Cellular DNA and nearby macromolecules within the alpha-particle track range

Cellular DNA and nearby macromolecules within the alpha-particle track range represent the primary site of action for targeted alpha therapy (TAT). Alpha particles are high-energy helium nuclei characterized by high linear energy transfer (LET) and a short path length of 50–100 µm in tissue (Sgouros et al., 2020, Nature Reviews Drug Discovery). When these particles traverse a cell, they deposit intense energy, causing dense ionization that leads to complex, clustered double-strand breaks (DSBs) in the DNA (Kim & Brechbiel, 2012, Tumour Biology). These lesions are significantly more difficult for cellular machinery to repair compared to the damage caused by beta particles or X-rays, frequently leading to apoptosis or mitotic catastrophe (Nelson et al., 2021, Journal of Nuclear Medicine). In addition to DNA, the alpha-particle track affects nearby proteins and lipids, inducing oxidative stress and structural damage that contributes to cell death. This localized mechanism allows for the potent destruction of cancer cells, including those resistant to conventional therapies, while sparing healthy tissues beyond the immediate track range (Parker et al., 2013, NEJM). Drugs such as Radium-223 dichloride and various Actinium-225-labeled conjugates are designed to deliver these alpha emitters directly to the vicinity of this target. The efficacy of targeting these macromolecules is often monitored through biomarkers of DNA damage, such as gamma-H2AX foci formation.

Other names

Genomic DNANuclear DNACellular macromoleculesAlpha-particle track targetsRadiobiological targets of alpha radiationTargeted Alpha Therapy (TAT) target zone

High linear energy transfer (LET) radiation induces dense ionization along the alpha-particle track, causing complex, irreparable double-strand DNA breaks and direct oxidative damage to surrounding macromolecules (Sgouros et al., 2020, Nature Reviews Drug Discovery).