Alpha radiation kills cancer cells in therapy primarily through the emission of alpha particles—helium nuclei consisting of two protons and two neutrons—that deliver a highly concentrated burst of energy over a very short distance inside the body. This intense energy causes severe and irreparable damage to the DNA of cancer cells, particularly double-stranded DNA breaks, which are lethal and prevent the cells from repairing themselves or dividing further.
In targeted alpha particle therapy, alpha-emitting radioactive isotopes are attached to molecules such as antibodies or peptides that specifically bind to cancer cells. Once these radioactive molecules localize to the tumor, the alpha particles they emit travel only a few cell diameters, depositing a large amount of energy directly into the cancer cells. This localized energy release leads to rapid and effective destruction of tumor cells while sparing most of the surrounding healthy tissue due to the very short range of alpha particles.
The high linear energy transfer (LET) of alpha particles means they cause dense ionization tracks along their path, resulting in complex DNA damage that cancer cells cannot easily repair. Unlike beta particles or gamma rays, which have longer ranges and lower LET, alpha particles induce double-strand breaks that overwhelm the cell’s repair mechanisms, triggering cell death pathways such as apoptosis or necrosis.
Several alpha-emitting isotopes are used in therapy, including radium-223, actinium-225, and bismuth-213. Radium-223, for example, mimics calcium and targets bone metastases in prostate cancer, delivering alpha radiation directly to cancer cells in bone. Actinium-225 is used experimentally in various cancers, including hematologic malignancies and solid tumors, often linked to molecules targeting specific tumor markers like PSMA in prostate cancer.
One challenge with alpha therapy is the short travel distance of alpha particles, which limits their ability to treat larger tumors uniformly. To address this, novel approaches such as Alpha DaRT (Diffusing Alpha-emitters Radiation Therapy) have been developed. This technique diffuses alpha-emitting atoms within the tumor mass, allowing a more even distribution of alpha radiation and overcoming the short-range limitation. This innovation shows promise in treating solid tumors like prostate and bladder cancer, where precise targeting is crucial to avoid damage to nearby organs.
Alpha particle therapy also has advantages over traditional radiation therapies because it kills cancer cells independently of oxygen levels or the cell cycle phase. This means it can be effective even in hypoxic tumor regions or in cells that are not actively dividing, which are often resistant to other treatments.
In clinical settings, targeted alpha therapy is being explored both as a standalone treatment and in combination with other therapies, such as beta-emitting radioligand therapies or chemotherapy, to enhance effectiveness and overcome resistance. The development of stable chelators that securely bind alpha emitters to targeting molecules has improved the safety profile of these treatments by reducing off-target toxicity, particularly to the kidneys and bone marrow.
Overall, alpha radiation therapy represents a powerful and precise weapon against cancer cells, leveraging the unique physical and biological properties of alpha particles to deliver lethal damage directly to tumors while minimizing harm to healthy tissues. This approach is rapidly evolving, with ongoing research aimed at expanding its applications, improving delivery methods, and combining it with other treatments to improve outcomes for patients with advanced and difficult-to-treat cancers.