High Yield Production and Radiochemical Isolation of Isotopically Pure Arsenic-72 and Novel Radioarsenic Labeling Strategies for the Development of Theranostic Radiopharmaceuticals

Abstract

Radioisotopes of arsenic are of considerable interest to the field of nuclear medicine with unique nuclear and chemical properties making them well-suited for use in novel theranostic radiopharmaceuticals. However, progress must still be made in the production of isotopically pure radioarsenic and in its stable conjugation to biological targeting vectors. This work presents the production and irradiation of isotopically enriched (72)Ge(m) discs in an irrigation-cooled target system allowing for the production of isotopically pure (72)As with capability on the order of 10 GBq. A radiochemical separation procedure isolated the reactive trivalent radioarsenic in a small volume buffered aqueous solution, while reclaiming (72)Ge target material. The direct thiol-labeling of a monoclonal antibody resulted in a conjugate exhibiting exceptionally poor in vivo stability in a mouse model. This prompted further investigations to alternative radioarsenic labeling strategies, including the labeling of the dithiol-containing chelator dihydrolipoic acid, and thiol-modified mesoporous silica nanoparticles (MSN-SH). Radioarsenic-labeled MSN-SH showed exceptional in vivo stability toward dearsenylation.

Figure 1

Boron nitride crucible containing germanium metal powder before melting at 1050 °C (left) and germanium metal disc after heating (right).

Figure 2

Germanium metal disc in irradiation pocket before (left) and after (right) flowing-liquid-cooled irradiation with 20 μA of 16 MeV protons for 1 h.

Figure 3

Representative serial PET maximum intensity projection images taken at three times following the injection of (a) ⁷²As–S-TRC105 and (b) free ⁷²As.

Figure 4

Molecular schematic of reduction of (1) lipoic acid to (2) dihydrolipoic acid and subsequent chelation of arsenic trihydroxide to form (3) As-DHLA.

Figure 5

(a) Radioarsenic activity profiles of RP-TLC analysis 10 min (left) and 18 h (right) after mixture of solutions containing carrier-added *As(OH)₃ (top), carrier-added *As(OH)₃ and DHLA (middle), and no-carrier-added *As(OH)₃ and DHLA (bottom). (b) RP-TLC profile analysis of no-carrier-added ⁷²As(OH)₃ combined with various amounts of DHLA. (c) Plot of ⁷²As-DHLA labeling percent as a function of moles of DHLA from results shown in Figure 4b.

Figure 6

(a) Representative serial PET maximum intensity projection images taken at six times following the injection of *As–S-MSN. (b) PET-quantified percent injected dose per gram (%ID/g) for regions of interests around the liver (red diamonds), bladder (blue squares), and spleen (yellow triangles) as a function of time since injection of *AsS-MSN.