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Diffusing Alpha-emitters Radiation Therapy or DaRT is an alpha-particle-based radiation therapy for the treatment of solid tumors. [1] [2]
This therapy was developed at Tel Aviv University in Israel, by Professors Itzhak Kelson and Yona Keisari. The treatment is delivered by the intratumoral insertion of metal tubes called “seeds”, which have Radium-224 atoms fixed to their surface. When the radium decays, its short-lived daughter Radon-220 is released from the seed through recoil energy. [3] The daughters of Radon-220, in particular Pb-212, disperse in the tumor, and emit high-energy alpha particles, which destroy the tumor. Because the alpha-emitting atoms diffuse only a few millimeters in tissue, the DaRT eradicates the tumor cells and spares the surrounding healthy tissue. [3]
Alpha radiation is a nuclear phenomenon in which a heavy radionuclide emits an energetic alpha particle (consisting of two protons and two neutrons) and transmutes to a different radionuclide. The emitted alpha particle has a range in tissue of only 40-90 microns, which minimizes collateral damage when used for treatment purposes. However, this also limits its ability to destroy tumors that are many millimeters in diameter. Alpha radiation possesses a potent cell-killing capability because it has a high linear energy transfer (LET) which translates into a high Relative Biological Effectiveness (RBE). [4]
The invention of DaRT makes possible the use of alpha radiation for treating solid tumors, because it overcomes the range limitation of alpha particles in tissue. The daughter atoms of Radium-224 can each diffuse several millimeters in tumor tissue, while emitting alpha particles. The tumor-killing capability of DaRT comes mainly from the ability of alpha radiation to irreparably break the double stranded DNA in tumor cells. [5] This capability does not seem to be dependent on the stage of the cell cycle or the level of oxygenation of the cancer cell.[ citation needed ]
Preclinical studies have demonstrated that DaRT can effectively damage all solid tumor types. Studies of 10 different tumor types in mice demonstrated that all responded to DaRT. [6] [7] [8] [9] [10] [11] [12] [ excessive citations ]
In preclinical studies, DaRT effectiveness was enhanced when combined with standard chemotherapies such as 5-FU. In addition, DaRT was able to turn the tumor into its own vaccine and stimulate a systemic anti-tumor immune response. [13] This immune response was effectively augmented by addition of immunostimulants and/or inhibitors of immunosuppressive cells. This immune effect was observed not only as enhanced local tumor destruction at the primary tumor site, but also by elimination of tumor metastases in the lungs. [12] [14] These results suggest that DaRT combined with immunotherapy induces a tumor-specific systemic immune response.[ citation needed ]
The first results of the DaRT in human patients, from a pilot study of 28 patients by Prof. Popovtzer (Israel) and Dr. Bellia (Italy), were published in 2020. [15] From among this cohort of elderly patients (median age, 80.5 years), 61% had recurrent and previously treated tumors, including 42% who were radioresistant from prior therapy. Patients were diagnosed with histopathologically confirmed squamous cell carcinoma of the skin or head and neck. One-hundred percent of tumors responded to DaRT, with complete responses occurring in greater than 78% of cases, and no major toxicity was noted. Thirty days after treatment, there was no measurable radioactivity in the blood or urine of patients. Additional studies in larger populations are now ongoing to strengthen support regarding the safety and effectiveness of this technique of intratumoral alpha radiation-based tumor ablation.[ citation needed ]
Alpha decay or α-decay is a type of radioactive decay in which an atomic nucleus emits an alpha particle and thereby transforms or "decays" into a different atomic nucleus, with a mass number that is reduced by four and an atomic number that is reduced by two. An alpha particle is identical to the nucleus of a helium-4 atom, which consists of two protons and two neutrons. It has a charge of +2 e and a mass of 4 Da. For example, uranium-238 decays to form thorium-234.
Polonium is a chemical element; it has symbol Po and atomic number 84. A rare and highly radioactive metal with no stable isotopes, polonium is a chalcogen and chemically similar to selenium and tellurium, though its metallic character resembles that of its horizontal neighbors in the periodic table: thallium, lead, and bismuth. Due to the short half-life of all its isotopes, its natural occurrence is limited to tiny traces of the fleeting polonium-210 in uranium ores, as it is the penultimate daughter of natural uranium-238. Though longer-lived isotopes exist, such as the 124 years half-life of polonium-209, they are much more difficult to produce. Today, polonium is usually produced in milligram quantities by the neutron irradiation of bismuth. Due to its intense radioactivity, which results in the radiolysis of chemical bonds and radioactive self-heating, its chemistry has mostly been investigated on the trace scale only.
Radium is a chemical element; it has symbol Ra and atomic number 88. It is the sixth element in group 2 of the periodic table, also known as the alkaline earth metals. Pure radium is silvery-white, but it readily reacts with nitrogen (rather than oxygen) upon exposure to air, forming a black surface layer of radium nitride (Ra3N2). All isotopes of radium are radioactive, the most stable isotope being radium-226 with a half-life of 1,600 years. When radium decays, it emits ionizing radiation as a by-product, which can excite fluorescent chemicals and cause radioluminescence. Of the radioactive elements that occur in quantity, radium is considered the most toxic.
A radionuclide (radioactive nuclide, radioisotope or radioactive isotope) is a nuclide that has excess numbers of either neutrons or protons, giving it excess nuclear energy, and making it unstable. This excess energy can be used in one of three ways: emitted from the nucleus as gamma radiation; transferred to one of its electrons to release it as a conversion electron; or used to create and emit a new particle (alpha particle or beta particle) from the nucleus. During those processes, the radionuclide is said to undergo radioactive decay. These emissions are considered ionizing radiation because they are energetic enough to liberate an electron from another atom. The radioactive decay can produce a stable nuclide or will sometimes produce a new unstable radionuclide which may undergo further decay. Radioactive decay is a random process at the level of single atoms: it is impossible to predict when one particular atom will decay. However, for a collection of atoms of a single nuclide the decay rate, and thus the half-life (t1/2) for that collection, can be calculated from their measured decay constants. The range of the half-lives of radioactive atoms has no known limits and spans a time range of over 55 orders of magnitude.
Radioactive decay is the process by which an unstable atomic nucleus loses energy by radiation. A material containing unstable nuclei is considered radioactive. Three of the most common types of decay are alpha, beta, and gamma decay. The weak force is the mechanism that is responsible for beta decay, while the other two are governed by the electromagnetism and nuclear force.
Radionuclide therapy uses radioactive substances called radiopharmaceuticals to treat medical conditions, particularly cancer. These are introduced into the body by various means and localise to specific locations, organs or tissues depending on their properties and administration routes. This includes anything from a simple compound such as sodium iodide that locates to the thyroid via trapping the iodide ion, to complex biopharmaceuticals such as recombinant antibodies which are attached to radionuclides and seek out specific antigens on cell surfaces.
A radioligand is a microscopic particle which consists of a therapeutic radioactive isotope and the cell-targeting compound - the ligand. The ligand is the target binding site, it may be on the surface of the targeted cancer cell for therapeutic purposes. Radioisotopes can occur naturally or be synthesized and produced in a cyclotron/nuclear reactor. The different types of radioisotopes include Y-90, H-3, C-11, Lu-177, Ac-225, Ra-223, In-111, I-131, I-125, etc. Thus, radioligands must be produced in special nuclear reactors for the radioisotope to remain stable. Radioligands can be used to analyze/characterize receptors, to perform binding assays, to help in diagnostic imaging, and to provide targeted cancer therapy. Radiation is a novel method of treating cancer and is effective in short distances along with being unique/personalizable and causing minimal harm to normal surrounding cells. Furthermore, radioligand binding can provide information about receptor-ligand interactions in vitro and in vivo. Choosing the right radioligand for the desired application is important. The radioligand must be radiochemically pure, stable, and demonstrate a high degree of selectivity, and high affinity for their target.
Polonium-210 (210Po, Po-210, historically radium F) is an isotope of polonium. It undergoes alpha decay to stable 206Pb with a half-life of 138.376 days (about 4+1⁄2 months), the longest half-life of all naturally occurring polonium isotopes (210–218Po). First identified in 1898, and also marking the discovery of the element polonium, 210Po is generated in the decay chain of uranium-238 and radium-226. 210Po is a prominent contaminant in the environment, mostly affecting seafood and tobacco. Its extreme toxicity is attributed to intense radioactivity, mostly due to alpha particles, which easily cause radiation damage, including cancer in surrounding tissue. The specific activity of 210
Po is 166 TBq/g, i.e., 1.66 × 1014 Bq/g. At the same time, 210Po is not readily detected by common radiation detectors, because its gamma rays have a very low energy. Therefore, 210
Po can be considered as a quasi-pure alpha emitter.
The Bragg peak is a pronounced peak on the Bragg curve which plots the energy loss of ionizing radiation during its travel through matter. For protons, α-rays, and other ion rays, the peak occurs immediately before the particles come to rest. It is named after William Henry Bragg, who discovered it in 1903 using alpha particles from radium, and wrote the first empirical formula for ionization energy loss per distance with Richard Kleeman.
Radioimmunotherapy (RIT) uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target cell. It is a form of unsealed source radiotherapy. In cancer therapy, an antibody with specificity for a tumor-associated antigen is used to deliver a lethal dose of radiation to the tumor cells. The ability for the antibody to specifically bind to a tumor-associated antigen increases the dose delivered to the tumor cells while decreasing the dose to normal tissues. By its nature, RIT requires a tumor cell to express an antigen that is unique to the neoplasm or is not accessible in normal cells.
Naturally occurring radioactive materials (NORM) and technologically enhanced naturally occurring radioactive materials (TENORM) consist of materials, usually industrial wastes or by-products enriched with radioactive elements found in the environment, such as uranium, thorium and potassium and any of their decay products, such as radium and radon. Produced water discharges and spills are a good example of entering NORMs into the surrounding environment.
Radiobiology is a field of clinical and basic medical sciences that involves the study of the effects of ionizing radiation on living things, in particular health effects of radiation. Ionizing radiation is generally harmful and potentially lethal to living things but can have health benefits in radiation therapy for the treatment of cancer and thyrotoxicosis. Its most common impact is the induction of cancer with a latent period of years or decades after exposure. High doses can cause visually dramatic radiation burns, and/or rapid fatality through acute radiation syndrome. Controlled doses are used for medical imaging and radiotherapy.
A gamma ray, also known as gamma radiation (symbol
γ
), is a penetrating form of electromagnetic radiation arising from the radioactive decay of atomic nuclei. It consists of the shortest wavelength electromagnetic waves, typically shorter than those of X-rays. With frequencies above 30 exahertz (3×1019 Hz) and wavelengths less than 10 picometers (1×10−11 m), gamma ray photons have the highest photon energy of any form of electromagnetic radiation. Paul Villard, a French chemist and physicist, discovered gamma radiation in 1900 while studying radiation emitted by radium. In 1903, Ernest Rutherford named this radiation gamma rays based on their relatively strong penetration of matter; in 1900, he had already named two less penetrating types of decay radiation (discovered by Henri Becquerel) alpha rays and beta rays in ascending order of penetrating power.
Alpha particles, also called alpha rays or alpha radiation, consist of two protons and two neutrons bound together into a particle identical to a helium-4 nucleus. They are generally produced in the process of alpha decay but may also be produced in other ways. Alpha particles are named after the first letter in the Greek alphabet, α. The symbol for the alpha particle is α or α2+. Because they are identical to helium nuclei, they are also sometimes written as He2+ or 4
2He2+ indicating a helium ion with a +2 charge (missing its two electrons). Once the ion gains electrons from its environment, the alpha particle becomes a normal (electrically neutral) helium atom 4
2He.
Radium-223 is an isotope of radium with an 11.4-day half-life. It was discovered in 1905 by T. Godlewski, a Polish chemist from Kraków, and was historically known as actinium X (AcX). Radium-223 dichloride is an alpha particle-emitting radiotherapy drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover. The principal use of radium-223, as a radiopharmaceutical to treat metastatic cancers in bone, takes advantage of its chemical similarity to calcium, and the short range of the alpha radiation it emits.
Neutron capture therapy (NCT) is a type of radiotherapy for treating locally invasive malignant tumors such as primary brain tumors, recurrent cancers of the head and neck region, and cutaneous and extracutaneous melanomas. It is a two-step process: first, the patient is injected with a tumor-localizing drug containing the stable isotope boron-10 (10B), which has a high propensity to capture low energy "thermal" neutrons. The neutron cross section of 10B is 1,000 times more than that of other elements, such as nitrogen, hydrogen, or oxygen, that occur in tissue. In the second step, the patient is radiated with epithermal neutrons, the sources of which in the past have been nuclear reactors and now are accelerators that produce higher energy epithermal neutrons. After losing energy as they penetrate tissue, the resultant low energy "thermal" neutrons are captured by the 10B atoms. The resulting decay reaction yields high-energy alpha particles that kill the cancer cells that have taken up enough 10B.
Targeted alpha-particle therapy is an in-development method of targeted radionuclide therapy of various cancers. It employs radioactive substances which undergo alpha decay to treat diseased tissue at close proximity. It has the potential to provide highly targeted treatment, especially to microscopic tumour cells. Targets include leukemias, lymphomas, gliomas, melanoma, and peritoneal carcinomatosis. As in diagnostic nuclear medicine, appropriate radionuclides can be chemically bound to a targeting biomolecule which carries the combined radiopharmaceutical to a specific treatment point.
Combinatorial ablation and immunotherapy is an oncological treatment that combines various tumor-ablation techniques with immunotherapy treatment. Combining ablation therapy of tumors with immunotherapy enhances the immunostimulating response and has synergistic effects for curative metastatic cancer treatment. Various ablative techniques are utilized including cryoablation, radiofrequency ablation, laser ablation, photodynamic ablation, stereotactic radiation therapy, alpha-emitting radiation therapy, hyperthermia therapy, HIFU. Thus, combinatorial ablation of tumors and immunotherapy is a way of achieving an autologous, in-vivo tumor lysate vaccine and treating metastatic disease.
Peptide receptor radionuclide therapy (PRRT) is a type of radionuclide therapy, using a radiopharmaceutical that targets peptide receptors to deliver localised treatment, typically for neuroendocrine tumours (NETs).
Yona Keisari is an Israeli Immunologist and cancer researcher, professor emeritus at the Department of Microbiology and Clinical Immunology in the Faculty of Medical and Health Sciences, Tel Aviv University. An expert in the field of immunology of cancerous tumors, and co-founder of the radiotherapy company "Alpha Tau Medical".