Induction of DNA‐Double‐Strand Breaks by Auger Electrons from ^99mTc Complexes with DNA‐Binding Ligands

Abstract

The potential of certain Auger electron emitting nuclides for systemic radiotherapeutic applications has recently gained much attention. In particular, the ability of several nuclides, including 111In, 125I, and 123I, to induce DNA double-strand breaks (dsb), a good indicator of cytotoxicity, has been extensively studied. However, this ability has never previously been shown experimentally for 99mTc, which, besides the well-known gamma radiation that is used for diagnostic applications, also emits an average of 1.1 conversion electrons and 4 Auger or Coster-Kronig electrons per decay. Owing to the short range of Auger electrons, the radionuclide needs to be located very close to the DNA for dsb to occur. We synthesized two cationic 99mTcI-tricarbonyl complexes with pendant DNA binders, pyrene and anthraquinone. The X-ray crystal structures of the two complexes could be elucidated. Linear dichroism and UV/Vis spectroscopy revealed that the complex with pyrene intercalates DNA with a stability constant, K, of 1.1 x 10(6) M(-1), while the analogous complex with anthraquinone interacts with DNA in a groove-binding mode and has an affinity value of K=8.9 x 10(4) M(-1). We showed with phiX174 double-stranded DNA that the corresponding 99mTc complexes induce a significant amount of dsb, whereas non-DNA-binding [TcO4]- and nonradioactive Re compounds did not. These results indicate that the Auger electron emitter 99mTc can induce dsb in DNA when decaying in its direct vicinity and this implies potential for systemic radiotherapy with 99mTc complexes.

Pyrazolyl–Diamine Ligands That Bear Anthracenyl Moieties and Their Rhenium(I) Tricarbonyl Complexes: Synthesis, Characterisation and DNA‐Binding Properties

“…The compounds 9-bromomethylanthracene, [27] 2-(9-antrylmethyl)propane-1,3-diol, [28] [10] [Re(CO) 5 Br] [29] and (NEt 4 ) 2 [Re(CO) 3 Br 3 ] [30] were prepared by the literature methods.…”

“…The 1,3-dialdehyde 1 was prepared by a Swern oxidation of the corresponding diol with DMSO/SO 3 ·pyridine, while the synthesis of the + core comprised the study of their reaction with the starting material [Re(CO) 5 Br]. In refluxing methanol, the reaction with L 2 -L 4 led to the formation of well-defined species that were formulated as fac-[Re(CO) 3 {3,5-Me 2 pzNN-Ant}]Br (7) and fac-[Re(CO) 3 -A C H T U N G T R E N N U N G {Antpz*NN}]Br (pz* = pz, 8; 3,5-Me 2 pz, 9) (Scheme 4).…”

“…Encouraging in vitro results have been reported that highlighted the relevance of this radiometal for the development of therapeutic radiopharmaceuticals. [5][6][7] Alberto et al have shown that a 99m Tc I -tricarbonyl complex that contains a pyrene intercalator and a nuclear localisation signal (NLS) peptide can target the nucleus of B16-F1 mouse melanoma cells, and shows a much stronger radiotoxic effect than 99m TcO 4 À , which is unable to penetrate the nucleus. [6] Most importantly, the same research group proved more recently that the presence of the NLS sequence is not strictly necessary for the targeting of the nucleus with tricarbonyl 99m Tc I or Re I complexes.…”

“…The achievement of this goal lies in the design of multifunctional complexes that include a DNA-binding moiety, a carrier to transport the complex into the nucleus, and/or a tumour-seeking vector. [4][5][6] The presence of the later should provide a specific recognition of the neoplastic cells and promote the internalisation of the complexes, while the DNA-binding moiety is expected to augment the stacking into DNA, and consequently to enhance the radiotoxicity of the Auger emitter.…”

“…Alberto et al have already found a similar behaviour for related Re I complexes that are anchored by aliphatic triamine ligands that are terminally functionalised with pyrene or anthraquinone moieties. [5] These authors reported that two diastereomeric pairs of complexes were obtained for the pyrene-containing triamines, but a preferential formation of one pair of enantiomers was observed for the anthraquinone derivative. These differences might reflect the presence of planar aromatic structures such as pyrene or anthraquinone that have different steric constraints.…”