Theranostic Imaging Research Articles

Graphene-Oxide Peptide-Containing Materials for Biomedical Applications.

This review explores the application of graphene-based materials (GBMs) in biomedicine, focusing on graphene oxide (GO) and its interactions with peptides and proteins. GO, a versatile nanomaterial with oxygen-containing functional groups, holds significant potential for biomedical applications but faces challenges related to toxicity and environmental impact. Peptides and proteins can be functionalized on GO surfaces through various methods, including non-covalent interactions such as π-π stacking, electrostatic forces, hydrophobic interactions, hydrogen bonding, and van der Waals forces, as well as covalent bonding through reactions involving amide bond formation, esterification, thiol chemistry, and click chemistry. These approaches enhance GO's functionality in several key areas: biosensing for sensitive biomarker detection, theranostic imaging that integrates diagnostics and therapy for real-time treatment monitoring, and targeted cancer therapy where GO can deliver drugs directly to tumor sites while being tracked by imaging techniques like MRI and photoacoustic imaging. Additionally, GO-based scaffolds are advancing tissue engineering and aiding tissues' bone, muscle, and nerve tissue regeneration, while their antimicrobial properties are improving infection-resistant medical devices. Despite its potential, addressing challenges related to stability and scalability is essential to fully harness the benefits of GBMs in healthcare.

Structural Evaluation of a Nitroreductase Engineered for Improved Activation of the 5-Nitroimidazole PET Probe SN33623.

Bacterial nitroreductase enzymes capable of activating imaging probes and prodrugs are valuable tools for gene-directed enzyme prodrug therapies and targeted cell ablation models. We recently engineered a nitroreductase (E. coli NfsB F70A/F108Y) for the substantially enhanced reduction of the 5-nitroimidazole PET-capable probe, SN33623, which permits the theranostic imaging of vectors labeled with oxygen-insensitive bacterial nitroreductases. This mutant enzyme also shows improved activation of the DNA-alkylation prodrugs CB1954 and metronidazole. To elucidate the mechanism behind these enhancements, we resolved the crystal structure of the mutant enzyme to 1.98 Å and compared it to the wild-type enzyme. Structural analysis revealed an expanded substrate access channel and new hydrogen bonding interactions. Additionally, computational modeling of SN33623, CB1954, and metronidazole binding in the active sites of both the mutant and wild-type enzymes revealed key differences in substrate orientations and interactions, with improvements in activity being mirrored by reduced distances between the N5-H of isoalloxazine and the substrate nitro group oxygen in the mutant models. These findings deepen our understanding of nitroreductase substrate specificity and catalytic mechanisms and have potential implications for developing more effective theranostic imaging strategies in cancer treatment.

Assessment of the Predictive Ability of Theranostics for Corneal Cross-linking in Treating Keratoconus: A Randomized Clinical Trial

PurposeTo validate the ability of theranostic imaging biomarkers in assessing the propensity of corneal cross-linking (CXL) in flattening the maximum keratometry (Kmax) index. DesignProspective, randomized, multicenter, masked clinical trial (NCT05457647). ParticipantsFifty patients with progressive keratoconus. InterventionParticipants were stratified to undergo epithelium-off (epi-off; 25 eyes) and epithelium-on (epi-on; 25 eyes) CXL protocols using UV-A medical device incorporating theranostic software module. The device used controlled UV-A light both for performing CXL and for estimating the corneal riboflavin concentration (riboflavin score) and assessing treatment effect (theranostic score) in real time. A 0.22% riboflavin formulation was applied onto the cornea for 15 minutes and 20 minutes in epi-off and epi-on protocols respectively. All eyes underwent 9 minutes UV-A irradiance at 10 mW/cm2. Main Outcome MeasuresThe primary outcome measure was validation of the combined use of theranostic imaging biomarkers through measurement of their accuracy (proportion of correctly classified eyes) and precision (positive predictive value) to correctly classify eyes and positively predict a Kmax flattening at 1 year after CXL. Other outcome measures were the change of Kmax, endothelial cell density, uncorrected and corrected distance visual acuity, manifest spherical equivalent refraction, and central corneal thickness one year after CXL. ResultsAccuracy and precision of the combined use of theranostic imaging biomarkers in predicting eyes that had more than 0.1 diopter (D) Kmax flattening at 1 year were 91% and 95% respectively. The Kmax value significantly flattened by a median of -1.3 D (IQR: -2.11, -0.49 D; P < 0.001); both the uncorrected and corrected distance visual acuity improved by a median of -0.1 LogMAR (IQR: -0.3, 0.0 LogMAR; P < 0.001 and IQR: -0.2, 0.0 LogMAR; P < 0.001 respectively). There were no significant changes in endothelial cell density (P = 0.33) and central corneal thickness (P = 0.07) 1 year postoperatively. ConclusionsThe study demonstrated the efficacy of integrating theranostics in a UV-A medical device for the precise and predictive treatment of keratoconus with epi-off and epi-on CXL protocols. The concentration of riboflavin and its UV-A light mediated photo-activation in the cornea are the primary factors determining CXL treatment efficacy.

Cadherin-17 as a target for the immunoPET of adenocarcinoma

PurposeCadherin-17 (CDH17) is a calcium-dependent cell adhesion protein that is overexpressed in several adenocarcinomas, including gastric, colorectal, and pancreatic adenocarcinoma. High levels of CDH17 have been linked to metastatic disease and poor prognoses in patients with these malignancies, fueling interest in the protein as a target for diagnostics and therapeutics. Herein, we report the synthesis, in vitro validation, and in vivo evaluation of a CDH17-targeted 89Zr-labeled immunoPET probe.MethodsThe CDH17-targeting mAb D2101 was modified with an isothiocyanate-bearing derivative of desferrioxamine (DFO) to produce a chelator-bearing immunoconjugate — DFO-D2101 — and flow cytometry and surface plasmon resonance (SPR) were used to interrogate its antigen-binding properties. The immunoconjugate was then radiolabeled with zirconium-89 (t1/2 ~ 3.3 days), and the serum stability and immunoreactive fraction of [89Zr]Zr-DFO-D2101 were determined. Finally, [89Zr]Zr-DFO-D2101’s performance was evaluated in a trio of murine models of pancreatic ductal adenocarcinoma (PDAC): subcutaneous, orthotopic, and patient-derived xenografts (PDX). PET images were acquired over the course of 5 days, and terminal biodistribution data were collected after the final imaging time point.ResultsDFO-D2101 was produced with a degree of labeling of ~ 1.1 DFO/mAb. Flow cytometry with CDH17-expressing AsPC-1 cells demonstrated that the immunoconjugate binds to its target in a manner similar to its parent mAb, while SPR with recombinant CDH17 revealed that D2101 and DFO-D2101 exhibit nearly identical KD values: 8.2 × 10−9 and 6.7 × 10−9 M, respectively. [89Zr]Zr-DFO-D2101 was produced with a specific activity of 185 MBq/mg (5.0 mCi/mg), remained >80% stable in human serum over the course of 5 days, and boasted an immunoreactive fraction of >0.85. In all three murine models of PDAC, the radioimmunoconjugate yielded high contrast images, with high activity concentrations in tumor tissue and low uptake in non-target organs. Tumoral activity concentrations reached as high as >60 %ID/g in two of the cohorts bearing PDXs.ConclusionTaken together, these data underscore that [89Zr]Zr-DFO-D2101 is a highly promising probe for the non-invasive visualization of CDH17 expression in PDAC. We contend that this radioimmunoconjugate could have a significant impact on the clinical management of patients with both PDAC and gastrointestinal adenocarcinoma, most likely as a theranostic imaging tool in support of CDH17-targeted therapies.

Real-time monitoring of riboflavin concentration using different clinically available ophthalmic formulations for epi-off and epi-on corneal cross-linking.

To assess the feasibility of theranostics to determine the riboflavin concentration in the cornea using clinically available ophthalmic formulations during epithelium-off (epi-off) and transepithelial (epi-on) corneal cross-linking procedures. Thirty-two eye bank human donor corneas were equally randomized in eight groups; groups 1 to 3 and groups 4 to 8 underwent epi-off and epi-on delivery of riboflavin respectively. Riboflavin ophthalmic solutions were applied onto the cornea according to the manufacturers' instructions. The amount of riboflavin into the cornea was estimated, at preset time intervals during imbibition time, using theranostic UV-A device (C4V CHROMO4VIS, Regensight srl, Italy) and expressed as riboflavin score (d.u.). Measurements of corneal riboflavin concentration (expressed as µg/cm3) were also performed by spectroscopy absorbance technique (AvaLight-DH-S-BAL, Avantes) for external validation of theranostic measurements. At the end of imbibition time in epi-off delivery protocols, the average riboflavin score ranged from 0.77 ± 0.38 (the average corneal riboflavin concentration was 213 ± 190µg/cm3) to 1.79 ± 0.07 (554 ± 103µg/cm3). In epi-on delivery protocols, the average riboflavin score ranged from 0.17 ± 0.01 to 0.67 ± 0.19 (corneal riboflavin concentration ranged from 6 ± 5µg/cm3 to 122 ± 39µg/cm3) at the end of imbibition time. A statistically significant linear correlation (P ≤ 0.05) was found between the theranostic and spectrophotometry measurements in all groups. Real-time theranostic imaging provided an accurate strategy for assessing permeation of riboflavin into the human cornea during the imbibition phase of corneal cross-linking, regardless of delivery protocol. A large variability in corneal riboflavin concentration exists between clinically available ophthalmic formulations both in epi-off and epi-on delivery protocols.

Unusual Sites of Visceral Spread in Prostate Cancer: A Prostate-Specific Membrane Antigen-Based Theranostic Imaging Series.

Prostate cancer commonly metastasizes to lymphatic and skeletal systems with lesser frequency to visceral organs; however, uncommon visceral sites have also been found and reported as case reports. We present a series of uncommon metastatic visceral spread in prostate cancer on prostate-specific membrane antigen-based diagnostic and posttherapeutic imaging modalities.

Theranostic imaging and treatment of chemotherapy resistant muscle invasive bladder cancer by targeting FAP and CXCR4: The Bladder BRIDGister experience.

550 Background: Patients with muscle invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NACT) have improved prognosis. Previously we did show that luminal tumors respond better to NACT (Ecke et al 2022), while the radioligand targets CXCR4 and FAP are found in chemoresistant, stroma-associated tumors. The objective of this study was to exploit the expression of CXCR4 &amp; FAP for theranostic imaging &amp; treatment in selected patients by radioligand instillation into the bladder to justify subsequent adopted clinical trials within the Bladder BRIDGister framework. Methods: FFPE tumor tissues from 511 TURB samples were prospectively collected as part of the Bladder BRIDGister. RNA was extracted by commercial kits, relative gene expression of subtyping markers and radioligand target genes were analyzed by RT-qPCR. Hierarchical clustering, Kruskal-Wallis and contingency tests were done by JMP 9.0.0 (SAS software). PET/CT Imaging by CXCR4 and/or FAP instillation was performed in selected patients followed by systemic radioligand application after completion of cisplatinum based NACT to enable improved staging. Results: The prospective molecular registry cohort consisted of 511 bladder cancer patients included into the Bladder BRIDGister (median age: 75, male 74% vs. female 26%) with 5% Tis, 54% Ta, 16% T1 and 15% T2 stage and concomitant CIS being in 7%. CXCR4 expression was negatively associated with ERBB2 &amp; FGFR3 mRNA (r=-0,3021 and r=-0,3326, p&lt;0,0001). Inverse relation of FAP expression with ERBB2 &amp; FGFR3 was even more pronounced (r=-0,4883 and r=-0,5177, p&lt;0,0001). Clustering validated that CXCR4 and FAP are elevated in non-luminal tumors not responding to NACT. Exemplarily one stromal rich pT2 G3 MIBC patient with elevated FAP expression, who was predicted to be unresponsive to NACT, was selected for FDG and FAP PET/CT imaging after two cycles of NACT. Indeed metastatic lesion were detected in the liver and pancreatic tissue. FAP imaging revealed to be more sensitive than conventional FDG imaging. In a next step 68Ga-CXCR4 was instilled into the bladder of a patient with NACT-resistant MIBC rejecting cystectomy to establish a non-systemic approach for radioligand therapy. Theranostic instillation imaging revealed strong uptake into the invading MIBC and subsequent instillation therapy with 177Lu-FAP led to partial remission and increased immune cell infiltration indicating initial effectivity. Conclusions: Expression of the radioligand targets CXCR4 and FAP are associated with aggressive stromal and basal like tumors being resistant to NACT. This could be validated by selecting patients for FAP &amp; CXCR4 PET/CT imaging. Instillation of radioligands into the bladder revealed to be safe with first signs of effectivity justifying clinical approaches as part of phase 1 / 2 clinical trials.

Cone-beam x-ray luminescence computed tomography (CB-XLCT) prototype development and performance evaluation.

This study developed a prototype for a rotational cone-beam x-ray luminescence computed tomography (CB-XLCT) system, considering its potential application in pre-clinical theranostic imaging. A geometric calibration method applicable to both imaging chains (XL and CT) was also developed to enhance image quality. The results of systematic performance evaluations were presented to assess the feasibility of commercializing XLCT technology. Monte Carlo GATE simulation was performed to determine the optimal imaging conditions for nanophosphor particles (NPs) irradiated by 70 kV x-rays. We acquired a low-dose transmission x-ray tube and designed a prone positioning platform and a rotating gantry, using mice as targets from commercial small animalμ-CT systems. We then employed the image cross-correlation (ICC) automatic geometric calibration method to calibrate XL and CT images. The performance of the system was evaluated through a series of phantom experiments with a linearity of 0.99, and the contrast-to-noise ratio (CNR) between hydroxyl-apatite (HA) and based epoxy resin is 19.5. The XL images of the CB-XLCT prototype achieved a Dice similarity coefficient (DICE) of 0.149 for a distance of 1 mm between the two light sources. Finally, the final XLCT imaging results were demonstrated using the Letter phantoms with NPs. In summary, the CB-XLCT prototype developed in this study showed the potential to achieve high-quality imaging with acceptable radiation doses for small animals. The performance of CT images was comparable to current commercial machines, while the XL images exhibited promising results in phantom imaging, but further efforts are needed for biomedical applications.

64Cu production via the 68Zn(p,nα)64Cu nuclear reaction: An untapped, cost-effective and high energy production route

IntroductionCopper-64 (64Cu, t1/2 = 12.7 h) is a positron emitter well suited for theranostic applications with beta-emitting 67Cu for targeted molecular imaging and radionuclide therapy. The present work aims to evaluate the radionuclidic purity and radiochemistry of 64Cu produced via the 68Zn(p,nα)64Cu nuclear reaction. Macrocyclic chelators DOTA, NOTA, TETA, and prostate-specific membrane antigen ligand PSMA I&T were radiolabeled with purified 64Cu and tested for in vitro stability. [64Cu]Cu-PSMA I&T was used to demonstrate in vivo PET imaging using 64Cu synthesized via the 68Zn(p,nα)64Cu production route and its suitability as a theranostic imaging partner alongside 67Cu therapy. Methods64Cu was produced on a 24 MeV TR-24 cyclotron at a beam energy of 23.5 MeV and currents up to 70 μA using 200 mg 68Zn encapsulated within an aluminum‑indium-graphite sealed solid target assembly. 64Cu semi-automated purification was performed using a NEPTIS Mosaic-LC synthesis unit employing CU, TBP, and TK201 (TrisKem) resins. Radionuclidic purity was measured by HPGe gamma spectroscopy, while ICP-OES assessed elemental purity. Radiolabeling was performed with NOTA at room temperature and DOTA, TETA, and PSMA I&T at 95 °C. 64Cu incorporation was studied by radio-TLC. 64Cu in vitro stability of [64Cu]Cu-NOTA, [64Cu]Cu-DOTA, [64Cu]Cu-TETA, and [64Cu]Cu-PSMA I&T was assessed at 37 °C from 0 to 72 h in human blood serum. Preclinical PET imaging was performed at 1, 24, and 48 h post-injection with [64Cu]Cu-PSMA I&T in LNCaP tumor-bearing mice and compared with [68Ga]Ga-PSMA I&T. ResultsMaximum purified activity of 4.9 GBq [64Cu]CuCl2 was obtained in 5 mL of pH 2–3 solution, with 2.9 GBq 64Cu concentrated in 0.5 mL. HPGe gamma spectroscopy of purified 64Cu detected <0.3 % co-produced 67Cu at EOB with no other radionuclidic impurities. ICP-OES elemental analysis determined <1 ppm Al, Zn, In, Fe, and Cu in the [64Cu]CuCl2 product. NOTA, DOTA, TETA, and PSMA I&T were radiolabeled with 64Cu, resulting in maximum molar activities of 164 ± 6 GBq/μmol, 155 ± 31 GBq/μmol, 266 ± 34 GBq/μmol, and 117 ± 2 GBq/μmol, respectively. PET imaging in PSMA-expressing LNCaP xenografts resulted in high tumor uptake (SUVmean = 1.65 ± 0.1) using [64Cu]Cu-PSMA I&T, while [68Ga]Ga-PSMA I&T yielded an SUVmean of 0.76 ± 0.14 after 60 min post-injection. Conclusions64Cu was purified in a small volume amenable for radiolabeling, with yields suitable for preclinical and clinical application. The 64Cu production and purification process and the favourable PET imaging properties confirm the 68Zn(p,nα)64Cu nuclear reaction as a viable 64Cu production route for facilities with access to a higher energy proton cyclotron, compared to using expensive 64Ni target material and the 64Ni(p,n)64Cu nuclear reaction. Advances in knowledge and implications for patient careOur 64Cu production technique provides an alternative production route with the potential to improve 64Cu availability for preclinical and clinical studies alongside 67Cu therapy.

Theranostic Imaging Surrogates for Targeted Alpha Therapy: Progress in Production, Purification, and Applications.

This article highlights recent developments of SPECT and PET diagnostic imaging surrogates for targeted alpha particle therapy (TAT) radiopharmaceuticals. It outlines the rationale for using imaging surrogates to improve diagnostic-scan accuracy and facilitate research, and the properties an imaging-surrogate candidate should possess. It evaluates the strengths and limitations of each potential imaging surrogate. Thirteen surrogates for TAT are explored: 133La, 132La, 134Ce/134La, and 226Ac for 225Ac TAT; 203Pb for 212Pb TAT; 131Ba for 223Ra and 224Ra TAT; 123I, 124I, 131I and 209At for 211At TAT; 134Ce/134La for 227Th TAT; and 155Tb and 152Tb for 149Tb TAT.

Testicular Metastasis From Neuroendocrine Tumors: Imaging and Theranostics Through 68Ga-DOTATATE PET/CT and 177Lu-DOTATATE-Based Peptide Receptor Radionuclide Therapy.

Neuroendocrine tumors (NETs) are rare neoplasms arising from enterochromaffin cells, which are predominantly noted in the gastrointestinal tract and lung; metastases of NETs to the testes in NET are further uncommon. Testicular NET usually has no symptoms and/or presents with painless swelling of the scrotum. Detection of testicular lesion can be challenging and frequently missed on conventional radiological imaging. We present testicular NET missed on conventional radiological imaging, where 68Ga-DOTATATE PET/CT imaging detected the testicular lesion, and further evident on 177Lu-DOTATATE-based post-peptide receptor radionuclide therapy theranostic imaging.

Theranostic imaging and multimodal photodynamic therapy and immunotherapy using the mTOR signaling pathway

Tumor metastases are considered the leading cause of cancer-associated deaths. While clinically applied drugs have demonstrated to efficiently remove the primary tumor, metastases remain poorly accessible. To overcome this limitation, herein, the development of a theranostic nanomaterial by incorporating a chromophore for imaging and a photosensitizer for treatment of metastatic tumor sites is presented. The mechanism of action reveals that the nanoparticles are able to intervene by local generation of cellular damage through photodynamic therapy as well as by systemic induction of an immune response by immunotherapy upon inhibition of the mTOR signaling pathway which is of crucial importance for tumor onset, progression and metastatic spreading. The nanomaterial is able to strongly reduce the volume of the primary tumor as well as eradicates tumor metastases in a metastatic breast cancer and a multi-drug resistant patient-derived hepatocellular carcinoma models in female mice.

The Role of Bone Scintigraphy and Parathyroid Scintigraphy on Multiple Osteolytic Lesions Which Misdiagnosed as Primary Bone Tumor (Giant Cell Tumor)

&lt;p&gt;Brown tumor is a non-neoplastic lesion that resulting from abnormal bone metabolism. It can be manifest in prolonged or untreated hyperparathyroidism. The clinical symptoms, radiological and histopathological examination were similar with giant cell tumor and can be mimicking metastases; or even misdiagnosed with giant cell tumor and mistreated the patient. Biochemical examination of calcium levels and parathyroid hormone should be included in the routine assessment of patients with multiple osteolytic lesions. A multidiscipline approach is needed.Throughout this case report, we would like to report the important role of Nuclear Medicine and Molecular Theranostic imaging modality in 38-year-old male with multiple osteolytic lesions, which was first diagnosed as giant cell tumor and differential diagnosis bone metastases but turnout to be a metabolic bone disease (brown tumor) with parathyroid adenoma as etiology.&lt;/p&gt;

Prediction of nonresponse and theranostic imaging in MIBC being resistant to NACT within the Bladder BRIDGister.

e16603 Background: Patients with muscle invasive urothelial carcinoma achieving pathological complete response upon neoadjuvant chemotherapy (NACT) have improved prognosis. Previously we did show that luminal tumors respond better to NACT, while FGFR1 expression is associated with NACT resistance (Ecke et al. 2022). Interestingly the expression of the radioligand targets CXCR4 and FAP is found in chemoresistant, stroma-associated tumors. The objective of this study was to prospectively validate the predictive value of molecular target typing from TUR biopsy samples and compare PET CT imaging by FDG and FAP radioligand imaging in selected patients after two cycles of NACT to justify subsequent adaptive trial concepts within the "Bladder BRIDGister." Methods: Formalin fixed paraffin embedded tissues (FFPE) from transurethral resections (TUR) before chemotherapy and cystectomy samples after NACT of 36 patients were retrospectively collected and 650 TURB samples were prospectively collected as part of the Bladder BRIDGister. RNA from FFPE tissues were extracted by commercial kits, relative gene expression of subtyping markers (KRT5, KRT20, FGFR1) and radioligand target genes (CXCR4, FAP) were analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). PET CT Imaging by FDG and FAP was performed after two cycles cisplatinum based NACT. Results: The neoadjuvant cohort consisted of 36 patients (median age 69, male 83%, female 17%) with 92% of patients being node negative. Hierarchical clustering revealed CXCR4 and FAP to be elevated in stromal rich, KRT5 &amp; KRT20 negative tumors not responding to NACT. Elevated FAP mRNA expression was sig. associated with resistance to NACT (chi2 4.314 p=0,0378). Combining elevated FAP and CXCR4 mRNA expression did identify 1/3 of the patients to be at high risk of NACT resistance (90%). Exemplarily one pT3 G3 patient was selected for PET CT imaging after two cycles that was predicted to be unresponsive to NACT by molecular subtyping. FDG PET CT revealed a hepatic metastatic lesion. In contrast FAP PET CT indicated multiple hepatic and a pancreatic metastatic lesion indicating tumor progression under NACT. Therapy was switched to MVAC with persistent non response. Then pembrolizumab monotherapy was administered due to PD-L1 positivity of the initial TURB (10% TPS /CPC 15). However there still was fulminant progression of the liver metastasis so that ICI therapy had to be stopped. Conclusions: Expression of the radioligand targets CXCR4 and FAP has been shown to be associated with aggressive stromal associated tumors and being resistant to NACT. This could be validated by selecting patients after two cycles of NACT for PET/CT imaging. Stratified FAP PET/CT turned out to be more sensitive than conventional FDG PET CT and may enable future theranostic treatment combinations in patients unresponsive to standard chemo- or immunotherapies.

First Superferromagnetic Remanence Characterization and Scan Optimization for Super-Resolution Magnetic Particle Imaging.

Magnetic particle imaging (MPI) is a sensitive, high-contrast tracer modality that images superparamagnetic iron oxide nanoparticles, enabling radiation-free theranostic imaging. MPI resolution is currently limited by scanner and particle constraints. Recent tracers have experimentally shown 10× resolution and signal improvements with dramatically sharper M-H curves. Experiments show a dependence on interparticle interactions, conforming to literature definitions of superferromagnetism. We thus call our tracers superferromagnetic iron oxide nanoparticles (SFMIOs). While SFMIOs provide excellent signal and resolution, they exhibit hysteresis with non-negligible remanence and coercivity. We provide the first quantitative measurements of SFMIO remanence decay and reformation using a novel multiecho pulse sequence. We characterize MPI scanning with remanence decay and coercivity and describe an SNR-optimized pulse sequence for SFMIOs under human electromagnetic safety limitations. The resolution from SFMIOs could enable clinical MPI with 10× reduced scanner selection fields, reducing hardware costs by up to 100×.

SPECT reconstruction with a trained regularizer using CT-side information: Application to 177Lu SPECT imaging.

Improving low-count SPECT can shorten scans and support pre-therapy theranostic imaging for dosimetry-based treatment planning, especially with radionuclides like 177Lu known for low photon yields. Conventional methods often underperform in low-count settings, highlighting the need for trained regularization in model-based image reconstruction. This paper introduces a trained regularizer for SPECT reconstruction that leverages segmentation based on CT imaging. The regularizer incorporates CT-side information via a segmentation mask from a pre-trained network (nnUNet). In this proof-of-concept study, we used patient studies with 177Lu DOTATATE to train and tested with phantom and patient datasets, simulating pre-therapy imaging conditions. Our results show that the proposed method outperforms both standard unregularized EM algorithms and conventional regularization with CT-side information. Specifically, our method achieved marked improvements in activity quantification, noise reduction, and root mean square error. The enhanced low-count SPECT approach has promising implications for theranostic imaging, post-therapy imaging, whole body SPECT, and reducing SPECT acquisition times.

First in vivo fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod.

Theranostic imaging methods could greatly enhance our understanding of the distribution of CNS-acting drugs in individual patients. Fluorine-19 magnetic resonance imaging (19F MRI) offers the opportunity to localize and quantify fluorinated drugs non-invasively, without modifications and without the application of ionizing or other harmful radiation. Here we investigated siponimod, a sphingosine 1-phosphate (S1P) receptor antagonist indicated for secondary progressive multiple sclerosis (SPMS), to determine the feasibility of in vivo 19F MR imaging of a disease modifying drug. Methods: The 19F MR properties of siponimod were characterized using spectroscopic techniques. Four MRI methods were investigated to determine which was the most sensitive for 19F MR imaging of siponimod under biological conditions. We subsequently administered siponimod orally to 6 mice and acquired 19F MR spectra and images in vivo directly after administration, and in ex vivo tissues. Results: The 19F transverse relaxation time of siponimod was 381 ms when dissolved in dimethyl sulfoxide, and substantially reduced to 5 ms when combined with serum, and to 20 ms in ex vivo liver tissue. Ultrashort echo time (UTE) imaging was determined to be the most sensitive MRI technique for imaging siponimod in a biological context and was used to map the drug in vivo in the stomach and liver. Ex vivo images in the liver and brain showed an inhomogeneous distribution of siponimod in both organs. In the brain, siponimod accumulated predominantly in the cerebrum but not the cerebellum. No secondary 19F signals were detected from metabolites. From a translational perspective, we found that acquisitions done on a 3.0 T clinical MR scanner were 2.75 times more sensitive than acquisitions performed on a preclinical 9.4 T MR setup when taking changes in brain size across species into consideration and using equivalent relative spatial resolution. Conclusion: Siponimod can be imaged non-invasively using 19F UTE MRI in the form administered to MS patients, without modification. This study lays the groundwork for more extensive preclinical and clinical investigations. With the necessary technical development, 19F MRI has the potential to become a powerful theranostic tool for studying the time-course and distribution of CNS-acting drugs within the brain, especially during pathology.

Leveraging a Dual Variable Domain Immunoglobulin to Create a Site-Specifically Modified Radioimmunoconjugate.

Site-specifically modified radioimmunoconjugates exhibit superior in vitro and in vivo behavior compared to analogues synthesized via traditional stochastic methods. However, the development of approaches to site-specific bioconjugation that combine high levels of selectivity, simple reaction conditions, and clinical translatability remains a challenge. Herein, we describe a novel solution to this problem: the use of dual-variable domain immunoglobulins (DVD-IgG). More specifically, we report the synthesis, in vitro evaluation, and in vivo validation of a 177Lu-labeled radioimmunoconjugate based on HER2DVD, a DVD-IgG containing the HER2-targeting variable domains of trastuzumab and the catalytic variable domains of IgG h38C2. To this end, we first modified HER2DVD with a phenyloxadiazolyl methlysulfone-modified variant of the chelator CHX-A″-DTPA (PODS-CHX-A''-DTPA) and verified the site-specificity of the conjugation for the reactive lysines within the catalytic domains via chemical assay, MALDI-ToF mass spectrometry, and SDS-PAGE. The chelator-bearing immunoconjugate was subsequently labeled with [177Lu]Lu3+ to produce the completed radioimmunoconjugate, [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD, in >80% radiochemical conversion and a specific activity of 29.5 ± 7.1 GBq/μmol. [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD did not form aggregates upon prolonged incubation in human serum, displayed 87% stability to demetalation over a 7 days of incubation in serum, and exhibited an immunoreactive fraction of 0.95 with HER2-coated beads. Finally, we compared the pharmacokinetic profile of [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD to that of a 177Lu-labeled variant of trastuzumab in mice bearing subcutaneous HER2-expressing BT-474 human breast cancer xenografts. The in vivo performance of [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD matched that of 177Lu-labeled trastuzumab, with the former producing a tumoral activity concentration of 34.1 ± 12.1 %ID/g at 168 h and tumor-to-blood, tumor-to-liver, and tumor-to-kidney activity concentration ratios of 10.5, 9.6, and 21.8, respectively, at the same time point. Importantly, the DVD-IgG did not exhibit a substantially longer serum half-life than the traditional IgG despite its significantly larger size (202 kDa for the former vs 148 kDa for the latter). Taken together, these data suggest that DVD-IgGs represent a viable platform for the future development of highly effective site-specifically labeled radioimmunoconjugates for diagnostic imaging, theranostic imaging, and radioimmunotherapy.

P800SO3-PEG: a renal clearable bone-targeted fluorophore for theranostic imaging

BackgroundDue to the deep tissue penetration and reduced scattering, NIR-II fluorescence imaging is advantageous over conventional visible and NIR-I fluorescence imaging for the detection of bone growth, metabolism, metastasis, and other bone-related diseases.MethodsBone-targeted heptamethine cyanine fluorophores were synthesized by substituting the meso-carbon with a sulfur atom, resulting in a bathochromic shift and increased fluorescence intensity. The physicochemical, optical, and thermal stability of newly synthesized bone-targeted NIR fluorophores was performed in aqueous solvents. Calcium binding, bone-specific targeting, biodistribution, pharmacokinetics, and 2D and 3D NIR imaging were performed in animal models.ResultsThe newly synthesized S-substituted heptamethine fluorophores demonstrated a high affinity for hydroxyapatite and calcium phosphate, which improved bone-specific targeting with signal-background ratios > 3.5. Particularly, P800SO3-PEG showed minimum nonspecific uptake, and most unbound molecules were excreted into the urinary bladder. Histological analyses demonstrated that P800SO3-PEG remained stable in the bone for over two weeks and was incorporated into bone matrices. Interestingly, the flexible thiol ethylene glycol linker on P800SO3-PEG induced a promising photothermal effect upon NIR laser irradiation, demonstrating potential theranostic imaging.ConclusionsP800SO3-PEG shows a high affinity for bone tissues, deeper tissue imaging capabilities, minimum nonspecific uptake in the major organs, and photothermal effect upon laser irradiation, making it optimal for bone-targeted theranostic imaging.

Tumor Response to Radiopharmaceutical Therapies: The Knowns and the Unknowns.

Radiopharmaceutical therapy (RPT) is defined as the delivery of radioactive atoms to tumor-associated targets. In RPT, imaging is built into the mode of treatment since the radionuclides used in RPT often emit photons or can be imaged using a surrogate. Such imaging may be used to estimate tumor-absorbed dose. We examine and try to elucidate those factors that impact the absorbed dose-versus-response relationship for RPT agents. These include the role of inflammation- or immune-mediated effects, the significance of theranostic imaging, radiobiology, differences in dosimetry methods, pharmacokinetic differences across patients, and the impact of tumor hypoxia on response to RPT.