Introduction: Radiohybrid prostate-specific membrane antigen (rhPSMA)-ligands allow for labelling with ¹⁸F and radiometals for endoradiotherapy. rhPSMA-7.3 is designated as lead compound with promising preclinical data for ¹⁷⁷Lu-rhPSMA-7.3 indicating higher tumor uptake compared with ¹⁷⁷Lu-PSMA-I&T. In this retrospective analysis we compared pre-therapeutic clinical dosimetry of both PSMA-ligands. Methods: Six mCRPC patients underwent both ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA-I&T pre-therapeutic dosimetry. Whole-body scintigraphy was performed at 1h, 4h, 24h, 48h and 7d post injection. Regions of interest (ROI) covering the whole body, organs, bone marrow and tumor lesions per patient were drawn. Absorbed doses for individual patients and pre-therapeutic applications were calculated using OLINDA/EXM. To facilitate comparison of both ligands we introduced the therapeutic index (TI) defined as ratio of mean pre-therapeutic doses to tumor lesions over relevant organs-at-risk. Results: Mean whole-body pre-therapeutic effective doses were 0.12±0.07 vs. 0.05±0.03 Sv/GBq and mean absorbed organ doses were e.g. 1.65±0.28 vs. 0.73±0.18 Gy/GBq for the kidneys; 0.19±0.09 vs. 0.07±0.03 Gy/GBq for the liver and 2.35±0.78 vs. 0.80±0.41 Gy/GBq for the parotid, for the bone marrow 0.67±0.62 vs. 0.30±0.27 Gy/GBq for ¹⁷⁷Lu-rhPSMA-7.3 vs. ¹⁷⁷Lu-PSMA-I&T, respectively. Tumor lesions received a mean absorbed doses of 6.44±6.44 vs. 2.64±2.24 Gy/GBq for ¹⁷⁷Lu-rhPSMA-7.3 vs. ¹⁷⁷Lu-PSMA-I&T, respectively. The mean TI(kidney) and TI(bone_marrow) were 3.7±2.2 vs. 3.6±2.2 and 15.2±10.2 vs. 15.1±10.2, for ¹⁷⁷Lu-rhPSMA-7.3 vs. ¹⁷⁷Lu-PSMA-I&T, respectively. Conclusion: Pre-therapeutic clinical dosimetry confirmed preclinical results with 2-3 times higher mean absorbed doses for tumors of ¹⁷⁷Lu-rhPSMA-7.3 compared to ¹⁷⁷Lu-PSMA-I&T. Absorbed doses to normal organs also tended to be higher for ¹⁷⁷Lu-rhPSMA-7.3 resulting overall in a similar average TI for both radiopharmaceuticals with considerable inter-patient variability. ¹⁷⁷Lu-rhPSMA-7.3 holds promise for similar therapeutic efficacy as ¹⁷⁷Lu-PSMA-I&T at lower amounts of injected activity simplifying radiation safety measurements (especially for large patient numbers and/or dose escalation regimes).

Background: Non-invasive tumor characterization and monitoring are among the key goals of medical imaging. Using hyperpolarized ¹³C-labelled metabolic probes fast metabolic pathways can be probed in real-time, providing new opportunities for tumor characterization. In this in vitro study, we investigated whether measurement of apparent diffusion coefficient (ADC) measurements and magnetic resonance spectroscopy (MRS) of co-polarized ¹³C-labeled pyruvic acid and fumaric acid can non-invasively detect both necrosis and changes in lactate export, which are parameters indicative of tumor aggressiveness.

Most Prostate Specific Membrane Antigens (PSMAs) targeting small molecules accumulate in the salivary glands (SGs), raising concerns about SG toxicity, especially after repeated therapies or therapy with ²²⁵Ac-labeled ligands. SG toxicity is assessed clinically by the severity of patient-reported xerostomia, but this parameter can be challenging to objectively quantify. Therefore, we explored the feasibility of using SG volume as a biomarker for toxicity. In 21 patients with late-stage metastatic resistant prostate cancer (mCRPC), the PSMA volume and ligand uptake of SG were analyzed retrospectively before and after two cycles of ¹⁷⁷Lu-PSMA (LuPSMA; cohort A) and before and after one cycle of ²²⁵Ac-PSMA-617 (AcPSMA, cohort B). Mean Volume-SG in cohort A was 59 ± 13 vs. 54 ± 16 mL (−10%, p = 0.4), and in cohort B, it was 50 ± 13 vs. 40 ± 11 mL (−20%, p = 0.007), respectively. A statistically significant decrease in the activity concentration in the SG was only observed in group B (SUV_mean: 9.2 ± 2.8 vs. 5.3 ± 1.8, p < 0.0001; vs. A: SUV_mean: 11.2 ± 3.3 vs. 11.1 ± 3.5, p = 0.8). SG volume and PSMA-ligand uptake are promising markers to monitor the SG toxicity after a PSMA RLT.

Evaluation of treatment response is among the major challenges in modern oncology. We herein used a monoclonal antibody targeting the EGF receptor (EGFR) labelled with the alpha emitter ²¹³Bi (²¹³Bi-anti-EGFR-MAb). EJ28Luc (bladder) and LN18 (glioma) cancer cells, both overexpressing EGFR, were incubated for 3 h with the radioimmunoconjugate. To assess the responses in the core carbon metabolism upon this treatment, these cancer cell lines were subsequently cultivated for 18 h in the presence of [U-¹³C₆]glucose. ¹³C-enrichment and isotopologue profiles of key amino acids were monitored by gas chromatography–mass spectrometry (GC/MS), in order to monitor the impacts of the radionuclide-treatment upon glucose metabolism. In comparison to untreated controls, treatment of EJ28Luc cells with ²¹³Bi-anti-EGFR-MAb resulted in a significantly decreased incorporation of ¹³C from [U-¹³C₆]glucose into alanine, aspartate, glutamate, glycine, proline and serine. In sharp contrast, the same amino acids did not display less ¹³C-enrichments during treatment of the LN18 cells. The data indicate early treatment response of the bladder cancer cells, but not of the glioma cells though cell lines were killed following ²¹³Bi-anti-EGFR-MAb treatment. The pilot study shows that the ¹³C-labelling approach is a valid tool to assess the responsiveness of cancer cells upon radionuclide-treatment in considerable metabolic detail.

Evaluation of response to therapy is among the key objectives of oncology. A new method to evaluate this response includes magnetic resonance spectroscopy (MRS) with hyperpolarized ¹³C-labelled metabolites, which holds promise to provide new insights in terms of both therapeutic efficacy and tumor cell metabolism. Human EJ28Luc urothelial carcinoma and LN18 glioma cells were treated with lethal activity concentrations of a ²¹³Bi-anti-EGFR immunoconjugate. Treatment efficacy was controlled via analysis of DNA double-strand breaks (immunofluorescence γH2AX staining) and clonogenic survival of cells. To investigate changes in metabolism of treated cells vs controls we analyzed conversion of hyperpolarized [1-¹³C]pyruvate to [1-¹³C]lactate via MRS as well as viability of cells, lactate formation and lactate dehydrogenase activity in the cellular supernatants and [¹⁸F]FDG uptake in treated cells vs controls, respectively. Treatment of malignant cancer cells with ²¹³Bi-anti-EGFR-MAb induced intense DNA double-strand breaks, resulting in cell death as monitored via clonogenic survival. Moreover, treatment of EJ28Luc bladder cancer cells resulted in decreased cell viability, [¹⁸F]FDG-uptake and an increased lactate export. In both EJ28Luc and LN18 carcinoma cells treatment with ²¹³Bi-anti-EGFR-MAb triggered a significant increase in lactate/pyruvate ratios, as measured with hyperpolarized [1-¹³C]pyruvate. Treatment with ²¹³Bi-anti-EGFR-MAb resulted in an effective induction of cell death in EJ28Luc and LN18 cells. Lactate/pyruvate ratios of hyperpolarized [1-¹³C]pyruvate proved to detect early treatment response effects, holding promise for future clinical applications in early therapy monitoring.