Purpose: Despite the clinical evidence of actinium-225 ( ²²⁵ Ac)-based targeted alpha therapies (TαT) efficacy, optimized treatment regimens are needed to improve overall clinical response rates and decrease toxicities. The nuclear recoil effect of ²²⁵ Ac and its resulting daughter nuclides have been hypothesized to contribute to non-targeted damage. However, a lack of generator concepts for radionuclidically pure francium-221 ( ²²¹ Fr), involvement of strong acids for elution, and its short half-life (4.8 min), has limited in vivo studies. Here, we report on a successful application of an ²²⁵ Ac/ ²²¹ Fr generator concept and the in vivo distribution of ²²¹ Fr and bismuth-213 ( ²¹³ Bi). Methods: The immobilization of ²²⁵ Ac and elution of ²²¹ Fr was performed on a LN2 resin column. The biodistribution of ²²¹ Fr and ²¹³ Bi was investigated in male SCID mice with LNCaP tumors at 5 and 15 min p.i. Results: Our results indicate that LN2 resin is a highly efficient resin for selective separation of ²²⁵ Ac and ²²¹ Fr. The use of 0.1 M NaOAc enabled continuous elution at a constant pH. The biodistribution study revealed a fast distribution of ²²¹ Fr and ²¹³ Bi already 5 min p.i. We observed a strong accumulation of ²²¹ Fr to the kidneys, salivary glands and small intestine. In ²¹³ Bi-injected mice, the highest accumulation was in kidney and liver. Conclusion: We present an unprecedented concept utilizing LN2 resin in ²²⁵ Ac/ ²²¹ Fr generator applications. Successfully eluted and injected ²²¹ Fr fractions showed strong accumulation of ²²¹ Fr and ²¹³ Bi in key organs. Our data provide preliminary evidence of the potential contribution of recoiled progeny radionuclides to side-effects in non-targeted organs.

Cancer is one of the most complex and challenging human diseases, with rising incidences and cancer-related deaths despite improved diagnosis and personalized treatment options. Targeted alpha therapy (TαT) offers an exciting strategy emerging for cancer treatment which has proven effective even in patients with advanced metastatic disease that has become resistant to other treatments. Yet, in many cases, more sophisticated strategies are needed to stall disease progression and overcome resistance to TαT. The combination of two or more therapies which have historically been used as stand-alone treatments is an approach that has been pursued in recent years. This review aims to provide an overview on TαT and the four main pillars of therapeutic strategies in cancer management, namely external beam radiation therapy (EBRT), immunotherapy with checkpoint inhibitors (ICI), cytostatic chemotherapy (CCT), and brachytherapy (BT), and to discuss their potential use in combination with TαT. A brief description of each therapy is followed by a review of known biological aspects and state-of-the-art treatment practices. The emphasis, however, is given to the motivation for combination with TαT as well as the pre-clinical and clinical studies conducted to date.

Locametz^®/Illuccix^®/Gozellix^TM (Novartis AG (Basel, Switzerland) and Telix Pharmaceuticals, Ltd. (Melbourne, Australia), all three [⁶⁸Ga]Ga-PSMA-11), Pylarify^®/Pylclari^® (Progenics Pharmaceuticals, Inc. (New York, USA) and Curium PET France SA (Paris, France), both [¹⁸F]DCFPyL), Radelumin^® (ABX GmbH (Radeberg, Germany), [¹⁸F]PSMA-1007), and Posluma^® (Blue Earth Diagnostics, Ltd. (Oxford, UK), [¹⁸F]rhPSMA-7.3) are four approved PSMA-PET imaging agents that have significantly advanced the diagnosis and management of prostate cancer. These agents offer a new level of precision and accuracy, enabling clinicians to detect prostate cancer with enhanced sensitivity. As a result, they play a critical role in improving detection, staging, and management, ultimately enhancing clinical outcomes for patients. Their use in routine clinical practice is expected to increase diagnostic precision and provide clearer pathways for personalized therapy. This review offers a comprehensive chemical, pharmaceutical, and medicinal overview, discusses comparative studies, and highlights additional highly relevant candidates for prostate cancer detection.

Kisspeptins (KPs) and their receptor (KISS1R) promote metastasis and tumor progression in various cancers such as triple-negative breast cancer (TNBC). Targeting KISS1R holds great promise for molecular imaging and targeted radionuclide therapy of aggressively disseminated cancers. First ligand-based approaches using Ga-68/Lu-177-labeled KPs (KP-10, KP-54) have demonstrated feasibility but suffer from proteolytic degradation and low uptake in KISS1R positive tumors. However, lead structure optimization alone is insufficient, as KISS1R biology remains unexplored in a radiotheranostic context. In this study, N-terminally functionalized conjugates of KP-10, KP-54, and the hybrid peptide KiSS-34 (AMBA-2-Nal-Gly-Leu-Arg-Trp-NH₂), including scrambled controls, were synthesized in high purity (≥95%) for comparative studies. The conjugation to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and Alexa-Fluor-488 (AF-488) functionalities preserved biological activity, confirmed by (sub)nanomolar EC₅₀-values (0.05–0.85 nM) in calcium mobilization assays in transfected CHO-KISS1R cells. Conventional target detection methods using antibodies (Abs) and AF-488-KPs failed to visualize KISS1R in both model (CHO-KISS1R) and native cancer cell lines, likely due to unspecific Abs and rapid KISS1R internalization upon agonist stimulation. However, rapid KISS1R internalization was successfully visualized via live-cell imaging using AF-488-KP-10 and novel analogue AF-488-KiSS-34. Furthermore, DOTA-KPs were radiolabeled with Lu-177 in high efficiencies (≥95%) and examined in internalization assays, showing highest uptake (4.8%) and internalization rate (45.9%) for [¹⁷⁷Lu]Lu-DOTA-KiSS-34 in CHO-KISS1R cells compared to its KP-10 analogue (total uptake: 1.3%; internalization rate: 37.6%). Higher uptakes likely derive from faster binding kinetics, improved KISS1R targeting, and/or slower dissociation as evidenced by oil-based kinetics assays showing higher total uptake for [¹⁷⁷Lu]Lu-DOTA-KiSS-34 (15.3%) compared to KP-10 (3.8%) and KP-54 (4.5%) counterparts after 30 min. Positron emission tomography/computerized tomography (PET/CT) imaging, urine analysis, and all in vitro studies indicate that Ga-68/Lu-177-labeled DOTA-KiSS-34 exhibits superior pharmacodynamics, pharmacokinetics, and in vivo stability compared to its KP-10 and KP-54 analogues, which are critically suffering from rapid in vivo degradation. These results position DOTA-KiSS-34 as a strong structural lead for KISS1R-based radiotheranostics. Nevertheless, the dynamics between KPs and KISS1R need to be further investigated to fully harness the radiotheranostic potential of KISS1R for TNBC and other cancers.

[¹⁷⁷Lu]Lu-PSMA-617 has recently been successfully approved by the FDA, the MHRA, Health Canada and the EMA as Pluvicto^®. However, salivary gland (SG) and kidney toxicities account for its main dose-limiting side-effects, while its corresponding uptake and retention mechanisms still remain elusive. Recently, the presence of different ATP-binding cassette (ABC) transporters, such as human breast cancer resistance proteins (BCRP), multidrug resistance proteins (MDR1), multidrug-resistance-related proteins (MRP1, MRP4) and solute cassette (SLC) transporters, such as multidrug and toxin extrusion proteins (MATE1, MATE2-K), organic anion transporters (OAT1, OAT2v1, OAT3, OAT4) and peptide transporters (PEPT2), has been verified at different abundances in human SGs and kidneys. Therefore, our aim was to assess whether [¹⁷⁷Lu]Lu-PSMA-617 and [²²⁵Ac]Ac-PSMA-617 are substrates of these ABC and SLC transporters. For in vitro studies, the novel isotopologue ([α,β-³H]Nal)Lu-PSMA-617 was used in cell lines or vesicles expressing the aforementioned human ABC and SLC transporters for inhibition and uptake studies, respectively. The corresponding probe substrates and reference inhibitors were used as controls. Our results indicate that [¹⁷⁷Lu]Lu-PSMA-617 and [²²⁵Ac]Ac-PSMA-617 are neither inhibitors nor substrates of the examined transporters. Therefore, our results show that human ABC and SLC transporters play no central role in the uptake and retention of [¹⁷⁷Lu]Lu-PSMA-617 and [²²⁵Ac]Ac-PSMA-617 in the SGs and kidneys nor in the observed toxicities.