Radiation dosimetry for alpha-particle radiopharmaceutical therapy and application to pediatric neuroblastoma

Project Summary/Abstract
Radiopharmaceutical treatments with α-particles represent a promising approach to treat some tumors and
metastases. This modality leverages the short range of α-particles, up to tens of microns, to deliver radiation
only to cancer cells while sparing the surrounding healthy tissue. To do so, an α-emitting radionuclide is bounded
to an affinitive ligand which is used to target biomolecules expressed in tumoral cells. Currently, here are several
clinical applications either approved, such as 223Ra for the treatment of bony metastases, or under investigation.
Particularly, α-RPT could be used for the treatment of high-risk pediatric neuroblastoma, whose prognosis keeps
poor. As the rationale behind radiopharmaceutical treatments is to exploit the differential amount of radiation
imparted to tumors and healthy tissue, a rigorous determination of radiation dosimetry and effects is requested
to develop this technique to their full extent. Starting with the study of α-particles in general, this research will be
oriented to the treatment of pediatric neuroblastoma using the radiopharmaceutical [211At]MM4, which targets
the overexpression of PARP-1 proteins in these tumors. In general, the absorbed dose generally predicts the
biological or clinical effect of X-rays, γ or β radiation. However, heavy-particle-based radiations, such as α-
particles, deposit their energy in a much denser fashion and are capable to produce more concentrated damage
to biological structures as the DNA, which tends to impair the repair mechanisms of a cell. Microdosimetry is the
study of these patterns of interaction at the microscopic level and allows for a better determination of the effect
of α-particles than absorbed dose. The principal investigator has previously investigated methods to calculate
microdosimetric quantities for α-particles. Therefore, this project is structured as follows. First, those
microdosimetric calculations will be connected with actual damage to the DNA using the Monte Carlo toolkit
TOPAS and its extension for subcellular structures, TOPAS-nBio. Second, initial damage to neuroblastoma cell
lines will be studied using the affinity of [211At]MM4 for PARP-1 in these cell lines to create realistic sub-cellular
models of α-particle irradiation. Permanent damage after the occurrence of repair mechanisms will be also
modelled assessed through experimental data published by Dr. Makvandi’s group from the University of
Pennsylvania. Finally, biodistribution of radiopharmaceutical across organs and blood in animal models and
phantoms will be assessed and used to predict treatment outcomes. The principal investigator will use the
experience and expertise of his mentoring team (Dr. Harald Paganetti and Dr. Jan Schuemann) to learn the skills
and abilities necessary to accomplish the proposed research. He will also attend seminars, coursework and
conferences on radiobiology, Monte Carlo simulations and grant writing and leadership skills, which will ensure
a strong foundation for running an independent laboratory after this project.

Grant Number: 5R00CA267560-05
NIH Institute/Center: NIH
Principal Investigator: Alejandro Bertolet Reina