognition by SR-B1 and the ability to internalize and release, in the cytosol of cancer cells, the molecules carried in their core. The biodistribution in mice showed a similar behavior between rHDL (without surface modification) and HYNIC-rHDL, while DOTA-rHDL exhibited a different biodistribution pattern due to the significant reduction in the lipophilicity of the modified cholesterol molecule. Both systems demonstrated characteristics for the development of suitable theranostic platforms for personalized cancer treatment.     

Targeting Colorectal Cancer Cells with a Functionalised Calix[4]arene Receptor: Biophysical Studies

Colorectal cancer (CRC) is a disease which is causing a high degree of mortality around the world. The present study reports the antiproliferative impact of the thioacetamide calix[4]arene, CAII receptor on a highly differentiated Caco-2 cell line. This statement is corroborated by the MTT assay results which revealed a reduction in the cell viability with an IC50 value of 19.02 ± 0.04 µM. Microscopic results indicated that at the starting amount of 10 µM of CAII, a decrease in cells confluency can already be observed in addition to changes in cells morphology. Cell metabolic pathway changes were also investigated. ¹H NMR findings showed downregulation in lactate, pyruvate, phosphocholine, lipids, and hydroxybutyrate with the upregulation of succinate, indicating a decline in the cells proliferation. Some biochemical alterations in the cells as a result of the CAII treatment were found by Raman spectroscopy.     

Inclusion Complex between Local Anesthetic/2-hydroxypropyl-β-cyclodextrin in Stealth Liposome

The drugs delivery system in the treatment of diseases has advantages such as reduced toxicity, increased availability of the drug, etc. Therefore, studies of the supramolecular interactions between local anesthetics (LAs) butamben (BTB) or ropivacaine (RVC) complexed with 2-hydroxypropyl-β-cyclodextrin (HP-βCD) and carried in Stealth liposomal (SL) are performed. ¹H-NMR nuclear magnetic resonance (DOSY and STD) were used as the main tools. The displacements observed in the ¹H-NMR presented the complexion between LAs and HP-βCD. The diffusion coefficients of free BTB and RVC were 7.70 × 10⁻¹⁰ m² s⁻¹ and 4.07 × 10⁻¹⁰ m² s⁻¹, and in the complex with HP-βCD were 1.90 × 10⁻¹⁰ m² s⁻¹ and 3.64 × 10⁻¹⁰ m² s⁻¹, respectively, which indicate a strong interaction between the BTB molecule and HP-βCD (98.3% molar fraction and Ka = 72.279 L/mol). With STD-NMR, the encapsulation of the BTB/HP-βCD and RVC/HP-βCD in SL vesicles was proven. Beyond the saturation transfer to the LAs, there is the magnetization transfer to the hydrogens of HP-βCD. BTB and RVC have already been studied in normal liposome systems; however, little is known of their behavior in SL.     

Synthesis and Evaluation of a Macrocyclic Actinium-225 Chelator,Quality Control and In Vivo Evaluation of 225Ac-crown-αMSH Peptide

Targeted alpha-therapy (TAT) has great potential for treating a broad range of late-stage cancers by delivering a focused and lethal radiation dose to tumors. Actinium-225 (²²⁵Ac) is an emerging alpha emitter suitable for TAT; however, the availability of chelators for Ac remains limited to a small number of examples (DOTA and macropa). Herein, we report a new Ac macrocyclic chelator named ‘ crown’ , which binds quantitatively and rapidly (<10 min) to Ac at ambient temperature. We synthesized ²²⁵Ac- crown -αMSH, a peptide targeting the melanocortin 1 receptor (MC1R), specifically expressed in primary and metastatic melanoma. Biodistribution of ²²⁵Ac- crown -αMSH showed favorable tumor-to-background ratios at 2 h post injection in a preclinical model. In addition, we demonstrated dramatically different biodistrubution patterns of ²²⁵Ac- crown -αMSH when subjected to different latency times before injection. A combined quality control methodology involving HPLC, gamma spectroscopy and radioTLC is recommended.     

Schiff Base in Ketoamine Form and Rh(η4-cod)-Schiff Base Complex with Z′ = 2 Structure from Pairwise C-H···Metallochelate-π Contacts

Condensation of 2-hydroxybenzaldehyde (salicylaldehyde) or 2-hydroxy-1-naphthaldehyde with 2-ethylaniline yields the Schiff base compound of (E)-2-(((2-ethylphenyl)imino)methyl)phenol (HL¹) or (E)-1-(((2-ethylphenyl)imino)methyl)naphthalen-2-ol (HL²), which in turn react with the dinuclear complex of [Rh(η⁴-cod)(µ-O₂CCH₃)]₂ (cod = cycloocta-1,5-diene) to afford the mononuclear (η⁴-cod){(E)-2-(((2-ethylphenyl)imino)methyl)phenolato-κ²N,O}rhodium(I), [Rh(η⁴-cod)(L¹)] (1) or (η⁴-cod){(E)-1-(((2-ethylphenyl)imino)methyl)naphthalen-2-olato-κ²N,O}rhodium(I), [Rh(η⁴-cod)(L²)] (2) (L¹ or L² = deprotonated Schiff base ligand). The X-ray structure determination revealed that the HL² exists in the solid state not as the usual (imine)N···H-O(phenol) form (enolamine form) but as the zwitterionic (imine)N-H⁺···^–O(phenol) form (ketoamine form). ¹H NMR spectra for HL² in different solvents demonstrated the existence of keto-enol tautomerism (i.e., keto ⇆ enol equilibrium) in solution. The structure for 1 and 2 showed that the deprotonated Schiff base ligand coordinates to the Rh(η⁴-cod)-fragment as a six-membered N^O-chelate around the rhodium atom with a close-to-square-planar geometry. Two symmetry-independent molecules (with Rh1 and Rh2) were found in the asymmetric unit in 1 in a structure with Z’ = 2. The supramolecular packing in HL² was organized by π-π and C-H···π contacts, while only two recognized C-H···π contacts were revealed in 1 and 2. Remarkably, there were reciprocal or pairwise C-H···π contacts between a pair of each of the symmetry-independent molecules in 1. This pairwise C-H contact to the Rh-N^O chelate (metalloaromatic) ring may be a reason for the two symmetry-independent molecules in 1. Differential scanning calorimetry (DSC) analyses revealed an irreversible phase transformation from the crystalline-solid to the isotropic-liquid phase and subsequently confirmed the thermal stability of the compounds. Absorption spectra in solution were explained by excited state properties from DFT/TD-DFT calculations.     

MiodesinTM Positively Modulates the Immune Response in Endometrial and Vaginal Cells

Endometriosis presents high prevalence and its physiopathology involves hyperactivation of endometrial and vaginal cells, especially by bacteria. The disease has no cure and therapies aiming to inhibit its development are highly desirable. Therefore, this study investigated whether Miodesin^TM (10 µg/mL = IC₈₀; 200 µg/mL = IC₅₀), a natural compound constituted by Uncaria tomentosa, Endopleura uchi, and astaxanthin, could exert anti-inflammatory and anti-proliferative effects against Lipopolysaccharides (LPS) stimulation in endometrial and Candida albicans vaginal cell lines. VK2 E6/E7 (vaginal) and KLE (epithelial) cell lines were stimulated with Candida albicans (1 × 10⁷ to 5 × 10⁷/mL) and LPS (1 μg/mL), respectively. Miodesin^TM inhibited mRNA expression for Nuclear factor kappa B (NF-κB), ciclo-oxigenase 1 (COX-1), and phospholipase A2 (PLA2), beyond the C–C motif chemokine ligand 2 (CCL2), CCL3, and CCL5 in VK2 E6/E7 cells (p < 0.05). In addition, the inhibitory effects of both doses of Miodesin^TM (10 µg/mL and 200 µg/mL) resulted in reduced secretion of interleukin-1β (IL-1β), IL-6, IL-8, tumor necrosis factor α (TNF-α) (24 h, 48 h, and 72 h) and CCL2, CCL3, and CLL5 (p < 0.05) by VK2 E6/E7 cells. In the same way, COX-1 Miodesin^TM inhibited LPS-induced hyperactivation of KLE cells, as demonstrated by reduced secretion of IL-1β, IL-6, IL-8, TNF-α (24 h, 48 h, and 72 h) and CCL2, CCL3, and CLL5 (p < 0.05). Furthermore, Miodesin^TM also inhibited mRNA expression and secretion of matrix metalloproteinase-2 (MMP-2), MMP-9, and vascular endothelial growth factor (VEGF), which are key regulators of invasion of endometrial cells. Thus, the study concludes that Miodesin^TM presents beneficial effects in the context of endometriosis, positively affecting the inflammatory and proliferative response.     

Insertion of Phosphenium Ions into a Bicyclo[1.1.0]Tetraphosphabutane Iron Complex

By reacting [{Cp‴Fe(CO)₂}₂(µ,η^1:1-P₄)] (1) with in situ generated phosphenium ions [Ph₂P][A] ([A]⁻ = [OTf]⁻ = [O₃SCF₃]⁻, [PF₆]⁻), a mixture of two main products of the composition [{Cp‴Fe(CO)₂}₂(µ,η^1:1-P₅(C₆H₅)₂)][PF₆] (2a and 3a) could be identified by extensive ³¹P NMR spectroscopic studies at 193 K. Compound 3a was also characterized by X-ray diffraction analysis, showing the rarely observed bicyclo[2.1.0]pentaphosphapentane unit. At room temperature, the novel compound [{Cp‴Fe}(µ,η^4:1-P₅Ph₂){Cp‴(CO)₂Fe}][PF₆] (4) is formed by decarbonylation. Reacting 1 with in situ generated diphenyl arsenium ions gives short-lived intermediates at 193 K which disproportionate at room temperature into tetraphenyldiarsine and [{Cp‴Fe(CO)₂}₄(µ₄,η^1:1:1:1-P₈)][OTf]₂ (5) containing a tetracyclo[3.3.0.0^2,7.0^3,6]octaphosphaoctane ligand.     

Synthesis and Characterization of a Mg2+-Selective Probe Based on Benzoyl Hydrazine Derivative and Its Application in Cell Imaging

A simple benzoyl hydrazine derivative P was successfully synthesized and characterized as Mg²⁺-selective fluorescent probe. The binding of P with Mg²⁺ caused an obvious fluorescence enhancement at 482 nm. The fluorescent, UV-vis spectra, ¹H-NMR, and IR spectra confirmed the formation of P-Mg²⁺ complex, and the formation of a 1:1 stoichiometry complex was proved by Job’s plot and mass spectrometry. The recognition mechanism of P to Mg²⁺ was owing to the photoinduced electron transfer effect (PET). The fluorescent response was linear in the range of 0.9–4.0 µM with the detection limit of 0.3 µM Mg²⁺ in water–ethanol solution (1:9, v:v, pH10.0, 20 mM HEPES). In addition, the results of cell imaging of Mg²⁺ in Hl-7701 cells was satisfying.     

Cytotoxic and apoptotic effects of Hypericum androsaemum on prostate adenocarcinoma (PC-3) and hepatocellular carcinoma (Hep G2) cell lines with identification of secondary metabolites by LC-HRMS

The study aims to determine the secondary metabolites of Hypericum androsaemum L. extracts by liquid chromatography-high resolution mass spectrometry (LC-HRMS), and investigate the antioxidant and cytotoxic activities of the plant. Cytotoxic activity was evaluated by MTT assay, and apoptosis induction abilities on human prostate adenocarcinoma (PC-3), and hepatocellular carcinoma (Hep G2) cell lines. Accordingly, major secondary metabolites were found as hederagenin (762 ± 70.10 μg/g) in the leaves dichloromethane (LD), herniarin (167 ± 1.50 μg/g) in fruit dichloromethane (FD), (-)-epicatechin (6538 ± 235.36 μg/g) in the leaves methanol (LM), (-)-epigallocatechin gallate (758 ± 20.46 μg/g) in the fruit methanol (FM), and caffeic acid (370 ± 8.88 μg/g) in the fruit water (FW), and (3313 ± 79.51 μg/g) in the leaves water (LW) extracts. LM exerted strong antioxidant activity in DPPH free (IC₅₀ 10.94 ± 0.08 μg/mL), and ABTS cation radicals scavenging (IC₅₀ 9.09 ± 0.05 μg/mL) activities. FM exhibited cytotoxic activity with IC₅₀ values of 73.23 ± 3.06 µg/mL and 31.64 ± 2.75 µg/mL on PC-3 and Hep G2 cell lines, respectively. Being the richest extract in terms of quillaic acid (630 ± 18.9 μg/g), which is a well-known cytotoxic triterpenoid with proven apoptosis induction ability on different cells, FM extract showed apoptosis induction activity with 64.75% on PC-3 cells at 50 μg/mL concentration. The study provides promising results about the potential of Hypericum androsaemum on cancer prevention.     

68Ga-Labeled [Leu13ψThz14]Bombesin(7–14) Derivatives: Promising GRPR-Targeting PET Tracers with Low Pancreas Uptake

The gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled receptor that is overexpressed in many solid cancers and is a promising target for cancer imaging and therapy. However, high pancreas uptake is a major concern in the application of reported GRPR-targeting radiopharmaceuticals, particularly for targeted radioligand therapy. To lower pancreas uptake, we explored Ga-complexed TacsBOMB2, TacsBOMB3, TacsBOMB4, TacsBOMB5, and TacsBOMB6 derived from a potent GRPR antagonist sequence, [Leu¹³ψThz¹⁴]Bombesin(7–14), and compared their potential for cancer imaging with [⁶⁸Ga]Ga-RM2. The K_i(GRPR) values of Ga-TacsBOMB2, Ga-TacsBOMB3, Ga-TacsBOMB4, Ga-TacsBOMB5, Ga-TacsBOMB6, and Ga-RM2 were 7.08 ± 0.65, 4.29 ± 0.46, 458 ± 38.6, 6.09 ± 0.95, 5.12 ± 0.57, and 1.51 ± 0.24 nM, respectively. [⁶⁸Ga]Ga-TacsBOMB2, [⁶⁸Ga]Ga-TacsBOMB3, [⁶⁸Ga]Ga-TacsBOMB5, [⁶⁸Ga]Ga-TacsBOMB6, and [⁶⁸Ga]Ga-RM2 clearly show PC-3 tumor xenografts in positron emission tomography (PET) images, while [⁶⁸Ga]Ga-TacsBOMB5 shows the highest tumor uptake (15.7 ± 2.17 %ID/g) among them. Most importantly, the pancreas uptake values of [⁶⁸Ga]Ga-TacsBOMB2 (2.81 ± 0.78 %ID/g), [⁶⁸Ga]Ga-TacsBOMB3 (7.26 ± 1.00 %ID/g), [⁶⁸Ga]Ga-TacsBOMB5 (1.98 ± 0.10 %ID/g), and [⁶⁸Ga]Ga-TacsBOMB6 (6.50 ± 0.36 %ID/g) were much lower than the value of [⁶⁸Ga]Ga-RM2 (41.9 ± 10.1 %ID/g). Among the tested [Leu¹³ψThz¹⁴]Bombesin(7–14) derivatives, [⁶⁸Ga]Ga-TacsBOMB5 has the highest tumor uptake and tumor-to-background contrast ratios, which is promising for clinical translation to detect GRPR-expressing tumors. Due to the low pancreas uptake of its derivatives, [Leu¹³ψThz¹⁴]Bombesin(7–14) represents a promising pharmacophore for the design of GRPR-targeting radiopharmaceuticals, especially for targeted radioligand therapy application.     

Separation of 44Sc from 44Ti in the Context of A Generator System for Radiopharmaceutical Purposes with the Example of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T Synthesis

Today, ⁴⁴Sc is an attractive radionuclide for molecular imaging with PET. In this work, we evaluated a ⁴⁴Ti/⁴⁴Sc radionuclide generator based on TEVA resin as a source of ⁴⁴Sc. The generator prototype (5 MBq) exhibits high ⁴⁴Ti retention and stable yield of ⁴⁴Sc (91 ± 6 %) in 1 mL of eluate (20 bed volumes, eluent—0.1 M oxalic acid/0.2 M HCl) during one year of monitoring (more than 120 elutions). The breakthrough of ⁴⁴Ti did not exceed 1.5 × 10⁻⁵% (average value was 6.5 × 10⁻⁶%). Post-processing of the eluate for further use in radiopharmaceutical synthesis was proposed. The post-processing procedure using a combination of Presep^® PolyChelate and TK221 resins made it possible to obtain ⁴⁴Sc-radioconjugates with high labeling yield (≥95%) while using small precursor amounts (5 nmol). The proposed method takes no more than 15 min and provides ≥90% yield relative to the ⁴⁴Sc activity eluted from the generator. The labeling efficiency was demonstrated on the example of [⁴⁴Sc]Sc-PSMA-617 and [⁴⁴Sc]Sc-PSMA-I&T synthesis. Some superiority of PSMA-I&T over PSMA-617 in terms of ⁴⁴Sc labeling efficiency was demonstrated (likely due to presence of DOTAGA chelator in the precursor structure). It was also shown that microwave heating of the reaction mixture considerably shortened the reaction time and improved radiolabeling yield and reproducibility of [⁴⁴Sc]Sc-PSMA-617 and [⁴⁴Sc]Sc-PSMA-I&T synthesis.     

Optimization of Sintering Conditions to Enhance the Dielectric Performance of Gd3+ and Ho3+ Codoped BaTiO3 Ceramics

BaTiO₃ dielectric capacitors, one of the important energy storage devices, play critical roles in storing electricity from renewable energies of water, wind, solar, etc. The synthesis of BaTiO₃ ceramics with weak temperature dependence and a high dielectric constant at room temperature (ε_RT′) is an urgent problem to meet the miniaturization and large capacity of dielectric capacitors. Doping rare earth elements into BaTiO₃ can solve this problem, but it is still challenging. In this work, we adopt a synergistic strategy of increasing ε_RT′ and improving the temperature stability by codoping Gd³⁺ and Ho³⁺, respectively, to address this challenge. By carefully adjusting the synthesis conditions in the solid-state reaction, codoping 7% Gd³⁺ and 7% Ho³⁺ in BaTiO₃ (BGTH7) ceramics were synthesized. The temperature-dependent dielectric constant reveals that the obtained optimal BGTH7 ceramic satisfies the X7U specification and displays a stable ε′ in the temperature range of −55~125 °C. The optimal BGTH7 ceramic after sintering at 1400 °C for 6 h exhibits a high dielectric constant of 5475 and low dielectric loss (tan δ) of 0.0176, hitherto exhibiting the best performance in X7U ceramics. The findings in this work are conducive to the miniaturization and stabilization of dielectric energy storage devices.     

Modulation of Mn3+ Spin State by Guest Molecule Inclusion

Spin state preferences for a cationic Mn³⁺ chelate complex in four different crystal lattices are investigated by crystallography and SQUID magnetometry. The [MnL₁]⁺ complex cation was prepared by complexation of Mn³⁺ to the Schiff base chelate formed from condensation of 4-methoxysalicylaldehyde and 1,2-bis(3-aminopropylamino)ethane. The cation was crystallized separately with three polyatomic counterions and in one case was found to cocrystallize with a percentage of unreacted 4-methoxysalicylaldehyde starting material. The spin state preferences of the four resultant complexes [MnL₁]CF₃SO₃·xH₂O, (1), [MnL₁]PF₆·xH₂O, (2), [MnL₁]PF₆·xsal·xH₂O, (2b), and [MnL₁]BPh₄, (3), were dependent on their ability to form strong intermolecular interactions. Complexes (1) and (2), which formed hydrogen bonds between [MnL₁]⁺, lattice water and in one case also with counterion, showed an incomplete thermal spin crossover over the temperature range 5–300 K. In contrast, complex (3) with the BPh₄⁻, counterion and no lattice water, was locked into the high spin state over the same temperature range, as was complex (2b), where inclusion of the 4-methoxysalicylaldehyde guest blocked the H-bonding interaction.     

The Determination of Cannabinoids in Urine Samples Using Microextraction by Packed Sorbent and Gas Chromatography-Mass Spectrometry

Cannabis is the most consumed illicit drug worldwide, and its legal status is a source of concern. This study proposes a rapid procedure for the simultaneous quantification of Δ⁹-tetrahydrocannabinol (THC), 11-hydroxy-Δ⁹-tetrahydrocannabinol (11-OH-THC), 11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol (THC-COOH), cannabidiol (CBD), and cannabinol (CBN) in urine samples. Microextraction by packed sorbent (MEPS) was used to pre-concentrate the analytes, which were detected by gas chromatography–mass spectrometry. The procedure was previously optimized, and the final conditions were: conditioning with 50 µL methanol and 50 µL of water, sample load with two draw–eject cycles, and washing with 310 µL of 0.1% formic acid in water with 5% isopropanol; the elution was made with 35 µL of 0.1% ammonium hydroxide in methanol. This fast extraction procedure allowed quantification in the ranges of 1–400 ng/mL for THC and CBD, 5–400 ng/mL for CBN and 11-OH-THC, and 10–400 ng/mL for THC-COOH with coefficients of determination higher than 0.99. The limits of quantification and detection were between 1 and 10 ng/mL using 0.25 mL of sample. The extraction efficiencies varied between 26 and 85%. This analytical method is the first allowing the for determination of cannabinoids in urine samples using MEPS, a fast, simple, and low-cost alternative to conventional techniques.