Most currently existing methods used to determine doses during radioimmunotherapy (RIT) often rely on the false assumption of a spatially homogeneous radio-innumoconjugate (RIC) distribution throughout the tumor. Such methods often are based on the MIRD formalism which is inadequate to describe the pattern of energy deposition at the level of resolution of individual cells. New calculation models are essential for the development of rational strategies in RIT. We propose to develop an integrated approach to high resolution alpha and beta particle RIC dosimetry which will define the 3-D pattern of energy deposition at the cell nuclear level. Dosimetry will be performed on tissue samples taken from congenic mice inoculated with the Thy 1.2+ murine tumor cell line EL-4 and subsequently treated with anti-Thy1.2 antibodies labeled with Y- 90 (for beta particle therapy) or Bi-212 (for alpha particle therapy) via a number of injection routes. Two complementary dosimetric approaches will be used: (1). Methodologies will be developed for a 3-D reconstruction of the radiolabel coordinates in relation to the tumor cell nuclei targets based on data obtained by computer-assisted image analysis performed on serial tumor tissue sections and autoradiographs. A Monte-Carlo method will be used to evaluate the energy deposition to the individual tumor cell nuclei from all surrounding radiolabels so that a 3-D distribution of dose to each individual target nucleus is defined. (2). A new type of real-time miniature solid state radiation probe (outer diameter approx. 0.5 mm) will be developed for insertion into tumor and normal tissue structures. This probe will be based on field effect transistor technology and works on the model of electron traps as in thermoluminescent dosimetry (TLD). Unlike TLD technology, these probes can provide continuous readings of total dose and dose-rates achieved within the tissue during RIT. By performing parallel clonogenic cell-survival assays on cells taken from RIC-treated animals, we will confirm experimentally the radiobiologic predictions obtained using these new approaches to RIC dosimetry. The overall goal of this proposal is to allow rigorous determinations of energy deposition patterns after alpha and beta particle RIT in mice and to use parallel radiobiologic cell-survival assays to interpret these data. The dosimetric tools developed here will be appropriate for later application to clinical radio-immunotherapy.
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