Synthesis and Characterization of Thallium-Texaphyrin Nanoparticles and Their Assessment as Potential Delivery Systems for Auger Electron-Emitting 201Tl to Cancer Cells.

Abstract

Thallium-201 is an Auger electron-emitting radionuclide with significant potential for targeted molecular radiotherapy of cancer. It stands out among other Auger electron emitters by releasing approximately 37 Auger and Coster-Kronig electrons per decay, which is one of the highest numbers in its category. It has also a convenient half-life of 73 h, a stable daughter product, established production methods, and demonstrated high in vitro radiotoxicity. However, its full potential in targeted radiotherapy remains unexplored, primarily due to the lack of available efficient chelators for [²⁰¹Tl]Tl⁺ or [²⁰¹Tl]Tl³⁺. This study aims to assess texaphyrin for macrocycle chelation of [²⁰¹Tl]Tl³⁺. Texaphyrins are known for effective binding of trivalent metals with similar ionic radii, such as indium and gadolinium. Optimization of [²⁰¹Tl]Tl⁺ to [²⁰¹Tl]Tl³⁺ oxidation and subsequent chelation with texaphyrin-lipid conjugate were assessed using thin-layer chromatography. The formation and stability of nonradioactive Tl-texaphyrin-lipid complexes were confirmed by UV-Vis spectroscopy and ultrahigh performance liquid chromatography-mass spectrometry. [²⁰¹Tl]Tl/Tl-texaphyrin-lipid nanoparticles (nanotexaphyrins) were assembled by using a microfluidic system, and their morphology and stability were evaluated by using dynamic light scattering and transmission electron microscopy. The uptake of these nanotexaphyrins in lung cancer and ovarian cancer cells was evaluated using both radioactive and nonradioactive methods. The conversion of [²⁰¹Tl]Tl⁺ to [²⁰¹Tl]Tl³⁺ in 0.25 M HCl achieved an average yield of 91.8 ± 3.1%, while the highest radiolabeling yield of the texaphyrin-lipid with [²⁰¹Tl]Tl³⁺ was 25.5 ± 4.5%. Tl-texaphyrin-lipid conjugates were stable at room temperature for at least 72 h. These conjugates were successfully assembled into homogeneous nanotexaphyrins with an average hydrodynamic diameter of 147.4 ± 1.4 nm. Throughout a 72 h period, no changes in size or polydispersity of the synthesized nanoparticles were observed. [²⁰¹Tl]Tl-nanotexaphyrins were synthesized with an average radiochemical purity of 77.4 ± 10.3% and a yield of 5.1 ± 4.4%. The release of [²⁰¹Tl]Tl⁺ from [²⁰¹Tl]Tl-nanotexaphyrins in phosphate-buffered saline exhibited a time- and temperature-dependent pattern, with a faster release observed at 37 °C than at room temperature. Additionally, the uptake of Tl-nanotexaphyrins and [²⁰¹Tl]Tl-nanotexaphyrins in cancer cells was similar to that of unbound Tl⁺ and [²⁰¹Tl]Tl⁺. This is the first time that texaphyrins have been investigated as chelators for radiothallium. Although [²⁰¹Tl]Tl-nanotexaphyrins were found to be thermodynamically and kinetically unstable, we successfully synthesized stable texaphyrin-lipid complexes with ^natTl³⁺. This opens up opportunities for further refinements in the nanotexaphyrin-lipid structure to enhance [²⁰¹Tl]Tl³⁺ stability and prevent its reduction to a 1+ oxidation state. Future research should consider further modifications to the texaphyrin structure or using texaphyrins without the lipid component.