Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The "Hopeful Eight".
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ABSTRACT:
SUBMITTER: Eychenne R
PROVIDER: S-EPMC8234975 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A search in PubMed revealed that 72 radionuclides have been considered for molecular or functional targeted radionuclide therapy. As radionuclide therapies increase in number and variations, it is important to understand the role of the radionuclide and the various characteristics that can render it either useful or useless. This review focuses on the physical characteristics of radionuclides that are relevant for radionuclide therapy, such as linear energy transfer, relative biological effectiveness, range, half-life, imaging properties, and radiation protection considerations. All these properties vary considerably between radionuclides and can be optimised for specific targets. Properties that are advantageous for some applications can sometimes be drawbacks for others; for instance, radionuclides that enable easy imaging can introduce more radiation protection concerns than others. Similarly, a long radiation range is beneficial in targets with heterogeneous uptake, but it also increases the radiation dose to tissues surrounding the target, and, hence, a shorter range is likely more beneficial with homogeneous uptake. While one cannot select a collection of characteristics as each radionuclide comes with an unchangeable set, all the 72 radionuclides investigated for therapy-and many more that have not yet been investigated-provide numerous sets to choose between.
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Project description:Brain metastases develop frequently in patients with breast cancer, and present a pressing therapeutic challenge. Expression of vascular cell adhesion molecule 1 (VCAM-1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. The aim of this study was to use a model of early brain metastasis to evaluate the efficacy of ?-emitting radionuclides, 149Tb, 211At, 212Pb, 213Bi and 225Ac; ?-emitting radionuclides, 90Y, 161Tb and 177Lu; and Auger electron (AE)-emitters 67Ga, 89Zr, 111In and 124I, for targeted radionuclide therapy (TRT). METHODS:Histologic sections and two photon microscopy of mouse brain parenchyma were used to inform a cylindrical vessel geometry using the Geant4 general purpose Monte Carlo (MC) toolkit with the Geant4-DNA low energy physics models. Energy deposition was evaluated as a radial function and the resulting phase spaces were superimposed on a DNA model to estimate double-strand break (DSB) yields for representative ?- and ?-emitters, 177Lu and 212Pb. Relative biological effectiveness (RBE) values were determined by only evaluating DNA damage due to physical interactions. RESULTS:177Lu produced 2.69 ± 0.08 DSB per GbpGy, without significant variation from the lumen of the vessel to a radius of 100 µm. The DSB yield of 212Pb included two local maxima produced by the 6.1 MeV and 8.8 MeV ?-emissions from decay products, 212Bi and 212Po, with yields of 7.64 ± 0.12 and 9.15 ± 0.24 per GbpGy, respectively. Given its higher DSB yield 212Pb may be more effective for short range targeting of early micrometastatic lesions than 177Lu. CONCLUSION:MC simulation of a model of early brain metastases provides invaluable insight into the potential efficacy of ?-, ?- and AE-emitting radionuclides for TRT. 212Pb, which has the attributes of a theranostic radionuclide since it can be used for SPECT imaging, showed a favorable dose profile and RBE.
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Project description:Peptide receptor radionuclide therapy (PRRT) has been applied to the treatment of neuroendocrine tumors (NETs) for over two decades. However, improvement is still needed, and targeted alpha therapy (TAT) with alpha emitters such as lead-212 (212Pb) represents a promising avenue. A series of ligands based on octreotate was developed. Lead-203 was used as an imaging surrogate for the selection of the best candidate for the studies with lead-212. 203/212Pb radiolabeling and in vitro assays were carried out, followed by SPECT/CT imaging and ex vivo biodistribution in NCI-H69 tumor-bearing mice. High radiochemical yields (≥99%) and purity (≥96%) were obtained for all ligands. [203Pb]Pb-eSOMA-01 and [203Pb]Pb-eSOMA-02 showed high stability in PBS and mouse serum up to 24 h, whereas [203Pb]Pb-eSOMA-03 was unstable in those conditions. All compounds exhibited a nanomolar affinity (2.5-3.1 nM) for SSTR2. SPECT/CT images revealed high tumor uptake at 1, 4, and 24 h post-injection of [203Pb]Pb-eSOMA-01/02. Ex vivo biodistribution studies confirmed that the highest uptake in tumors was observed with [212Pb]Pb-eSOMA-01. [212Pb]Pb-eESOMA-01 displayed the highest absorbed dose in the tumor (35.49 Gy/MBq) and the lowest absorbed dose in the kidneys (121.73 Gy/MBq) among the three tested radioligands. [212Pb]Pb-eSOMA-01 is a promising candidate for targeted alpha therapy of NETs. Further investigations are required to confirm its potential.
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