Development of Targeted Alpha Particle Therapy for Solid Tumors

Abstract

Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prostate cancer. In this comprehensive review, we discuss the current consensus regarding the properties of the α-particle-emitting radionuclides that are potentially relevant for use in the clinic; the TAT-mediated mechanisms responsible for cell death; the different classes of targeting moieties and radiometal chelators available for TAT development; current approaches to calculating radiation dosimetry for TATs; and lead optimization via medicinal chemistry to improve the TAT radiopharmaceutical properties. We have also summarized the use of TATs in pre-clinical and clinical studies to date.

Keywords: chelation; clinical studies; mechanism of cell death; medicinal chemistry; radiation dosimetry; solid tumors; targeted alpha-particle therapy; targeting moieties.

Figure 1

⁶⁸Ga-PSMA-11 PET/CT images of a treatment-naïve patient with extensive bone metastasis at primary diagnosis. A complete remission was observed after three cycles of ²²⁵Ac-PSMA-617 with de-escalating activities of 8/7/6 MBq. The patient remained symptom-free with undetectable serum PSA and a negative ⁶⁸Ga-PSMA-11 PET/CT at 11-month follow-up evaluation. This figure and legend were reproduced from Sathekge, et al. [6].

Figure 2

(A) Linear energy transfer (LET) versus distance in water traveled by typical α-particles emitted by radionuclides in development for α-particle radioimmunotherapy: ²²⁵Ac (5.829 MeV)/²¹³Bi (8.375 MeV), ²¹¹At (5.867 MeV), ²¹²Bi (6.08 MeV)/²¹²Po (8.78 MeV), ²²³Ra (5.716 MeV). The range of the α-particle and the position of the Bragg peaks are correlated with the initial energy of the α-particles. LET of α-particles in water was calculated using stopping-power and range tables (continuous slowing down approximation range) for electrons, protons and helium ions from the National Institute of Standards and Technology (NIST). (B) The deposition of heavy ion energy as a function of penetrating depth of (a) a pristine beam and (b) a modulated beam with widened stopping region (spread out Bragg peaks). This figure and legend were reproduced from [19].

Figure 3

Survival of a human kidney T-cell culture irradiated with ionizing particles of different kinds: (1) particles with E = 2.5 MeV, LET = 165 keV/m; (2) particles with E = 27 MeV, LET = 25 keV/m; (3) deuterons with E = 3.0 MeV, LET = 20 keV/m; (4) X-rays with E = 20 keV and LET = 6 keV/m; (5) X-rays with E = 250 keV and LET = 2.5 keV/m; and (6) particles with E = 2.2 MeV, LET = 0.3 keV/m. This figure and legend were reproduced from [21].

Figure 4

The somatostatin mimetic octreotide and its DOTA-containing analogs. Octreotide: R₁ = H, R₂ = H and R₃ = CH₂OH; DOTATOC (endotreotide): R₁ = DOTA, R₂ = OH and R₃ = CO₂H; DOTATATE (Octreotate): R₁ = DOTA, R₂ = OH and R₃ = CH₂OH.

Figure 5

Common metal chelators and binders used to attach radionuclides to targeting ligands.

Figure 6

Common conjugation chemistries used to functionalize biomolecules. Countless other schemes have been well characterized and the reader is directed to Bioconjugates Techniques for a review and protocols [117].