Solid‐tumor radionuclide therapy dosimetry: New paradigms in view of tumor microenvironment and angiogenesis
Authors: Zhu Xuping , Palmer Matthew R. , Makrigiorgos G. Mike , Kassis Amin I. 
Published: June 2010

Purpose

The objective of this study is to evaluate requirements for radionuclide‐based solid tumor therapy by assessing the radial dose distribution of beta‐particle‐emitting and alpha‐particle‐emitting molecules localized either solely within endothelial cells of tumor vasculature or diffusing from the vasculature throughout the adjacent viable tumor cells.

Methods

Tumor blood vessels were modeled as a group of microcylindrical layers comprising endothelial cells (one‐cell thick, diameter), viable tumor cells (25‐cell thick, radius), and necrotic tumor region ( from any blood vessel). Sources of radioactivity were assumed to distribute uniformly in either endothelial cells or in concentric cylindrical shells within the viable tumor‐cell region. The EGSnrc Monte Carlo simulation code system was used for beta particle dosimetry and a dose‐point kernel method for alpha particle dosimetry. The radioactive decays required to deposit cytocidal doses in the vascular endothelial cells (endothelial cell mean dose) or, alternatively, at the tumor edge [tumor‐edge mean dose (TEMD)] of adjacent viable tumor cells were then determined for six beta (, , , , , and ) and two alpha ( and ) particle emitters.

Results

Contrary to previous modeling in targeted radionuclide therapy dosimetry of solid tumors, the present work restricts the region of tumor viability to around tumor blood vessels for consistency with biological observations. For delivering at the viable tumor edge (TEMD) rather than throughout a solid tumor, energetic beta emitters , , and can be effective even when the radionuclide is confined to the blood vessel (i.e., no diffusion into the tumor). Furthermore, the increase in tumor‐edge dose consequent to beta emitter diffusion is dependent on the energy of the emitted beta particles, being much greater for lower‐energy emitters , , and relative to higher‐energy emitters , , and . Compared to alpha particle emitters, a times higher number of beta‐particle‐emitting radioactive atoms is required to deposit the same dose in tumor neovasculature. However, for the alpha particle emitters and to be effective in irradiating viable tumor‐cell regions in addition to the vasculature, the carrier molecules must diffuse substantially from the vasculature into the viable tumor.

Conclusion

The presented data enable comparison of radionuclides used for antiangiogenic therapy on the basis of their radioactive decay properties, tumor neovasculature geometry, and tumor‐cell viability. For alpha particle emitters or low‐energy beta particle emitters, the targeting carrier molecule should be chosen to permit the radiopharmaceutical to diffuse from the endothelial wall of the blood vessel, while for long‐range energetic beta particle emitters that target neovasculature, a radiopharmaceutical that binds to newly formed endothelial cells and does not diffuse is preferable. The work is a first approximation to modeling of tumor neovasculature that ignores factors such as pharmacokinetics and targeting capability of carrier molecules. The calculations quantify the interplay between irradiation of neovasculature, the surrounding viable tumor cells, and the physical properties of commonly used radionuclides and can be used to assist estimation of radioactivity to be administered for neovasculature‐targeted tumor therapy.