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Beyond the Barrier: Targeted Radionuclide Therapy in Brain Tumors and Metastases.

ABSTRACT: Brain tumors are notoriously difficult to treat. The blood-brain barrier provides a sanctuary site where residual and metastatic cancer cells can evade most therapeutic modalities. The delicate nature of the brain further complicates the decision of eliminating as much tumorous tissue as possible while protecting healthy tissue. Despite recent advances in immunotherapy, radiotherapy and systemic treatments, prognosis of newly diagnosed patients remains dismal, and recurrence is still a universal problem. Several strategies are now under preclinical and clinical investigation to optimize delivery and maximize the cytotoxic potential of pharmaceuticals with regards to brain tumors. This review provides an overview of targeted radionuclide therapy approaches for the treatment of primary brain tumors and brain metastases, with an emphasis on biological targeting moieties that specifically target key biomarkers involved in cancer development.

SUBMITTER: Puttemans J

PROVIDER: S-EPMC6723032 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Beyond the Barrier: Targeted Radionuclide Therapy in Brain Tumors and Metastases.

Puttemans Janik J Lahoutte Tony T D'Huyvetter Matthias M Devoogdt Nick N

Pharmaceutics 20190801 8

Brain tumors are notoriously difficult to treat. The blood-brain barrier provides a sanctuary site where residual and metastatic cancer cells can evade most therapeutic modalities. The delicate nature of the brain further complicates the decision of eliminating as much tumorous tissue as possible while protecting healthy tissue. Despite recent advances in immunotherapy, radiotherapy and systemic treatments, prognosis of newly diagnosed patients remains dismal, and recurrence is still a universal ...[more]

PMID: 31374991

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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.

Dataset Information

Beyond the Barrier: Targeted Radionuclide Therapy in Brain Tumors and Metastases.

Publications

Beyond the Barrier: Targeted Radionuclide Therapy in Brain Tumors and Metastases.

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