A model for optimizing delivery of targeted radionuclide therapies into resection cavity margins for the treatment of primary brain cancers.

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Radionuclides conjugated to molecules that bind specifically to cancer cells are of great interest as a means to increase the specificity of radiotherapy. Currently, the methods to disseminate these targeted radiotherapeutics have been either systemic delivery or by bolus injection into the tumor or tumor resection cavity. Herein we model a potentially more efficient method of delivery, namely pressure-driven fluid flow, called convection-enhanced delivery (CED), where a device infuses the molecules in solution (or suspension) directly into the tissue of interest. In particular, we focus on the setting of primary brain cancer after debulking surgery, where the tissue margins surrounding the surgical resection cavity are infiltrated with tumor cells and the most frequent sites of tumor recurrence. We develop the combination of fluid flow, chemical kinetics, and radiation dose models needed to examine such protocols. We focus on Auger electron-emitting radionuclides (e.g. 67Ga, 77Br, 111In, 125I, 123I, 193mPt, 195mPt) whose short range makes them ideal for targeted therapy in this setting of small foci of tumor spread within normal tissue. By solving these model equations, we confirm that a CED protocol is promising in allowing sufficient absorbed dose to destroy cancer cells with minimal absorbed dose to normal cells at clinically feasible activity levels. We also show that Auger emitters are ideal for this purpose while the longer range alpha particle emitters fail to meet criteria for effective therapy (as neither would energetic beta particle emitters). The model is used with simplified assumptions on the geometry and homogeneity of brain tissue to allow semi-analytic solutions to be displayed, and with the purpose of a first examination of this new delivery protocol proposed for radionuclide therapy. However, we emphasize that it is immediately extensible to personalized therapy treatment planning as we have previously shown for conventional CED, at the price of requiring a fully numerical computerized approach.





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Raghavan, Raghu, Roger W Howell and Michael R Zalutsky (2017). A model for optimizing delivery of targeted radionuclide therapies into resection cavity margins for the treatment of primary brain cancers. Biomed Phys Eng Express, 3(3). 10.1088/2057-1976/aa6db9 Retrieved from https://hdl.handle.net/10161/15825.

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Michael Rod Zalutsky

Jonathan Spicehandler, M.D. Distinguished Professor of Neuro Oncology, in the School of Medicine

The overall objective of our laboratory is the development of novel radioactive compounds for improving the diagnosis and treatment of cancer. This work primarily involves radiohalo-genation of biomolecules via site-specific approaches, generally via demetallation reactions. Radionuclides utilized for imaging include I-123, I-124 and F-18, the later two being of particular interest because they can be used for the quantification of biochemical and physiological processes in the living human through positron emission tomography. For therapy, astatine-211 decays by the emission of alpha-particles, a type of radiation considerably more cytotoxic that the beta-particles used in conventional endoradiotherapy. The range of At-211 alpha particles is only a few cell diameters, offering the possibility of extremely focal irradiation of malignant cells while leaving neighboring cells intact. Highlights of recent work include: a)
development of reagents for protein and peptide radioiodination that decrease deiodination in vivo by up to 100-fold, b) demonstration that At-211 labeled monoclonal antibodies are effective in the treatment of a rat model of neoplastic meningitis, c) synthesis of a thymidine analogue labeled with At-211 and the demonstration that this molecule is taken up in cellular DNA with highly cytotoxicity even at levels of only one atom bound per cell and d) development of
radiohalobenzylguanidines which are specifically cytotoxic for human neuroblastoma cells.

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