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.

Preliminary Study of a 1,5-Benzodiazepine-Derivative Labelled with Indium-111 for CCK-2 Receptor Targeting

“…For this reason, the use of a milder base, such as a 50% morpholine/DMF solution, was preferred to obtain almost quantitative results [23]. Finally, in an alternative synthetic approach, CDI-activated Z-360 (5) was firstly reacted with N-Boc-1,6-hexanediamine (1), and, after the elimination of the Boc group, the obtained intermediate was further reacted with CDI-activated N 19 -Fmoc-4-oxo-9,12,15-trioxa-5,19-diaza-onadecanoic acid (2). However, this method did not show significant advantages with respect to the former one, exhibiting the same side-reactions described above and, moreover, implying an elevate loss of Z-360 due to the low yield of the first reaction.…”

“…The organic phase was then concentrated to dryness, and the product was purified by column chromatography (eluent: CHCl3/MeOH 95:5) to yield 3 (0.3 g, 0.46 mmol, 46% yield, chemical structure in Figure 9). 1 19, A solution of 3 (0.3 g, 0.5 mmol) in DCM (3.5 mL) was cooled to 0 °C by an ice bath for 20 min, and then TFA (1 mL) was added dropwise. The mixture was stirred for 1 h at room temperature (TLC: CHCl3/MeOH 9:1) and then evaporated to dryness to obtain 4 (0.2 g, 0.5 mmol, quantitative yield, chemical structure in Figure 10).…”

Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy

“…Recently, alpha emitters have attracted particular attention for radionuclide therapy. Long confined to hematological tumors, they are now being considered for the potential treatment of solid tumors [ 192 ]. In vitro, α-labeled somatostatin analogs (DOTATOC and DOTATATE) demonstrated a significantly higher killing effect compared to 177 Lu [ 193 , 194 , 195 ].…”

Estimating the Relative Biological Effectiveness of Auger Electron Emitter 123I in Human Lymphocytes

“…This might be beneficial to homogenize the radiation dose in large solid tumors, but it is rather disadvantageous for the treatment of a small cluster of tumor cells and it might also result in greater hematological toxicity [10][11][12]. In recent years, α-particle emitters have regained interest and popularity, based on new, optimized production processes and the availability of various targeting vectors, such as monoclonal antibodies [13,14]. Their range in tissues is about 50-100 µm depending on the α-particle energy.…”