Liver Uptake Research Articles

P-2126. ‘SPECIFIC’ First-In-Human Clinical Trial of 68Ga-triacetylfusarinine (TAFC) Siderophore PET/CT for Detection of Invasive Aspergillosis

Abstract Background Invasive Aspergillus spp. infections (IAI) confer high morbidity and mortality in immunocompromised patients. Diagnosis often requires invasive and risky sampling. 18F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT) is useful in diagnosis but is non-specific. Siderophores are pathogen-specific iron chelators which are a promising radiolabelling target for IAI diagnosis. Aspergillus fumigatus secretes 2 siderophores, fusarinine C and triacetylfusarinine (TAFC), which are upregulated during IAI. Gallium-68 (68Ga)-labelled TAFC is attractive due to its short half life, rapid renal clearance, and low radiation risk. Preclinical mouse studies demonstrate diagnostic potential of 68Ga-TAFC PET/CT with specific visualisation of A. fumigatus infection.Figure 1:68Ga-TAFC-PET/CT in a patient with leukemia and probable pulmonary A. fumigatus IAI. Specific infective uptake of known pulmonary lesions at around blood pool level intensity (SUVmax 3.5, SUVmean 2.3). There was minimal liver and marrow uptake, with progressive washout to 60 minutes. Methods We report the first result from a 10 patient pilot trial of 68Ga-TAFC PET/CT for IAI diagnosis (NCT06105411). Inclusion criteria are adults with pulmonary IAI within 2 weeks of diagnosis. Exclusion criteria are pregnant/lactating patients or those within a week of iron infusion. 68Ga-TAFC PET/CT was performed at 15, 62, and 209 minutes after IV 139 MBq 68Ga-TAFC administration. Findings pertinent to IAI and physiologic uptake were analysed. Results The patient had probable A. fumigatus IAI in the setting of leukemia. Galactomannan and Aspergillus fumigatus PCR were positive on bronchoalveolar lavage fluid. Empiric antifungal treatment was commenced with fever resolution at 72 hours. 68Ga-TAFC-PET/CT was performed 10 days after treatment start and 4 days after microbiological diagnosis. Blood pool activity (SUVmax at 15/60/209 mins: 4.1/2.7/1.9) was demonstrated with minimal liver, spleen and gastrointestinal tract uptake (SUVmax 2.7), early renal excretion, and no marrow or other organ uptake. There was focal uptake in multiple pulmonary lesions (SUVmax 3.5), similar to blood pool activity, with synchronous washout over time. No adverse effects occurred. Conclusion Very low background physiologic biodistribution was seen in the first participant in this study. Focal low grade pulmonary uptake was visualised, likely demonstrating specific activity for A.fumigatus. Trial recruitment continues. Disclosures Abby Douglas, MBBS, Gilead Sciences: Honoraria

Do you know your PSMA-tracer? Variability in the biodistribution of different PSMA ligands and its potential impact on defining PSMA-positivity prior to PSMA-targeted therapy

BackgroundIn clinical practice, several radiopharmaceuticals are used for PSMA-PET imaging, each with distinct biodistribution patterns. This may impact treatment decisions and outcomes, as eligibility for PSMA-directed radioligand therapy is usually assessed by comparing tumoral uptake to normal liver uptake as a reference. In this study, we aimed to compare tracer uptake intraindividually in various reference regions including liver, parotid gland and spleen as well as the respective tumor-to-background ratios (TBR) of different 18F-labeled PSMA ligands to today’s standard radiopharmaceutical 68Ga-PSMA-11 in a series of patients with biochemical recurrence of prostate cancer who underwent a dual PSMA-PET examination as part of an individualized diagnostic approach.ResultsDifferences in background activity among different PSMA-PET tracers lead to variations in tumor-to-background ratios (TBR). In [18F]F-DCFPyL-PET, TBR with the liver as the reference organ (TBRliver) was comparable to [68Ga]Ga-PSMA-11-PET, while [18F]F-PSMA-1007-PET and [18F]F-JK-PSMA-7-PET showed significantly lower values. Using the parotid gland as the reference (TBRparotidgland), [18F]F-DCFPyL-PET exhibited significantly higher values, whereas [18F]F-PSMA-1007-PET and [18F]F-JK-PSMA-7-PET were comparable. For the spleen (TBRspleen), [18F]F-JK-PSMA-7-PET was comparable, but [18F]F-DCFPyL-PET and [18F]F-PSMA-1007-PET showed significantly higher and lower values, respectively. An additional Bland-Altman analyses revealed low bias for [18F]F-DCFPyL-PET in TBRparotidgland, whereas significant differences in TBRliver and TBRspleen for the other tracers resulted in higher bias.ConclusionDifferent PSMA-PET tracers exhibit distinct biodistribution patterns, leading to variations in tumor-to-background ratios (TBR) in reference organs such as the liver, parotid gland, and spleen. Patient selection for PSMA-directed radioligand therapy is currently based on a semiquantitative approach using the liver as a reference region in [68Ga]Ga-PSMA-11-PET. Thus, the use of alternative [18F]-labeled tracers may result in under- or overestimation of a patient’s suitability for therapy. This highlights the importance of a comprehensive understanding of the differences in tracer-specific uptake behavior for accurate decisions regarding PSMA-expression levels. However, as the patient cohort in this study is at earlier disease stages, the generalizability of these findings to later-stage patients remains unclear and requires further investigation.

CD38-specific immunoPET imaging for multiple myeloma diagnosis and therapeutic monitoring: preclinical and first-in-human studies.

CD38 is a glycoprotein highly specific to multiple myeloma (MM). Therapeutics using antibodies targeting CD38 have shown promising efficacy. However, the efficient stratification of patients who may benefit from daratumumab (Dara) therapy and timely monitoring of therapeutic responses remain significant clinical challenges. To address these issues, we developed a novel nanobody-based PET tracer, [68Ga]Ga-TOHP-CD3813, which exhibits rapid clearance from the blood and rapid accumulation in targeted tumor lesions, facilitating the detection of CD38 expression in murine models of MM and lymphoma. Furthermore, we conducted the world's first-in-human trials using CD38-targeted nanobodies to validate and assess the clinical imaging effectiveness of [68Ga]Ga-TOHP-CD3813 in guiding cancer immunotherapy. We prepared a new PET imaging probe based on a CD38-targeted nanobody CD3813, [68Ga]Ga-TOHP-CD3813, via the site-specific radiolabeling for noninvasive PET imaging of CD38 expression. [68Ga]Ga-TOHP-CD3813 was assessed for its affinity and specificity to CD38 and its ability to image CD38 expression in MM and lymphoma xenograft models. Biodistribution and the relationship between tumor uptake and CD38 expression were evaluated. Subsequently, we conducted a translational PET imaging of 2 MM patients using [68Ga]Ga-TOHP-CD3813, while compared with [18F]FDG PET/CT head-to-head. Dosimetry was also calculated based on the animal data. TOHP-CD3813 retained a high affinity for CD38 with a KD of 0.0826 nmol/L. [68Ga]Ga-TOHP-CD3813 was successfully synthesized at room temperature within 10min, exhibiting optimal radiochemical properties. Preclinical assessments revealed rapid blood clearance, high CD38 affinity, and significant uptake in CD38-positive xenograft mouse models (6.50 ± 2.69%ID/g). [68Ga]Ga-TOHP-CD3813 showed pronounced accumulation in the kidneys and bladder, with moderate liver uptake, indicating its potential as a viable clinical PET radiotracer for diagnosing MM. Additionally, in first-in-human trials, [68Ga]Ga-TOHP-CD3813 PET/CT provides a substantial improvement over [18F]FDG PET/CT for the visualization of MM. [68Ga]Ga-TOHP-CD3813, with its high affinity, specificity, and robust imaging capabilities, rapidly and specifically accumulates in tumors with high CD38 expression, offering a significant advantage over [18F]FDG PET/CT for visualizing MM and enabling same-day PET imaging. Initial human trial results are promising, suggesting its potential as a companion diagnostic tool for optimizing CD38-targeted treatments in tumors. Ongoing larger trials aim to further confirm these findings.

Comparative evaluation of a novel [18F] F-Labeled PET tracer XTR004 against [13N] ammonia in myocardial perfusion imaging for coronary artery disease.

This study aimed to evaluate image quality, myocardial perfusion, and diagnostic performance of a novel [18F]F-labeled PET tracer, XTR004 PET, myocardial perfusion imaging (MPI) compared with [13N]Ammonia (NH3) PET MPI. Forty-seven patients with suspected or known coronary artery disease (CAD) were prospectively enrolled to undergo one-day rest/ATP-stress XTR004 and NH3 electrocardiograph-gated PET imaging within 2 weeks. Among them, twenty-six patients underwent invasive coronary angiography (ICA), and nineteen were identified with flow-limited CAD (stenosis ≥ 70%). Image quality (excellent/good/average) and certainty of interpretation were evaluated by two independent, blinded readers. Despite a higher liver uptake, XTR004 achieved good to excellent image quality in 83% of cases, comparable to 95.7% of NH3(P = 0.091). Additionally, the diagnostic certainty, measured as the percentage of cases with definitely abnormal or normal interpretations, was similar between XTR004 and NH3, with results of 87.2% and 89.2%, respectively. The sensitivity and specificity levels of XTR004 and NH3 MPI were similar (79% vs. 79%, 86% vs. 71%, P = 1.00). Linear regression of rest/stress myocardial perfusion in 17 segments revealed the linear slope close to unity with excellent R2 value (rest: slope = 0.954-1.074, R2 = 0.990-0.997; stress: slope = 0.951-1.082, R2 = 0.971-0.996). XTR004 was tolerated well by all patients. No adverse events were reported. XTR004 PET MPI demonstrated promising image quality, diagnostic certainty and myocardial perfusion characteristics comparable to NH3 PET MPI. Future research should concentrate on the quantitative analysis of myocardial blood flow to explore the clinical implications of XTR004 PET MPI.

Preclinical comparison of (radio)lanthanides using mass spectrometry and nuclear imaging techniques: biodistribution of lanthanide-based tumor-targeting agents and lanthanides in ionic form.

With the growing interest in exploring radiolanthanides for nuclear medicine applications, the question arises as to whether they are generally interchangeable without affecting a biomolecule's pharmacokinetic properties. The goal of this study was to investigate similarities and differences of four (radio)lanthanides simultaneously applied as complexes of biomolecules or in ionic form. Inductively coupled plasma mass spectrometry (ICP-MS) was employed for the simultaneous detection of four lanthanides (Ln = lutetium, terbium, gadolinium and europium) in biological samples. In vitro tumor cell uptake and in vivo biodistribution studies were performed with Ln-DOTATATE, Ln-DOTA-LM3, Ln-PSMA-617 and Ln-OxFol-1. AR42J cells, PC-3 PIP cells and KB cells expressing the somatostatin receptor, the prostate-specific membrane antigen and the folate receptor, respectively, were used in vitro as well as to obtain the respective tumor mouse models for in vivo studies. The distribution of lanthanides in ionic form was investigated in immunocompetent mice. Dual-isotope SPECT/CT imaging studies were performed with mice administered with the radiolabeled biomolecules or chloride salts of lutetium-177 and terbium-161. Similar in vitro cell uptake was observed for all four lanthanide complexes of each biomolecule into the respective tumor cell lines. AR42J tumor uptake of Ln-DOTATATE and Ln-DOTA-LM3 in mice showed similar values for all lanthanide complexes (3.8‒5.1% ID/g and 4.5‒5.0% ID/g; 1h p.i., respectively). Accumulation of Ln-PSMA-617 in PC-3 PIP tumors (24-25% ID/g; 1h p.i.) and of Ln-OxFol-1 in KB tumors (28-31% ID/g; 24h p.i.) were also equal for the four lanthanide complexes of each biomolecule. After injection of lanthanide chloride salts (LnCl3; Ln = natLu, natTb, natGd, natEu), the liver uptake was different for each metal (~ 12% ID/g, ~ 22% ID/g, ~ 31% ID/g and ~ 37% ID/g; 24h p.i., respectively) which could be ascribed to the radii of the respective lanthanide ions. In the bones, accumulation was considerably higher for lutetium than for other lanthanides (25 ± 5% ID/g vs. 14‒15% ID/g; 24h p.i.). These data were confirmed visually by 177Lu/161Tb-based dual-isotope SPECT/CT images. The presented study confirmed similar properties of Ln-complexes, suggesting that lutetium-177 can be replaced by other radiolanthanides, most probably without affecting the tissue distribution profile of the resultant radiopharmaceuticals. On the other hand, the different radii of the lanthanide ions affected their uptake and resorption mechanisms in liver and bones when injected in uncomplexed form.

Development of a homotrimeric PSMA radioligand based on the NOTI chelating platform

BackgroundThe NOTI chelating scaffold can readily be derivatized for bioconjugation without impacting its metal complexation/radiolabeling properties making it an attractive building block for the development of multimeric/-valent radiopharmaceuticals. The objective of the study was to further explore the potential of the NOTI chelating platform by preparing and characterizing homotrimeric PSMA radioconjugates in order to identify a suitable candidate for clinical translation.ResultsAltogether, three PSMA conjugates based on the NOTI-TVA scaffold with different spacer entities between the chelating unit and the Glu-CO-Lys PSMA binding motif were readily prepared by solid phase-peptide chemistry. Cell experiments allowed the identification of the homotrimeric conjugate 9 comprising NaI-Amc spacer with high PSMA binding affinity (IC50 = 5.9 nM) and high PSMA-specific internalization (17.8 ± 2.5%) compared to the clinically used radiotracer [68Ga]Ga-PSMA-11 with a IC50 of 18.5 nM and 5.2 ± 0.2% cell internalization, respectively. All 68Ga-labeled trimeric conjugates showed high metabolic stability in vitro with [68Ga]Ga-9 exhibiting high binding to human serum proteins (> 95%). Small-animal PET imaging revealed a specific tumor uptake of 16.0 ± 1.3% IA g−1 and a kidney uptake of 67.8 ± 8.4% IA g−1 for [68Ga]Ga-9. Clinical PET imaging allowed identification of all lesions detected by [68Ga]Ga-PSMA-11 together with a prolonged blood circulation as well as a significantly lower kidney and higher liver uptake of [68Ga]Ga-9 compared to [68Ga]Ga-PSMA-11.ConclusionsTrimerization of the Glu-CO-Lys binding motif for conjugate 9 resulted in a ~ threefold higher binding affinity and cellular uptake as well as in an altered biodistribution profile compared to the control [68Ga]Ga-PSMA-11 due to its intrinsic high binding to serum proteins. To fully elucidate its biodistribution, future studies in combination with long-lived radionuclides, such as 64Cu, are warranted. Its prolonged biological half-life and favorable tumor-to-kidney ratio make this homotrimeric conjugate also a potential candidate for future radiotherapeutic applications in combination with therapeutic radionuclides such as 67Cu.

Exploring 18F-FDG uptake patterns in liver, spleen, and bone marrow: Implications for inflammatory and infectious conditions.

This study aimed to explore the relationship between fluorine-18-fluorodeoxyglucose (18F-FDG) uptake in the liver, spleen, and bone marrow and inflammatory markers such as c-reactive protein (CRP), albumin, and erythrocyte sedimentation rate (ESR) in patients undergoing positron emission tomography/computed tomography (PET/CT) imaging for cancer diagnosis. This retrospective cross-sectional study included a total of 708 patients with a diagnosis of malignancy. Fluorine-18-FDG PET/CT images acquired between January 2021 and December 2022. Exclusion criteria comprised prior chemotherapy, radiotherapy, hematological malignancies, or liver/spleen tumors. Statistical analysis included correlation analysis, univariate, and multivariate regression analysis. C-reactive protein levels demonstrated a significant positive correlation with 18F-FDG uptake in the spleen (r=0.104, P=0.006) and bone marrow (r=0.112, P=0.003). Albumin showed a negative correlation with liver 18F-FDG uptake (r=-0.220, P<0.001). Regression analysis revealed ESR's impact on spleen-to-liver (P=0.023) and bone marrow-to-liver (P=0.012) 18F-FDG uptake. This study demonstrates the association between inflammatory markers and 18F-FDG uptake in liver, spleen and bone marrow. C-reactive protein and ESR showing significant correlations with spleen and bone marrow 18F-FDG uptake, and albumin correlated with liver 18F-FDG uptake negatively. Erythrocyte sedimentation rate had significant impact on spleen and bone marrow 18F-FDG uptakes. These findings suggest the potential of 18F-FDG PET/CT in diagnosing inflammatory conditions, warranting further investigation into its clinical implications.

Statins Combined with AAV8-TBG-LOX-1 Reduce the Vascular Lipid-driven Inflammatory Response and Inhibit Atherosclerosis.

Imbalances in liver lipid metabolism and inflammatory reactions driven by oxidized lipid deposition in blood vessels constitute the core of atherosclerosis. Insufficient degradation of cholesterol in the liver promotes oxidative modification of lipid particles and their deposition on the blood vessel wall in the peripheral circulation. The blood vessel wall engulfs and processes oxidized low-density lipoprotein (Ox-LDL) as foreign matter through pattern recognition receptors, ultimately forming lipid-encapsulated plaques. Among them, endothelial cell oxidized low density lipoprotein receptor 1 (LOX1) phagocytosis is an important link in initiating and promoting this mechanism, and hepatocytes, which are the core of lipid metabolism, are unable to process oxidized lipid particles because of the lack of receptors for the uptake of Ox-LDL. The objective of this study was to investigate whether continuous clearance of Ox-LDL through the liver metabolic pathway could provide better protection against statins therapy. This study used statins combined with an adeno-associated virus (AAV8-TBG-LOX-1) liver-specific transfection system developed by our research group, in which statins reduced the level of LDL and promoted the ectopic expression of LOX-1 in hepatocytes to clear the continuous production of Ox-LDL. An ApoE knockout mouse model was used to study the effects of virus transfection and liver uptake and degradation of Ox-LDL. Laser confocal detection, Oil red staining and immunofluorescence staining were used to observe the effects of combined therapy on anti-atherosclerotic lesions. Laser confocal microscopy revealed that the recombinant viral vector AAV8-TBG-LOX-1 could specifically transfect hepatocytes and express LOX-1, which mediate hepatocyte phagocytosis and clearance of Ox-LDL. Oil red O staining of the aorta and valvular ring suggested that statins combined with AAV8-TBG-LOX-1 significantly inhibited atherosclerotic lesions. Tissue immunofluorescence staining suggested that statins could reduce the aggregation of macrophages in plaques and that combined therapy could further reduce the aggregation of macrophages in plaques. Statins combined with AAV8-TBG-LOX-1 can alleviate the inflammatory response driven by lipids in the vascular wall, reduce the deposition of macrophages in plaques and inhibit atherosclerosis.

Preventive effect of sea bass protein-based high internal phase Pickering emulsion loaded with astaxanthin on DEHP-induced liver lipid metabolism disorder.

The present study was to investigate the effect of the astaxanthin high internal phase Pickering emulsion (H-AXT) on DEHP-induced liver lipid metabolism disorder and to demonstrate its possible protective mechanism. We have developed an antioxidant activity emulsion system to deliver astaxanthin into the liver to maximize its ability to protect the liver. In vitro, H-AXT intervention inhibited oxidative stress restored the level of mitochondrial membrane potential to 90 % of that of normal LO2 cells, and alleviated the imbalance of energy metabolism by protecting mitochondrial structure and function. Based on metabonomics, it was proved that H-AXT inhibited triglyceride accumulation by antagonizing lipid metabolism disorder. In DEHP-induced mice, H-AXT intervention mitigated liver damage by inhibiting oxidative stress and inflammatory reaction, and alleviated metabolic dysfunction by regulating lipid levels and inhibiting fat accumulation. Meanwhile, H-AXT alleviated DEHP-induced testicular tissue damage and maintained the integrity of testicular tissue. The encapsulation of the emulsion system effectively promoted the liver uptake of astaxanthin to prevent liver diseases associated with metabolic disorders.

Comparative transcriptomes and metabolome reveal heterosis in zig zag eel (Mastacembelus armatus)

In the process of artificial breeding, due to the lack of rigorous and standardized screening and cultivation of parent fish, the quality of M. armatus' seedlings had sharply declined, seriously affecting the sustainable and healthy development of the artificial breeding industry of M. armatus. Therefore, we set up four breeding combinations (HH, Huizhou ♂ x Huizhou ♀; KK, Kaiping ♂ x Kaiping ♀; HK, Huizhou ♂ x Kaiping ♀; KH, Kaiping ♂ x Huizhou ♀) to study the effect of hybridization on the growth performance of M. armatus. After hatching, the juvenile fish were continuously farmed for 180 days, and their total length and weight were measured every 60 days. Liver tissues from various combinations were collected for transcriptome and metabolomic analysis. Compared with the HH combination and the KK combination, the total length and weight of individuals in the HK combination and the KH combination were significantly increased, and the expression levels of GH in brain tissue and GH, IGF-Ⅰ in muscle tissue were significantly up-regulated. Transcriptome analysis showed that the growth of individuals in the dominant hybrid combination (HK combination) was related to genes such as SCD, FASN, PPARα, ACO, etc. in the lipid metabolism pathways. Metabolomic analysis showed that the glycerol content in the HK combination was significantly lower than that in the KK combination. The combined analysis of transcriptome and metabolome showed that hybrid advantage was well demonstrated in the lipid metabolism pathways, and high expression of PPARα could promote the expression of AQP9 protein, further promoting the liver's uptake and metabolism of glycerol. The research results indicated that individuals in the HK combination had higher lipid synthesis and metabolic ability, and one of the hybrid advantages of M. armatus was its efficient utilization of glycerol.

Positron Emission Tomography Imaging of Cathepsin B in Tumors with Activable Small Molecule Tracers.

Cathepsin B (CTB) is overexpressed in several types of tumors, and precise evaluation of the CTB activity can offer a promising method for the early diagnosis of tumors. In this study, two CTB-activated positron emission tomography (PET) tracers, [68Ga]NOTA-SFCVM and [68Ga]NOTA-SFCVHEM, were developed for sensitive and specific detection of CTB. Both tracers undergo a click condensation between 2-cyano-6-aminobenzothiazole (CBT) and cysteine (Cys) to form a cyclization product, thereby enhancing and prolonging the PET signal in tumors. In vitro cellular experiments showed that the tracers could differentiate tumor cells with different expression levels of CTB. In vivo PET imaging further revealed that the tracers selectively accumulated in the CTB-positive tumors. Compared with [68Ga]NOTA-SFCVM, [68Ga]NOTA-SFCVHEM containing a morpholine group and a histidine-glutamate-histidine-glutamate-histidine-glutamate sequence exhibited faster catalytic efficiency toward CTB, higher tumor uptake, and reduced liver uptake. These findings suggest that [68Ga]NOTA-SFCVHEM holds potential for clinical use in the early diagnosis of CTB-related tumors.

A novel selenoglycoside compound GlcSeCys alleviates diets-induced obesity and metabolic dysfunctions with the modulation of Galectin-1 and selenoproteins

Selenium, an essential trace element in human, has been shown to play protective roles in obesity and metabolic disorders despite insufficient understanding of mechanisms. Moreover, it's well known that biological actions of selenium compounds differed greatly due to divergent chemical forms. Selenoglycoside is a type of organoselenium compounds with excellent hydrophilicity, but biological activity of which in vivo are almost unknown. We have designed and synthesized Se-β-D-glucopyranosyl-D-selenocysteine, a novel selenoglycoside compound named GlcSeCys. Herein, GlcSeCys was given to high fat high cholesterol (HFHC) fed mice to determine its actions as well as relevant molecular mechanisms using transcriptome and multiple molecular biological methods. It was revealed that GlcSeCys displayed pronounced anti-obesity effect and significantly alleviated hyperglycemia, hyperinsulinemia along with hepatic steatosis in HFHC diets-induced mice. Mechanistically, GlcSeCys was found to inhibit lipogenesis, lipid uptake and inflammation in liver, along with attenuation of Galectin-1 and induction of selenoprotein S (SELENOS). With regard to adipose tissues, GlcSeCys ameliorated hypertrophy of adipocytes, suppressed lipids biosynthesis and stimulated WAT browning along with abrogated WAT inflammation activation, which were in line with repression of Galectin-1 and increase of GPx3. Collectively, our results uncovered, for the first time, that selenoglycoside compound GlcSeCys possessed excellent protective effects against obesity and metabolic disorders, and the mechanisms were correlated with modulation of Galectin-1 and selenoproteins, shedding lights upon molecular biology of selenium and novel therapeutic for obesity and relevant metabolic disorders.

Responsive Magnetic Particle Imaging Tracer: Overcoming "Always-On" Limitation, Eliminating Interference, and Ensuring Safety in Adaptive Therapy.

Magnetic particle imaging (MPI) has emerged as a novel technology utilizing superparamagnetic nanoparticles as tracers, essential for disease diagnosis and treatment guidance in preclinical animal models. Unlike other modalities, MPI provides high sensitivity, deep tissue penetration, and no signal attenuation. However, existing MPI tracers suffer from "always-on" signals, which complicate organ-specific imaging and hinder accuracy. To overcome these challenges, we have developed a responsive MPI tracer using pH-responsive PdFe alloy particles coated with a gatekeeper polymer. This tracer exhibits pH-sensitive Fe release and modulation of the MPI signal, enabling selective imaging with a higher signal-to-noise ratio and intratumoral pH quantification. Notably, this responsive tracer facilitates subtraction-enhanced MPI imaging, effectively eliminating interference from liver uptake and expanding the scope of abdominal imaging. Additionally, the tracer employs a dual-function mechanism for adaptive cancer therapy, combining pH-switchable enzyme-like catalysis with dual-key co-activation of ROS generation, and Pd skeleton that scavenges free radicals to minimize Fe-related toxicity. This advancement promises to significantly expand MPI's applicability in diagnostics and therapeutic monitoring, marking a leap forward in imaging technology.

Utility of Quantitative Assessment of Tc-99m-diethylenetriamine-penta-acetic acid-galactosyl Human Serum Albumin SPECT/CT in the Identification of Severe Liver Fibrosis: Its Complementary Diagnostic Value with Other Liver Function Indices.

To evaluate the value of Tc-99m-diethylenetriamine-penta-acetic acid-galactosyl human serum albumin (99mTc-GSA) single photon emission computed tomography (SPECT) for assessing liver fibrosis, and to assess its complementary value to other liver function indices such as fibrosis-4 (FIB-4) index and indocyanine green (ICG) clearance test parameters (ICG-R15 and ICG-K). Seventy-eight patients with chronic liver disease and hepatocellular carcinoma who underwent 99mTc-GSA scintigraphy and other liver function tests including ICG test and FIB-4 index prior to hepatectomy were studied. 99mTc-GSA imaging was performed with SPECT/CT scanner (Discovery NM/CT 670). Immediately after injection of 99mTc-GSA, dynamic imaging was performed for 20min, followed by SPECT data acquisition for 6min. LHL15 which is a conventional index by 99mTc-GSA planar images, and liver uptake ration (LUR) was measured from 99mTc-GSA SPECT images. From the liver resection specimens, the degree of liver fibrosis was graded according to the Ludwig scale (F0-4). Significant differences in LUR, LHL15, ICG-R15, ICG-K, platelet count and FIB-4 index were found between the F0-3 and F4 liver fibrosis patient groups (P < 0.05). Multivariate logistic regression analysis revealed that LUR and ICG-K were independent factors for identifying severe liver fibrosis (F4). Area under the curve of receiver operating curve analysis for the logistic regression model using LUR and ICG-K was 0.83. In the patient group with higher FIB-4 (≥ 3.16), the diagnostic performance of LUR for detecting severe liver fibrosis was significantly better than LHL15 (AUC: 0.83 vs. 0.75, P = 0.048). In the high FIB-4 index group, the sensitivity and specificity for identifying F4 was 88% and 85%, respectively, with LUR cutoff value of 41.2%. LUR, measured by 99mTc-GSA SPECT, is a useful indicator for identifying sever liver fibrosis. Particularly in patients with high FIB-4 index (≥ 3.16), LUR can be a valuable indicator to identify severe liver fibrosis with high diagnostic accuracy.

MPS blockade with liposomes controls pharmacokinetics of nanoparticles in a size-dependent manner

Pharmacokinetics of nanomedicines can be improved by a temporal blockade of mononuclear phagocyte system (MPS) through the interaction with other biocompatible nanoparticles. Liposomes are excellent candidates as blocking agents, but the efficiency of the MPS blockade can greatly depend on the liposome properties. Here, we investigated the dependence of the efficiency of the induced MPS blockadein vitroandin vivoon the size of blocking liposomes in the 100-500 nm range. Saturation of RAW 264.7 macrophage uptake was observed for phosphatidylcholine/cholesterol liposomes larger than 200 nmin vitro. In mice, liposomes of all sizes exhibited a blocking effect on liver macrophages, prolonging the circulation of subsequently administrated magnetic nanoparticles in the bloodstream, reducing their liver uptake, and increasing accumulation in the spleen and lungs. Importantly, these effects became more pronounced with the increase of liposome size. Optimization of the size of the blocking liposomes holds the potential to enhance drug delivery and improve cancer therapy.

Comparing total-body metabolic PET imaging signatures of lung cancer cachexia to other wasting conditions

Cancer cachexia (CC) is a debilitating wasting condition. While anorexia and muscle wasting are features of cachexia, CC is a distinct and poorly understood metabolic syndrome1. We harnessed preclinical models of lung cancer to study how glucose uptake changes during CC and performed comparative analyses with anorexia and muscle wasting. Lung K-rasG12D/+;Lkb1-/-(KL) mice suffering CC were imaged using [18F]fluorodeoxyglucose (FDG) PET at 15-19% weight loss alongside K-ras wild-type (WT) non-tumour bearing controls. Mice were injected with 12-18MBq of FDG, imaging 80-100 minutes post injection with the Mediso nanoScan® PET/MRI 1T. In non-tumour bearing male animals, we modelled anorexia, muscle wasting, and circulation of cachexia factor GDF15 as follows, respectively: fasted overnight for 20 hr, treated with dexamethasone 21-phosphate (dexa) (2mg/kg, i.p. daily, 21 days) and single injection of recombinant human GDF15 hormone (0.1 mg/kg s.c.). FDG ex vivo biodistribution showed increased uptake in myocardium (p&lt;0.05), brain and liver (both p&lt;0.01) of KL cachexic animals with no significant change in FDG blood pool. Like cachexic KL animals, FDG uptake in fasted animals increased in brain (p&lt;0.0001), perhaps due to increased FDG blood pool. FDG uptake in skeletal muscles and brown adipose tissue decreased (both p&lt;0.05) in fasted state suggesting lower muscle activity and decreased thermogenesis respectively. Dexa-induced muscle atrophy also resulted in decreased FDG uptake in gastrocnemius/soleus muscles (SUVmean 0.63 vehicle vs. 0.45 dexa, p&lt;0.05) but no changes in skeletal muscle FDG uptake were noted in cachexic animals. In contrast to KL animals, GDF15 injection resulted in decreased FDG uptake in myocardium (p&lt;0.05). Overall, the cachexic FDG signature showed differences to other wasting conditions in this mouse model, suggesting different underlying mechanisms. Total-body PET can reveal diverse metabolic wasting states. We aim to elucidate mechanisms of metabolic changes in cachexia to allow metabolic subtyping and personalised treatment options. Please click on the 'PDF' for the full abstract!

Baseline and interim 18F-FDG PET/CT metabolic parameters predict the efficacy and survival in patients with diffuse large B-cell lymphoma.

The prognostic value of 18F-FDG PET/CT metabolic parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), in diffuse large B-cell lymphoma (DLBCL) remains inadequately explored. This study aims to assess the correlation between these parameters and patient outcomes. A cohort of 156 DLBCL patients underwent 18F-FDG PET/CT imaging at baseline and after 3-4 cycles of R-CHOP or CHOP-like regimen. The third quartiles of liver uptake values were used as thresholds for calculating MTV and TLG. Patient outcomes were analyzed based on Ann Arbor staging and the 5-PS score. A nomogram was developed to predict overall survival (OS). Patients with low baseline TLG exhibited significantly better outcomes compared to those with high baseline TLG in both Ann Arbor stages I-II and III-IV (1-year PFS: 78.9% vs. 40%, p=0.016; OS: 94.7% vs. 40%, p=0.005 for stage I-II; 1-year PFS: 74.1% vs. 46.8%, p=0.014; OS: 85.4% vs. 71.8%, p=0.007 for stage III-IV). In interim PET/CT patients with a 5-PS score >3, the high ΔTLG group had superior prognosis (1-year PFS: 82.3% vs. 35.7%, p=0.003; OS: 88.2% vs. 85.7%, p=0.003). The nomogram achieved a C-index of 0.9 for OS prediction. The findings suggest that baseline TLG is a robust prognostic indicator for patients with DLBCL, particularly in early stages, while ΔTLG effectively distinguishes those with favorable outcomes in higher-risk groups. These metabolic parameters from 18F-FDG PET/CT could enhance treatment decision-making and patient management strategies.

Assessing functional suitability of a lyophilized formulation containing designed ankyrin repeat proteins for radionuclide imaging of HER2/neu overexpression in malignant tumors

Aim. To study in vitro and in vivo the functional suitability of 99mTc-labeled lyophilized formulation containing designed ankyrin repeat protein (DARPin) G3-(GGGS)3Cys for radionuclide imaging of HER2/neu overexpression in malignant tumors.Materials and methods. To create a targeted protein, a modified genetic construct with the sequence encoding DARPin G3-(GGGS)3Cys was used. To generate the experimental probe, we used a lyophilized formulation containing DARPin G3-(GGGS)3Cys with auxiliary substances and 99mTc sodium pertechnetate (500 MBq) incubated at 60 °C for 30 min. Radiochemical purity of 99mTc-G3-(GGGS)3Cys was analyzed by thin-layer radiochromatography. SKOV-3, BT-474, and DU-145 cell lines were used to test binding specificity in vitro. The dissociation constant was determined via a saturation binding assay on SKOV-3 cells with a range of protein concentrations from 0.2 to 40 nM. Nu/j mice bearing HER2-positive SKOV-3 xenografts and HER2-negative Ramos xenografts were used to evaluate the targeting properties and biodistribution.Results. A radiocomplex based on 99mTc and a lyophilized formulation with DARPin G3-(GGGS)3Cys was obtained with the radiochemical purity of more than 96%. Binding of 99mTc-G3-(GGGS)3Cys to the cells was specific (KD 3.9 ± 0.5 nM) and proportional to the level of HER2/neu expression in the cells. The uptake of 99mTc-G3-(GGGS)3Cys in SKOV-3 xenografts was significantly higher than in Ramos xenografts. 99mTc-G3-(GGGS)3Cys demonstrated rapid blood and renal clearance and had low activity in the salivary glands and stomach. Liver uptake was about 5–7%ID/g. In addition, 99mTc-G3-(GGGS)3Cys exhibited very low uptakes in the lungs, muscles, small intestine, and bones.Conclusion. The 99mTc-labeled lyophilized formulation with DARPin G3-(GGGS)3Cys is functionally suitable for imaging HER2/neu overexpression in tumors, as it binds specifically to the receptor, is stable in vivo, and has favorable biodistribution in organs and tissues. The radiocomplex based on 99mTc-G3-(GGGS)3Cys was obtained by a simple method with high radiochemical purity.

Molecular imaging of macrophage composition and dynamics in MASLD

Background and AimsMetabolic-dysfunction associated steatohepatitis (MASH) is associated with obesity and diabetes and is linked to liver fibrosis and cardiovascular disease. Identification of patients who have MASH is challenging and the development of non-invasive strategies to diagnose and follow this condition is an important unmet need. Recent studies in mouse and humans have identified that significant changes occur in liver macrophage composition during MASH progression, namely resident Kupffer cells decrease in number while recruited monocyte-derived macrophages increase. MethodsWe developed peptide radiotracers targeted to C-C motif chemokine receptor 2 (CCR2) and CD163 to conduct postitron emssion tomography (PET) imaging of recuited vs. resident macrophages, respectively. Mice were placed on a MASH-inducing diet and non-invasive PET imaging of the liver was performed with tissue confirmation studies using flow cytometry and immunofluorescence. Statistical analyses were conducted using t-testing, Pearson correlational analysis and linear regression. ResultsUsing a mouse model of MASH, we found that the liver uptake of both CCR2 and CD163 radiotracers detected an increase in recruited cells and a decrease in resident macrophages. These findings correlated well with tissue macrophage content assessed by flow cytometry with an r value of 0.77 (p = 0.002) and 0.78 (p=0.001) for CCR2 and CD163, respectively. Serial imaging with these radiotracers at several timepoints during MASH progression and regression, revealed good correlation between liver macrophage composition and PET signal intensity. ConclusionWe demonstrate that novel PET radiotracers targeting CCR2 and CD163 can be used to image macrophage composition in MASH. Non-invasive molecular imaging of inflammation has the potential for diagnosis and monitoring of disease activity in humans with MASH. Impact and ImplicationsMacrophage mediated inflammation contributes to MASH progression and fibrosis; however, liver biopsy is currently the only tool to assess this response. Thus, the development of non-invasive imaging modalites to identify and follow inflammatory activation is an area of need for patient care. In this study we leverage molecular imaging using PET radiotracers to follow changes in macrophage composition that are related to MASH disease activity. The results in our pre-clinical model provide important proof of concept evidence that this approach can be used to diagnose MASH and to follow disease activty in response to intervention. Ongoing studies will evaluate the utility of this modality in humans with MASH.

Radiolabeling and preclinical evaluation of technetium-99m labeled colistin

IntroductionAntibiotic resistance is a burden on the healthcare system. In present study, we have labeled an antibiotic named Colistimethate sodium (CMS) with technetium-99m (99mTc) to develop a SPECT based imaging tracer. MethodsWe standardised the labeling using 0.5–2 mg of CMS (in water) using stannous chloride dihydrate as a reducing agent followed by addition of 370 ± 74 MBq of 99mTc. A group of mice were injected intravenously (in tail vein) with 4–6 MBq of [99mTc]Tc-CMS diluted with saline and euthanized at various time intervals. microSPECT Imaging (ϒ-eye) was acquired to study the biodistribution in the healthy mice. ResultsWe standardised the labeling using 0.5 mg of colistin in 0.5 ml of saline with addition of 30 μg stannous chloride dihydrate. The retention factor value was 0.1–0.3 as compared to 0.9–1.0 for free 99mTc by TLC and retention time was found to be 14.2 ± 1.3 min as evaluated by HPLC. The biodistribution data showed uptake in lungs, spleen, and liver at 30 min but the uptake decreased in lung at 60 min. The imaging data corroborated with the biodistribution data. ConclusionsWe could successfully label [99mTc]Tc-CMS 99mTc and we could study its biodistribution in healthy mice.