Deoxyribonucleic acid (DNA) and associated cellular biomolecules (DNA)

General cellular DNA and nearby biomolecules are the primary targets for Targeted Alpha Therapy (TAT), a potent form of internal radiotherapy used to treat various malignancies. Alpha particles are heavy, charged helium nuclei that exhibit high linear energy transfer (LET), meaning they deposit a large amount of energy over a very short distance of approximately 50 to 100 micrometers (Nelson et al., 2021, JNM). This localized energy deposition causes dense ionization tracks that result in complex, clustered DNA double-strand breaks (DSBs) which are often irreparable by standard cellular machinery. Beyond direct DNA damage, alpha radiation causes the radiolysis of water and nearby proteins, generating reactive oxygen species that further damage the cell. Because the range of alpha particles is limited to a few cell diameters, the cytotoxic effect is confined to the immediate vicinity of the radionuclide, sparing distant healthy tissues. This makes DNA an ideal target for treating micrometastases and small tumor volumes that are resistant to conventional beta-emitting isotopes. Clinical success has been demonstrated with agents like Radium-223 dichloride, which targets bone-seeking areas in metastatic prostate cancer (Parker et al., 2013, NEJM). Ongoing research focuses on conjugating alpha emitters to monoclonal antibodies or small molecules to precisely deliver this lethal payload to specific cancer cell populations.

Other names

Genomic DNANuclear DNAChromatinCellular macromoleculesTargeted Alpha Therapy target

Alpha-emitting radionuclides deliver high linear energy transfer (LET) radiation directly to the target, causing dense ionization tracks that result in complex, irreparable double-strand breaks (DSBs) in DNA and oxidative damage to nearby biomolecules (Sgouros et al., 2020, Nature Reviews Drug Discovery).