Radionuclides (unstable isotopes of chemical elements that decay releasing radiation) have been used in nuclear medicine for many decades for the treatment of benign and malignant disorders. Each radionuclide has individual characteristics; these cover the type of radiation they emit (alpha, beta, or gamma), the intensity of the radiation they emit (governing the dose of radiation they deliver), the rate at which they break down (radioactive decay), as well as the basic chemistry of the compounds they form (affecting the type of medical compound, its toxicity within the body, and how it is eventually eliminated). Radionuclides can be used to identify disease (as in imaging techniques), and they can also be used to deliver radiation to treat cancers directly (such as in a theranostic therapy). Careful selection of the most appropriate radionuclides is critical both for the safety and effectiveness of the proposed treatment.
When a theranostic product is designed, the chosen radionuclide is linked with the most appropriate chemical ‘ligand’ (a special type of molecule which binds to a biochemical target in the body) which has been developed to specifically target the cancer type. If successful, the theranostic compound specifically targets the correct cell types within tumorous tissue, delivers a dose of radiation sufficient to kill these target cells, without causing damage to nearby tissues and cells, or radiation-induced cancers in other body organs or systems.
In radiomolecular theranostics, identical ligands are used for both diagnosis and therapy. It is the type of radionuclide that distinguishes diagnostic radiolabeled ligands from their therapeutic counterparts. The characteristics determining their theranostic applicability are their half-life (the time it takes for the radiation emitted to decrease by half, reflecting the decay of the isotope), their type of emitted radiation and corresponding energies, and their tissue penetration depth.
Theranostic Purposes
For diagnostic purposes, positron emission tomography (PET), single-photon emission computed tomography (SPECT), and handheld gamma probes are widely used. In case of PET imaging, radionuclides (Ga-68, F-18) emit positrons. When these positrons (e+) collide with negatively charged electrons (e-) at low energies, the result of the collision is the annihilation of the electron and positron, and the creation of energetic photons (two 511 keV gamma photons). For SPECT imaging and handheld probes, radionuclides (In-111, Tc-99m) directly emitting gamma photons with various energies are being used. The detection of the emitted gamma photons in both PET, SPECT, and probes enables sensitive imaging with sufficient spatial resolution to allow accurate and precise tumor detection and location. These measurements techniques can then be used to monitor progression of the disease and the response to therapy.
For therapeutic purposes, an effective dose of energy in the form of radiation must be delivered to the tumors in order to achieve cell killing. Different sorts of radionuclides are being used. In addition to the overall energy they deliver they have varying penetrance (or path length) depending on the radiation they emit. Some radionuclides emit (a combination of) different types of particles, i.e. alpha-particles (At-211, Ac-225), kinetic electrons (Y-90, Lu-177) or Auger electrons (In-111, I-125). Alpha-particles are positively charged and are composed of two protons and two neutrons, while kinetic and Auger electrons both are negatively charged. The emitted particles differ in energy, penetration range, and linear energy transfer (LET). Alpha-particles have the highest energy and due to their relatively small tissue range, a high LET is reached. Alternatively, the longer penetration depth of kinetic electrons provides a clear advantage regarding their kill zone. The applicability of Auger electrons is somewhere in between alpha-particles and kinetic electrons.
Collateral Damage
Due to a crossfire effect, radionuclide loaded cells can also irradiate their neighbouring cells. This can be very advantageous in larger heterogeneous tumors in which not all cancer cells express the targeted biomarker. Whereas, in the case of small sized tumours, the short penetration depth of alpha-particles and Auger electrons may limit the radiation-induced collateral damage and protect the surrounding healthy tissue. The ideal choice for any theranostic radionuclide will therefore depend on the type of radioactive decay and several tumour features, such as tumor size, stage & grade, and their biomarker heterogeneity.
Half Lives
The half-life is important in choosing the right nuclide. Diagnostic radionuclides preferably have a shorter half-life (Ga-68: 68 minutes) in comparison to therapeutic radioisotopes (Lu-177: 6.7 days, Y-90: 64 hours). For diagnostic purposes, it is important that the radionuclides decay away rapidly, limiting overall dose and as a consquence tissue damage. In contrast, for therapeutic purposes, it is important that the ionizing radiation is deposited over a longer period of time to induce cytotoxic effects by damaging the cancer DNA.
Theranostic Pairs
Some radionuclides can be used for both diagnostic and therapeutic purposes, thereby enabling the radiotheranostic concept of utilizing chemically identical radiopharmaceuticals for imaging and subsequent therapy. For example, Lu-177 emits both low-energy gamma photons (SPECT imaging) and kinetic electrons (therapy). Similarly, I-123 emits both gamma photons (SPECT; low dose) and Auger electrons (therapy; high dose). There are two single metal theranostic radionuclides of particular interest: Scandium (Sc) and Terbium (Tb). Sc presents three radionuclides for theranostic application: Sc-43 (PET), Sc-44 (PET) and Sc-47 (Auger therapy & SPECT). The “Swiss knife” Tb presents even four radionuclides for theranostic application: Tb-149 (alpha therapy), Tb-152 (PET), Tb-155 (SPECT), and Tb-161 (Auger therapy). Next to these theranostic radionuclides, there are theranostic pairs of radionuclides (showing chemically similar behaviour) which are often matched in combination, such as Ga-68 (PET) and Lu-177 (therapy).
In conclusion, apart from the biomarker expression discussed in blog episode 2, the choice for the appropriate radionuclide selectively irradiating and damaging cancer cells while limiting radiation exposure of healthy tissue is also an important factor determining the success of radiomolecular theranostics. In the next two episodes, other contributing factors will be discussed.
