Alpha Particle Emitter Radiolabeled Antibody for Metastatic Cancer: What Can We Learn from Heavy Ion Beam Radiobiology?

Abstract

Alpha-particle emitter labeled monoclonal antibodies are being actively developed for treatment of metastatic cancer due to the high linear energy transfer (LET) and the resulting greater biological efficacy of alpha-emitters. Our knowledge of high LET particle radiobiology derives primarily from accelerated heavy ion beam studies. In heavy ion beam therapy of loco-regional tumors, the modulation of steep transition to very high LET peak as the particle approaches the end of its track (known as the Bragg peak) enables greater delivery of biologically potent radiation to the deep seated tumors while sparing normal tissues surrounding the tumor with the relatively low LET track segment part of the heavy ion beam. Moreover, fractionation of the heavy ion beam can further enhance the peak-to-plateau relative biological effectiveness (RBE) ratio. In contrast, internally delivered alpha particle radiopharmaceutical therapy lack the control of Bragg peak energy deposition and the dose rate is determined by the administered activity, alpha-emitter half-life and biological kinetics of the radiopharmaceutical. The therapeutic ratio of tumor to normal tissue is mainly achieved by tumor specific targeting of the carrier antibody. In this brief overview, we review the radiobiology of high LET radiations learned from ion beam studies and identify the features that are also applicable for the development of alpha-emitter labeled antibodies. The molecular mechanisms underlying DNA double strand break repair response to high LET radiation are also discussed.

Nanostructure of Clustered DNA Damage in Leukocytes after In-Solution Irradiation with the Alpha Emitter Ra-223

“…Systemic patient treatment with alpha particle-emitting radiopharmaceuticals is increasingly being applied in standard care for patients with metastatic castrate-resistant prostate cancer [4,5]. Alpha particles considered for treatment have a range of up to 90 µm in water [6] and they have a kinetic energy of about 1.4 to 2.2 MeV per nucleon. They pass cells with a mean LET of about 100 keV µm −1 [6].…”

“…Alpha particles considered for treatment have a range of up to 90 µm in water [6] and they have a kinetic energy of about 1.4 to 2.2 MeV per nucleon. They pass cells with a mean LET of about 100 keV µm −1 [6]. While the alpha particles lose energy and slow down when traversing matter, their interaction probability increases.…”

“…While the alpha particles lose energy and slow down when traversing matter, their interaction probability increases. The LET of alpha particles peaks towards the end of their tracks at the so-called Bragg peak with a LET of about 220 keV µm −1 [6]. Ra-223 is an α-emitter with a half-life of 11.43 days and is known to decay in six steps [see e.g.…”

Progress in Targeted Alpha-Particle Therapy. What We Learned about Recoils Release from In Vivo Generators

“…The range in tissues is about 50–100 µm depending on the alpha-particle energy. The energy deposition then occurs in a very small tissue volume and with high relative biological effectiveness (RBE) [ 1 ]. This is fully true for single α particle decays.…”

Energy loss and straggling of α-particles in Ag and Sn metallic foils

“…In the contemporary era, a-particles emerge out as an imperative ion beam for the characterization of materials, particularly, through Rutherford backscattering (RBS) (Chu, Mayer, & Nicolet, 1978). Furthermore, a-particles play a significant role in medical applications to cure cancer via radionuclide therapy (Mulford, Scheinberg, & Jurcic, 2005;Sgouros, 2008;Song, Senthamizhchelvan, Hobbs, & Sgouros, 2012). For effective use of a-particles in these applications, the precise values of energy loss and straggling in different target are highly essential.…”