Energy is lost from alpha particles as they pass through a medium resulting from a series of primary collisions with the negatively charged electrons of the atoms in the medium. These interactions result in ionization and excitation of the atoms in the medium. The energy lost by the moving alpha particles increases with de-acceleration. The loss of energy of a typical alpha particle in air is shown in Fig. 3.2, which is called the Bragg curve.

The linear energy transfer (LET) is the measure of the energy transferred to the medium through which ionizing radiation passes. The LET term is used to quantify the effect of ionizing radiation within the medium such as a biological specimen. LET is expressed in energy lost per unit distance travelled (i.e., MeV/cm, Fig. 3.2). For practical purposes, LET of alpha particles is expressed in the more realistic keV/μm unit. The energy lost is directly related to the density of the medium traversed by the alpha particle. The alpha particles lose energy within a short distance of travel through aqueous medium (soft tissue), for example, usually in a few centimeters in air (Fig. 3.2). Biological systems have much higher density as compared to air. In biological soft tissue, for example, the complete energy of an alpha particle is dissipated within a very short path length, which is often less than 100 μm (i.e., only a few cell diameters). Figure 3.3 illustrates the estimated path lengths of two alpha particles with different energies in a biological system.

The alpha particle LET is inversely related to energy, where higher energy alpha particles lose less energy within a given path length or they have lower LET and vice versa. For example, the LET of 5.750 MeV alpha particles is ~80 keV/m, whereas the path length is ~47 μm. The LET of 8.375 MeV alpha particle is ~60 keV/μm which have a path length of ~85 μm (12–15). The majority of the alpha particle energy loss occurs at the end of the path and at that moment the LET of the alpha particle increases to 200–250 keV/μm. All alpha particles irrespective of the initial energy will have identical LET at endpoint. Hence, the LET of alpha particles of different energies are quoted as the initial loss of energy per unit volume. As the naturally occurring alpha particles have energy values in the 4–8 MeV range, the average range of alpha particles in soft tissues is ~50–80 μm. A comparison between the short path length of energy deposition from alpha particle decay and β⁻ decay is illustrated in Fig. 12.​1. The advantages of high-LET radiation over low-LET radiation are the favorable dose distribution between tumor cells and normal cells and less dependence on tumor hypoxia, dose rate, and cell cycle position (Barendsen et al. 1966; Pouget and Mather 2001; Wang et al 2009). At the same time, the biological effects in the cells are more severe after high-LET radiation, resulting in high RBE.

The biological damage caused by ionizing radiations is expressed as the relative biological effectiveness (RBE), which relates to the biological damage of a radiation of interest compared with a reference radiation, usually 250 keV X-rays or the gamma rays emitted by ⁶⁰Co (1.33 and 1.17 MeV). RBE is used as a multiplicative term to adjust the estimated absorbed dose so that it reflects the likelihood or severity of a biological effect. If the biological endpoint is stochastic such as cancer induction, then the RBE is approximately 20. In targeted therapy the relevant biological endpoint is not carcinogenesis but rather efficacy or toxicity. Such therapeutic endpoints are deterministic and the measure associated with them is not probability of occurrence (i.e., risk) but severity of toxicity or level of response. The RBE for such endpoints is in the range of 3–7. Among nuclear radiations, the RBE of alpha particles is the highest followed by β-particles and gamma rays. Owing to the high concentrated dose deposited along the track and short range in tissues on the order of cellular dimensions, alpha particles have a high probability of inducing damage to DNA, making them quite cytotoxic. By contrast radiation-induced cellular inactivation for low-LET radiation requires the accumulation of sublethal damage, achieved only at much higher dose. This specific radiation quality of alpha particles, characterized by localized spatial distribution of the imparted energy and high density of ionization per unit path length, causes direct DNA damage rather than indirect free radical-mediated DNA damage. Toxicity originates from the increased frequency of clustered DNA double-strand breaks observed with high-LET radiation (Azure et al. 1994; Goodhead 1994; Howell et al. 1997). The higher the RBE value, the greater the damages encountered from radiation for the same absorbed energy (Azure et al. 1994; Schwarz et al. 1998; Zalutsky and Narula 1988) (Fig. 3.4).

The cytotoxicity of α particles has been shown as independent of both dose rate and oxygenation status of the cells (Hall 1994). In addition to directly damaging DNA, alpha particles have been demonstrated to cause chromosomal instability even in the descendants of non-irradiated stem cells in the vicinity of irradiated cells. This “bystander effect” reflects the potential for interaction between irradiated and non-irradiated cells in the production of genetic damage (Lorimore et al. 1998). The spatial distribution of alpha-particle sources and the geometry of the cells (thickness, diameter of the cell nucleus, distribution of DNA) have to be considered as important parameters in order to correlate the absorbed dose distribution with the observed biological response for the tissue of interest (tumor and/or critical organs).

The dimensions and size of human cells are quite variable; however, the average cell diameter of most common cells is the order of 10–100 μm. Hence, most alpha particles lose their complete energy within 2–10 cell diameters. Since the total energy of alpha particle is dissipated in a small volume of cells, the damage caused to biological systems by an alpha particle-emitting radionuclide decaying in the vicinity of human cells is very high. In radiation biology, the effect of radiation is measured by multiplying the absorbed dose with a term called the quality factor (QF) or radiation weighing factor (W _R). The W _R of the alpha particles is 20. Hence, alpha-emitting radionuclides cause very high radiation damage once they are inside a living system. As per the International Atomic Energy Agency (IAEA) classification, alpha-emitting radionuclides are listed in Group 1, which means they have the highest toxicity and hence the maximum permissible body burden (MPBB) is the lowest (IAEA 1963).

Alpha particles cause primary and secondary ionizations to atoms with which they interact and create several ions and excited molecules within cells. The net result of this intracellular turbulence is intermolecular bond biomolecule cleavage. Such events can occur with cytoplasm and all intracellular components as well as the cell nucleus. The desirable feature of alpha radiotherapy is the ability of the decaying alpha particle to cause intramolecular DNA bond cleavage within targeted cancer cells. The DNA molecule is double stranded and cleavage can occur in one or both the strands. The cartoon in Fig. 3.5 depicts the traverse of an alpha particle through a double-stranded DNA molecule and the resultant DNA fragments.

The DNA molecule has inherent ability to repair single-strand damage; however, the repair of a scission in double-stranded DNA to its original form is generally not possible. This damage is the intended therapeutic effect to sterilize cells which can then no longer divide. Repair of double-stranded scission of the DNA molecule can lead to gene mutation, which is an undesirable yet very uncommon outcome of controlled radiation exposure. There is an estimated 20–40 % probability that an α particle interacting with the DNA molecule can ensure breakage of the double strand leading to eventual cell death. In contrast, ⁻ radionuclide therapy requires several β⁻ decays (“hits”) to take place in the vicinity of the cell to ensure cell killing (Wessels and Rogus 1984; Humm and Cobb 1990). However, alpha decay must occur in close proximity to the target cell because of the very short path length. In β⁻ radionuclide therapy, the much longer soft tissue penetration (Fig. 12.​1) always irradiation of many cells in addition to the targeted cell because of the “cross-fire” effect to induce nontarget cell death. For this reason, an essential condition for ensuring α therapy efficacy is the high degree of accuracy required to deliver the radiation dose to the target cells and at the same time to spare adjacent healthy cells. In the same context, β⁻ emitting radionuclides are generally more desirable for therapy of solid tumors.

For α-particle emitters, accurate dosimetry calculations are required. In light of the perceived need to estimate the dose distribution, detailed knowledge of the activity distribution as a function of time at the cellular and subcellular levels as well as an accurate representation of the geometry is a necessity (Sgouros et al. 2011; Chouin and Bardies 2011). Efforts to use clinical scintigraphic imaging turned out to be futile owing to the requirement of spatial resolution of the order of several mm, which is two orders of magnitude greater than the microscopic scale at which one dose is deposited with alpha particles (Allen 2011). Owing to the important stochastic variations in the energy deposited in cell nuclei, macroscopic dosimetry approaches become less relevant and microscopic approaches are required. In this premise, the fundamental quantities required for microdosimetry are specific energy (energy per unit mass) and linear energy (energy per unit path length through the target) which can be used for the calculation adopting analytical methods (convolution via Fourier transforms) or Monte Carlo simulation methods (Bardiès 2000). In this context of long half-lives, the distribution of both the parent and all daughters must take into account while performing dosimetry calculations (Koch et al 1999). Absorbed dose calculations for alpha-particle emitters can be routinely performed using the dosimetry formalism described in the Medical Internal Radiation Dose (MIRD) Committee Pamphlet 21 (Bolch et al. 2009) with the guidance provided in MIRD Pamphlet 22 (Sgouros et al. 2010).

Astatine-211 is an artificially produced alpha radionuclide with a half-life of 7.2 h and which decays via a branched pathway to stable lead as shown in Fig. 3.7. Electron capture (EC) decay (58.3 %) of ²¹¹At leads to the production of ²¹¹Po (t _1/2 0.516 s) which decays by emission of an alpha particle (7.45 MeV, 100 %) to stable ²⁰⁷Pb. The second branch (41.7 %) decays to ²⁰⁷Bi via emission of an alpha particle (5.87 MeV, 100 %). Although long lived (t _1/2 33.4 years), the ²⁰⁷Bi will not contribute to any radiation dose during therapy. Through these two branching routes, each of the decaying ²¹¹At atoms contributes to the production of one alpha particle per decay. In addition, decay of ²¹¹At emits β⁻particles (58.3 %, β_max 786 keV). The soft tissue ranges of the two alpha particles are ~55 μm and ~80 μm with a mean initial LET of ~100 keV/μm (Fig. 3.8). The electron capture decay of ²¹¹At to ²¹¹Po (58 %) emits 77–92 KeV K X-rays of polonium which are suitable for scintigraphic imaging.