Pamedic Spotlight｜Performance Comparison between α-isotopes and β-isotopes

As medical science and technology develops, radioisotope therapy has become an innovative part of the field of tumour treatment, in which alpha and beta isotopes both play a key role.

01 Basic Principles of Alpha Isotope Therapy

Alpha isotope therapy is based on the properties of the alpha particle, a heavy particle with two protons and two neutrons. Compared to beta particles, alpha particles have a larger mass and charge and interact in matter in a very different way to beta particles.

Theα-particle is heavier (the size of a He atom), has a shorter propagation range (40-90 µm) and therefore a LET that is hundreds of times higher (α = 100 keV/µm vs. β = 0.2 keV/µm), and deposits more energy in a smaller volume in comparison with β-emission, leading to the direct break of a covalent bond, for example, the double-stranded DNA break.

02 Basic principles of beta isotope therapy

The principle of beta isotope therapy is based on the radioactive properties of beta-particles that are negatively charged, high energy particles.

β-particles are proportional to the size of the electrons, compared with α-particles, have a relatively long propagation range in tissues (0.5-12 mm) , thus with a relatively low LET,to produce hydroxyl radical tissues by disrupting the covalent bonds of water molecules in the tissues. These free radicals cause oxidative damage to cellular DNA macromolecules, leading to double-strand breaks.

03 Alpha isotope therapy VS beta isotope therapy

Linear Energy Transfer (LET)

α-particles: with a greater linear energy transfer (LET), can release linear energy 400 times higher than β-particles, able to deposit a large amount of energy in a smaller volume, thus more lethal to tumour tissue.

Beta particles: have a smaller LET, relatively longer propagation range, energy deposited over a larger area, thus relatively less effective against small tumours or cell foci.

DNA double-strand breaks

Alpha particles: witha high LET, directly cause double-strand breaks in DNA. Unlike beta particles, alpha particles concentrate their energy over very short distances and therefore directly affect DNA in the nucleus as they travel through the cell.

Beta particles: cause the breaking of covalent bonds by interacting with electrons in the tissue, which occurs mainly by reacting with surrounding water molecules to produce hydroxyl radicals, and ultimately lead to damage to the cell's DNA.

Effect of destruction

α particles: with a much shorter propagation range (40-90 µm) and able to produce a large amount of damage in a relatively small area. Compared to β particles, αparticles kill a cell with only one traversal through the orbital.

Beta particles: with a relatively long travelling range (0.5-12 mm), deposit their energy over a larger area. To achieve the same effect as α particles, β particles need to be traversed thousands of times.

Penetrability

α particles: weaker penetrating ability, easier to deposit energy locally, thus less damage to surrounding normal tissues.

Beta particles: relatively stronger penetration ability, energy release in a larger area which may cause some impact on the surrounding normal tissue.

Risk of drug resistance

Alpha particles: alpha particles kill tumour cells by causing DNA double-strand breaks, which makes more complex damage to the tumors and make them hard to repair themselves effectively, as the result, the risk of resistance to α particles is reduced.

β-particles: β-particles mainly react with surrounding water molecules to produce hydroxyl radicals, ultimately leading to cellular DNA damage, whereby some tumours may be allowed to repair and become resistant to β-particles.

Range

α particles: shorter propagation range, lower delivery dose, more precise delivery of energy in a smaller radiation radius (3-5 cells), and reduced off-target radiation.

β-particles: relatively longer propagation range, higher delivery dose, higher off-target radiation (radiation radius up to 200 cells).

In summary, α-isotope therapy achieves a high killing effect on tumour cells by exploiting the high LET, direct DNA damage and low penetrability of α-particles. β-isotope therapy, on the other hand, treats tumour cells through the covalent bond-breaking mechanism, the relatively long range, and the radionuclide that binds to antibodies.

04 Therapeutic efficacy of alpha isotopes

Ac-225 (actinium-225): its effectiveness in advanced metastatic cancers has been demonstrated in clinical trials and particularly in some difficult-to-treat cancers performing greatly.

225Ac-DOTA-lintuzumab (leukaemia treatment): in the treatment of HL60 leukaemia, its specificity and efficacy are demonstrated.

225Ac-DOTA-trastuzumab (Breast Cancer Therapy): good destruction efficacy against HER2 overexpressing breast cancer cells in vitro.

225Ac-PSMA-617 (prostate cancer treatment): in some clinical trials, its good therapeutic effects on PSMA-positive prostate cancer is obvious, such as a decrease in serum PSA and complete remission in some patients.

225Ac-DOTATATE (neuroendocrine tumour therapy): in the treatment of neuroendocrine tumours, especially in difficult-to-treat gastroenteropancreatic neuroendocrine tumours, its high safety profile, low side-effects and a short time-consumption is obvious.

05 Therapeutic effects of beta isotopes

Pluvicto, Lutathera (neuroendocrine tumour therapy): as therapeutic drugs containing the beta-particle emitting isotope Lu-177 for the treatment of neuroendocrine tumours.

In clinical trials, significant results have been achieved, for exaacmple, reduction in tumour markers, improved patient survival, lower adverse effects and higher tolerability). It was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

06 Recent applications of alpha isotopes (Ac225) in drug direction

225Ac-PSMA-617 for the treatment of prostate cancer:

For the treatment of PSMA (prostate-specific membrane antigen)-positive prostate cancer.

In clinical trials, 225Ac-PSMA-617 has shown promising results in the treatment of prostate cancer, such as a significant decrease in serum PSA (prostate-specific antigen) and objective and complete remission in some patients.

225Ac-DOTATATE for neuroendocrine tumours:

In the field of neuroendocrine tumours, 225Ac-DOTATATE is used to treat tumours with SSTR (somatostatin receptor) positive tumours.

In clinical trials, 225Ac-DOTATATE demonstrated therapeutic efficacy in refractory, growth inhibitor receptor-positive neuroendocrine tumours, with a high safety profile and relatively low side effects.

225Ac-DOTA-lintuzumab for the treatment of leukaemia:

as a drug to treat HL60 leukaemia by targeting leukaemia cells, the drug has shown good results in clinical trials with high specificity. 

225Ac-DOTA-trastuzumab for the treatment of breast cancer:

To treat HER2 overexpressing breast cancer, it has been demonstrated in in vitro experiments with good killing effects on HER2 overexpressing breast cancer cells, and with therapeutic potential for ovarian cancer in animal models as well.

Overall, Ac-225 has demonstrated multifaceted potential in tumour therapy, especially showing good therapeutic effects in some refractory cancers and cases with high drug resistance. These studies and applications provide new ideas and possibilities for the future development of radiopharmaceuticals.

Conclusion

Radioisotope therapy, centred on α and β, has created a new era of targeted treatment for a wide range of cancers, bringing new hope to cancer patients.

As an isotope research enterprise, Pamedic Holdings will continue to dive into the unique mechanism of isotope action and its application in different diseases, and keep promoting the development of the medical isotope field to open up a broader prospect for cancer treatment.