Dosimetric evaluation of radionuclides for VCAM-1-targeted radionuclide therapy of early brain metastases.
Falzone N., Ackerman NL., Rosales LDLF., Bernal MA., Liu X., Peeters SG., Soto MS., Corroyer-Dulmont A., Bernaudin M., Grimoin E., Touzani O., Sibson NR., Vallis KA.
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 and225Ac; β-emitting radionuclides,90Y,161Tb and177Lu; and Auger electron (AE)-emitters67Ga,89Zr,111In and124I, 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 and212Pb. Relative biological effectiveness (RBE) values were determined by only evaluating DNA damage due to physical interactions. RESULTS: 177 Lu 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 of212Pb included two local maxima produced by the 6.1 MeV and 8.8 MeV α-emissions from decay products,212Bi and212Po, with yields of 7.64 ± 0.12 and 9.15 ± 0.24 per GbpGy, respectively. Given its higher DSB yield212Pb may be more effective for short range targeting of early micrometastatic lesions than177Lu. 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.