The global network of cyclotrons has expanded rapidly over the last decade. The bulk of its industrial potential is composed of small medical cyclotrons with a proton energy below 20 MeV for radionuclides production. This review focuses on the recent developments of novel medical radionuclides produced by cyclotrons in the energy range of 3 MeV to 20 MeV. The production of the following medical radionuclides will be described based on available literature sources: Tc-99 m, I-123, I-124, Zr-89, Cu-64, Ga-67, Ga-68, In-111, Y-86 and Sc-44. Remarkable developments in the production process have been observed in only some cases. More research is needed to make novel radionuclide cyclotron production available for the medical industry.

Over the years, a broad spectrum of applications of the radionuclide holmium-166 as a medical isotope has been established. The isotope holmium-166 is attractive as it emits high-energy beta radiation which can be used for a therapeutic effect and gamma radiation which can be used for nuclear imaging purposes. Furthermore, holmium-165 can be visualized by MRI because of its paramagnetic properties and by CT because of its high density. Since holmium-165 has a natural abundance of 100%, the only by-product is metastable holmium-166 and no costly chemical purification steps are necessary for production of nuclear reactor derived holmium-166. Several compounds labelled with holmium-166 are now used in patients, such Ho166-labelled microspheres for liver malignancies, Ho166-labelled chitosan for hepatocellular carcinoma (HCC) and [166Ho]Ho DOTMP for bone metastases. The outcomes in patients are very promising, making this isotope more and more interesting for applications in interventional oncology. Both drugs as well as medical devices labelled with radioactive holmium are used for internal radiotherapy. One of the treatment possibilities is direct intratumoural treatment, in which the radioactive compound is injected with a needle directly into the tumour. Numerous other applications have been developed, like patches for treatment of skin cancer and holmium labelled antibodies and peptides. The second major application that is currently clinically applied is selective internal radiation therapy (SIRT, also called radioembolization), a novel treatment option for liver malignancies. This review discusses medical drugs and medical devices based on the therapeutic radionuclide holmium-166.

Purpose: To systematically review all current evidence into the dose-response relation of yttrium-90 and holmium-166 selective internal radiation therapy (SIRT) in primary and secondary liver cancer. Methods: A standardized search was performed in PubMed (MEDLINE), Embase, and the Cochrane Library in order to identify all published articles on dose-response evaluation in SIRT. In order to limit the results, all articles that investigated SIRT in combination with other therapy modalities (such as chemotherapy) were excluded. Results: A total of 3038 records were identified of which 487 were screened based on the full text. Ultimately, 37 studies were included for narrative analysis. Meta-analysis could not be performed due to the large heterogeneity in study and reporting designs. Out of 37 studies, 30 reported a ‘mean dose threshold’ that needs to be achieved in order to expect a response. This threshold appears to be higher for hepatocellular carcinoma (HCC, 100–250 Gy) than for colorectal cancer metastases (CRC, 40–60 Gy). Reported thresholds tend to be lower for resin microspheres than when glass microspheres are used. Conclusion: Although the existing evidence demonstrates a dose-response relationship in SIRT for both primary liver tumours and liver metastases, many pieces of the puzzle are still missing, hampering the definition of standardized dose thresholds. Nonetheless, most current evidence points towards a target mean dose of 100–250 Gy for HCC and 40–60 Gy for CRC. The field would greatly benefit from a reporting standard and prospective studies designed to elucidate the dose-response relation in different tumour types.

The objective of this study was to prepare and characterize alginate microgels loaded with temperature sensitive liposomes, which release their payload after mild hyperthermia. It is further aimed that by using these microgels both the drug release and the microgel deposition can be visualized by magnetic resonance imaging (MRI) after their administration (e.g. in the vicinity of a tumor). To this end, temperature sensitive (TSL) and non-temperature sensitive liposomes (NTSL) loaded with fluorescein (drug mimicking dye) and a T1 MRI contrast agent (Prohance®, [Gd(HPDO3A)(H2O)]) were encapsulated in alginate microgels crosslinked by holmium ions (T2∗ MRI contrast agent). The drug release could be monitored by the release of [Gd(HPDO3A)(H2O)] while the microgels could be visualized using MRI via the holmium ions in the microgels. The microgels were prepared with a JetCutter and had an average size of 325 μm and contained ∼0.6 wt% Ho3+. Microgels loaded with NTSL (NTSL-Ho-microgels) were stable at 37 and 42 °C with only a minimal release of fluorescein and [Gd(HPDO3A)(H2O)]. Microgels encapsulating TSL (TSL-Ho-microgels) released fluorescein and [Gd(HPDO3A)(H2O)] only marginally at 37 °C while, importantly, their payload was co-released within 2 min at 42 °C. TSL-Ho-microgels were administered in an ex vivo sheep kidney via a catheter. Clusters of TSL-Ho-microgels could be visualized via MRI and were deposited in the interlobular blood vessels. In conclusion, these alginate TSL-Ho-microgels are promising systems for real-time, MR-guided embolization and triggered release of drugs in vivo

Purpose: Transarterial radioembolization (TARE) is a treatment for liver tumours based on injection of radioactive microspheres in the hepatic arterial system. It is crucial to achieve a maximum tumour dose for an optimal treatment response, while minimizing healthy liver dose to prevent toxicity. There is, however, no intraprocedural feedback on the dose distribution, as nuclear imaging can only be performed after treatment. As holmium-166 (¹⁶⁶Ho) microspheres can be quantified with MRI, we investigate the feasibility and safety of performing ¹⁶⁶Ho TARE within an MRI scanner and explore the potential of intraprocedural MRI-based dosimetry. Methods: Six patients were treated with ¹⁶⁶Ho TARE in a hybrid operating room. Per injection position, a microcatheter was placed under angiography guidance, after which patients were transported to an adjacent 3-T MRI system. After MRI confirmation of unchanged catheter location, ¹⁶⁶Ho microspheres were injected in four fractions, consisting of 10%, 30%, 30% and 30% of the planned activity, alternated with holmium-sensitive MRI acquisition to assess the microsphere distribution. After the procedures, MRI-based dose maps were calculated from each intraprocedural image series using a dedicated dosimetry software package for ¹⁶⁶Ho TARE. Results: Administration of ¹⁶⁶Ho microspheres within the MRI scanner was feasible in 9/11 (82%) injection positions. Intraprocedural holmium-sensitive MRI allowed for tumour dosimetry in 18/19 (95%) of treated tumours. Two CTCAE grade 3–4 toxicities were observed, and no adverse events were attributed to treatment in the MRI. Towards the last fraction, 4/18 tumours exhibited signs of saturation, while in 14/18 tumours, the microsphere uptake patterns did not deviate from the linear trend. Conclusion: This study demonstrated feasibility and preliminary safety of a first in-human application of TARE within a clinical MRI system. Intraprocedural MRI-based dosimetry enabled dynamic insight in the microsphere distribution during TARE. This proof of concept yields unique possibilities to better understand microsphere distribution in vivo and to potentially optimize treatment efficacy through treatment personalization. Registration: Clinicaltrials.gov, identifier NCT04269499, registered on February 13, 2020 (retrospectively registered).

The aim of this study was the development of radioactive holmium phosphate microspheres (HoPO4-MS) with a high holmium content and that are stable in human serum for selective internal radiation therapy (SIRT) of liver cancer. To this end, holmium acetylacetonate microspheres (HoAcAc-MS) were prepared (34.2 ± 1.0 µm in diameter, holmium content of 46.2 ± 0.8 and density of 1.7 g/cm3) via an emulsification and solvent evaporation method. The concentration of HoAcAc in the organic solvent, the temperature of emulsification and the stirring speed were varied for the preparation of the HoAcAc-MS to obtain microspheres with different diameters ranging from 11 to 35 µm. Subsequently, the AcAc ligands of the HoAcAc-MS were replaced by phosphate ions by simply incubating neutron irradiated HoAcAc-MS in a phosphate buffer solution (0.116 M, pH 4.2) to yield radioactive HoPO4-MS. The obtained microspheres were analyzed using different techniques such as SEM-EDS, ICP-OES and HPLC. The prepared HoPO4-MS (29.5 ± 1.2 µm in diameter and a density of 3.1 g/cm3) present an even higher holmium content (52 wt%) than the HoAcAc-MS precursor (46 wt%). Finally, the stability of the HoPO4-MS was tested by incubation in human serum at 37 °C which showed no visible changes of the microspheres morphology and only 0.1% of holmium release was observed during the 2 weeks period of incubation. In conclusion, this study shows that stable radioactive HoPO4-MS can be prepared with suitable properties to be used for cancer therapy.