Dosimetric evaluation of radionuclides for VCAM-1-targeted radionuclide therapy of early brain metastases

Abstract

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 α-emitting radionuclides, 149Tb, 211At, 212Pb, 213Bi and 225Ac; β-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 β- and α-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 α-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 α-, β- 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.

Targeted Brain Tumor Radiotherapy Using an Auger Emitter

“…S5B). The radiobiological effectiveness of Auger-emitting compounds is critically dependent on the proximity of the electron emitter to the cellular DNA (45,46). This distancedependent relationship for double strand break production has been shown for I-125 (47).…”

Radionuclide spatial distribution and dose deposition for in vitro assessments of 212Pb‐αVCAM‐1 targeted alpha therapy

“…The development of new radiopharmaceuticals goes along with preclinical studies assessing their efficiency in tumor control as well as toxic effects in healthy tissues. It is also highly desirable to compare their effects to other radiotherapy treatments such as x‐ray external beam radiotherapy (EBRT) or β‐emitting targeted radiotherapy . It is thus necessary to have an accurate knowledge of the activity administered to the biological sample and of the mean absorbed dose to the cells per unit time‐integrated activity (S‐values) .…”

“…This work formed part of a preclinical study that evaluated the therapeutic potential of TAT, combining an α‐emitting radionuclide ( 212 Pb) to an anti‐VCAM‐1 antibody ( 212 Pb‐αVCAM‐1). The upregulation of vascular adhesion molecule (VCAM‐1) has been shown to be specific to early stage brain metastases . The objective of this study was thus to perform accurate and reliable dosimetry for in vitro irradiations with 212 Pb‐αVCAM‐1.…”

“…It is also highly desirable to compare their effects to other radiotherapy treatments such as x-ray external beam radiotherapy (EBRT) or b-emitting targeted radiotherapy. 8 It is thus necessary to have an accurate knowledge of the activity administered to the biological sample and of the mean absorbed dose to the cells per unit time-integrated activity (S-values). [9][10][11][12] In vitro dosimetry in TAT is particularly challenging because of the short range of a-particles and the µm diameter of cell cultures.…”

“…The upregulation of vascular adhesion molecule (VCAM-1) has been shown to be specific to early stage brain metastases. 8,[13][14][15] The objective of this study was thus to perform accurate and reliable dosimetry for in vitro irradiations with 212 Pb-aVCAM-1. The first step of this work was the experimental determination of the spatial distribution of radionuclides in culture medium using a energy spectra measurements and Monte Carlo (MC) simulations.…”