Exploring biochemical considerations for diffusive alpha radiation therapy (DaRT) models

Abstract

Diffusing alpha-emitting Radiation Therapy (DaRT) is a cancer treatment currently undergoing clinical trials. DaRT utilizes localized 224-Radium (²²⁴Ra) seeds to deliver high linear energy transfer (LET) alpha radiation. Its main advantage over other alpha radiation treatments is that the diffusion of ²²⁴Ra decay chain products allows for a more spatially distributed dose. In silico models are used to simulate the physical dynamics of DaRT and the diffusion of DaRT progeny radionuclides into cancer tissue. These models mostly rely on physical principles, often neglecting biochemical interactions with the tumor microenvironment (TME), which affect DaRT dosimetry in human cancer tissue. Here, we address this gap by reviewing how the daughter isotope 212-Lead (²¹²Pb) interacts with chemically heterogeneous TMEs during DaRT treatments. ²¹²Pb is given special attention due to its high physiological activity and long half-life compared to other DaRT radionuclides. By investigating Pb-binding molecules in the TME and their molecular dynamics, we aim to highlight key biochemical processes to be considered by computational models. We identify several species with prevalent roles in cancer tissue as possible binding partners with ²¹²Pb. These species include Glutathione (GSH), Metallothioneins (MTs), Calmodulin (CaM), and Human Serum Albumin (HSA). GSH, MTs, CaM, and HSA were selected based on their known ability to bind to Pb and their concentration in cancer tissue and were examined for their variability in diverse TMEs. Ultimately, this article seeks to guide future research by providing a basic framework of molecular species important for the accurate simulation of DaRT within the TME.