Microdimetry and Nanodosimetry Study for Targeted Therapy in Nuclear Medicine (I)

The rapid development of targeted therapy in nuclear medicine has promoted the study of microdosimetry (or cellular dosimetry) and nanodosimetry (or molecular dosimetry) for internal radionuclides. The biological sensitive volume of dosimetry interest was shifted from the organ to the cell nucleus and to the DNA. To assess the therapeutic effectiveness, information on both radiation dose and radiation quality is required. Traditional radiation dosimetry deals with the average absorbed dose to a target organ from radiation emitters uniformly distributed in a source organ for strongly penetrating radiations such as gamma-rays and high-energy beta particles,. The MIRD schema, developed by the Medical Internal Radiation Dose Committee of the Nuclear Medicine Society, was the primary source of data used clinically. The organ S-values calculated by MIRD were published in the MIRD pamphlets for tens of radiopharmaceutical compounds. Targeted radiotherapeutics, on the other hand, made use of short-ranged alpha particles, low-energy beta particles or Auger electrons emitted from cellular- or DNA-bound radionuclides. Because of their short ranges, dense ionizations and cellular/molecular bindings, these particles could kill the tumor cells highly selectively. In such a case, radiation dose depends on the spatial distribution of radionuclides in the cell (cell surface, cytoplasm, or cell nucleus) and the ionization pattern along the particle track (track structure). Thus, microdosimetric calculations of the spatial distribution of energy deposition within the target cell volume require stochastic simulations of particle tracks accompanied with a transport scheme using the event-by-event Monte Carlo code. In 1997, MIRD published the cellular S-values, i.e. the mean absorbed doses to a subcellular target per nuclear transformation of the radionuclide in a subcellular source, for alpha particles and low-energy electrons. Data were available for source regions: whole cell (C), cytoplasm (Cy), cell surface (CS), and cell nucleus (N) and target regions: C and N. In addition, Monte Carlo data were available for the energy depositions in nanometric volumes. These data provided an estimate of strand breaks of DNA due to direct and indirect actions in a simplified DNA model to evaluate the therapeutic efficiency of Auger emitters. The PI and his team have had extensive research experience on microdosimetry and nanodosimetry in both theoretical calculations and experimental measurements. Subjects of their previous study include (1) inelastic interactions of low-energy electrons with biological media, (2) calculations of specific cellular doses for low-energy electrons, (3) calculations of cellular microdosimetry parameters for alpha particles and electrons, (4) low-energy electron interactions with liquid water and energy depositions in nanometric volumes, (5) microdosimetry study of THOR BNCT beam using tissue equivalent proportional counter, and (6) microdosimetric spectra of the thor neutron beam for boron neutron capture therapy. The purpose of this work, with the support of a three-year project, is to evaluate the therapeutic efficacy and limitations of radiolabeled compounds in targeted therapy by means of microdosimetric and nanodosimetric approaches. Topics to be studied include (1) the development of biophysical models based on microdosimetry for the dose response of biological systems, (2) the evaluation of relative biological effectiveness and radiation quality parameters used in radiation therapy and protection, (3) model calculation of the stochastic energy deposition in a microscopic volume of biological materials, and (4) the effects of cell cycle progression and radiocompound microdistribution. Works to be completed in the first-year project include (1) the development of microdosimetric models for targeted therapy in nuclear medicine, (2) the use of microdosimetric biophysical models to evaluate RBE and radiation weighting factor, and (3) the construction of the MOSFET microdosimeter for microdosimetric measurements.

Project ID:PC9902-2190
External Project ID:NSC99-2623-E182-007-NU