**2.3 Alpha particle**

Alpha particles have a similar structure to a <sup>4</sup> He nucleus without surrounding electrons (sometimes denoted as He2+) [19]. They are produced in alpha decay and emitted from the nucleus of a radioactive atom [2, 40]. Alpha particles have higher energy (4–9 MeV) and travel in tissue over a few cell diameters. Thus, the particle range is equivalent to the thickness of 1–3 cell widths (40–100 μm) [1, 2, 40]. They have high LET (~100 keV/μm) throughout their range and three times greater at the end of the path range (the Bragg peak) [19, 40]. Intracellular accumulation of the alpha particle effectively creates double-strand breaks (DSBs) in DNA [2, 40]. The cytotoxicity of α-particles is thus considered much higher than that of β-particles (**Figure 2**). Another advantage of α-particles compared with β-particles is the short distance traveled by the ionization products, reducing the damage to healthy surrounding cells. Moreover, the effect is not dependent on dose and oxygen concentration during any cell cycle (**Table 2**) [1].

Targeted alpha therapy (TAT) is an attractive therapeutic option for multiple micro-metastases. It has many advantages, such as easy administration, the ability


#### **Table 2.**

*Physics and biology characteristic of alpha and beta particles [2, 19, 40, 41].*

to treat multiple lesions simultaneously, and the possibility of combining with other therapeutic approaches, and primarily for cancer treatment. By attaching an α-particles to a biological molecule with targeting capabilities, such as a monoclonal antibody (mAb), with the help of a bi-specific chelating agent or bonding it to a disease-targeting vector, and the vector used as a targeting agent. In this way, RPT selectively delivers a high radiation dose directly to the target, with generally limited toxicity to the surrounding normal tissues. Advances in understanding tumor biology, together with progress in mAb technology, chemical labeling techniques, and other related disciplines, provide significant advances in developing of new clinical applications of α-particles radionuclides in novel therapeutic agents [1, 2, 42].

The α-particles are used for RPT over 40 years included as bismuth-212 ( 212Bi), bismuth-213 (213Bi) and astatine-211 (211At), actinium-225 (225Ac), radium-223 (223Ra) and thorium-227 (227Th) as shown in **Table 1** [2]. 223RaCl2 is the first alpha-emitting radiopharmaceutical for prostate and breast cancer patients' bone pain palliation [2, 3, 8, 19, 40]. The energetic α-particles emitted by 223Ra can generate irreparable DNA DSBs in the adjacent osteoblasts and osteoclasts, leading to their death. The results in detrimental effects on the neighboring cells, inhibit abnormal bone formation, both at a cellular level and a signaling level, ultimately negatively affect tumor growth [2]. 223Ra is being studied in combination with other cytotoxic agents such as docetaxel (DORA trial), poly(ADP-ribose) polymerase inhibitors (olaparib), and new androgen axis inhibitors as enzalutamide and abiraterone citrate. It is also being explored in combination with immuno-oncology agents such as pembrolizumab and in combination with external-beam radiotherapy [2].

Bismuth-213 (213Bi) and astatine-211 (211At) labeled monoclonal antibodies in patients with leukemia and brain tumors, respectively [3, 22]. Moreover, 225Ac and 213Bi labeled somatostatin receptor (SSR) are preclinical and clinical trials [1, 19, 40]. 213Bi has a short half-life and can be produced from the generator, and because of that, it is required on-site labeling to produce TAT compound. The short half-life of 213Bi has some advantages as higher dose rates given over a short period are more effective than low dose rates given over a longer period [19, 40]. Studies reported that 213Bi had been labeled with DOTA peptides in preclinical and clinical trials with >99% purity [1, 19].

Furthermore, also there is a growing interest in using 255Ac as a therapeutic alpha particle source. It is produced via the neutron transmutation of 226Ra or decay of 233U [19]. The type of production caused 225Ac has a lack the capacity of clinical use of labeled peptide. So, production via a high-energy proton accelerator at multiple sites will overcome 225Ac labeled to treat neuroendocrine tumors. It has been labeled with PSMA with a radiochemical purity of >98% to treat prostate cancer [19]. 225Ac labeled antibodies are being tested in advanced myeloid malignancy [8]. 225Ac shows a potential appealing radionuclide for TAT, and post-therapy imaging of 225Ac is possible, although images are also suboptimal 19, 40, 41].

The results of clinical trials using TAT indicate that this treatment strategy presents a promising alternative for targeted therapy of cancer [22]. Lately, it has been gaining popularity that TAT to be a successful treatment in prostate cancer in patients refractory to 177Lu prostate-specific membrane antigen (PSMA) [19]. Therefore, alpha-emitters and Auger electron emitters (77Br, 111In, 123I, 125I) are getting more attention for targeted therapy lately. Auger electron and alpha-emitter are intermediate (4–26 keV/μM) and high (50–230 keV/μM) of LET radiation respectively. They deliver the radiation dose within the short range of the tissue (~ tens microns) have an actual tumor cell killing if they can be conjugated with suitable ligands that effectively targeted micro-metastasis therapy [3, 22, 23].
