Searching for a Paradigm Shift in Auger-Electron Cancer Therapy with Tumor-Specific Radiopeptides Targeting the Mitochondria and/or the Cell Nucleus

Abstract

Although 99mTc is not an ideal Auger electron (AE) emitter for Targeted Radionuclide Therapy (TRT) due to its relatively low Auger electron yield, it can be considered a readily available “model” radionuclide useful to validate the design of new classes of AE-emitting radioconjugates. With this in mind, we performed a detailed study of the radiobiological effects and mechanisms of cell death induced by the dual-targeted radioconjugates 99mTc-TPP-BBN and 99mTc-AO-BBN (TPP = triphenylphosphonium; AO = acridine orange; BBN = bombesin derivative) in human prostate cancer PC3 cells. 99mTc-TPP-BBN and 99mTc-AO-BBN caused a remarkably high reduction of the survival of PC3 cells when compared with the single-targeted congener 99mTc-BBN, leading to an augmented formation of γH2AX foci and micronuclei. 99mTc-TPP-BBN also caused a reduction of the mtDNA copy number, although it enhanced the ATP production by PC3 cells. These differences can be attributed to the augmented uptake of 99mTc-TPP-BBN in the mitochondria and enhanced uptake of 99mTc-AO-BBN in the nucleus, allowing the irradiation of these radiosensitive organelles with the short path-length AEs emitted by 99mTc. In particular, the results obtained for 99mTc-TPP-BBN reinforce the relevance of targeting the mitochondria to promote stronger radiobiological effects by AE-emitting radioconjugates.

Synthesis and Preclinical Evaluation of PSMA-Targeted 111In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

“…The studies with 99m Tc showed that mitochondria targeting is as effective as the nuclear targeting to induce lethal radiobiological effects in tumor cells. 24,25 Therefore, these results pinpointed that cell-specific mitochondria targeting strategies justify further attention in the design of radioconjugates for AE-RPT of cancer.…”

“…99m Tc is not an ideal AE emitter for TRT due to its relatively low Auger electron yield but can be considered a readily available “model” radionuclide, useful to “validate” the design of new classes of AE-emitting radioconjugates. The studies with 99m Tc showed that mitochondria targeting is as effective as the nuclear targeting to induce lethal radiobiological effects in tumor cells. , Therefore, these results pinpointed that cell-specific mitochondria targeting strategies justify further attention in the design of radioconjugates for AE-RPT of cancer.…”

“…The design of the dual-targeted conjugates relied on the modification of the PSMA-617 structure used to obtain the clinically approved [ 177 Lu]­Lu-PSMA-617 (Pluvicto), considering that its biological specificity is rather resilient toward the inclusion of different types of modifiers (e.g., albumin binding domains to slow blood clearance or linkers to tune the hydro/lipophilicity). − By considering the TPP pharmacophore, we have taken into account our encouraging results with the TPP- 99m Tc-BBN complexes , and the large body of evidence supporting the suitability of TPP derivatives as mitochondrion-tropic carriers for drug delivery applications . For example, MitoQ is a molecule combining ubiquinone with TPP, through a decylene chain, used as a mitochondria-targeted antioxidant supplement and undergoing several clinical trials involving patients with different mitochondria-related diseases …”

DNA‐Targeted Complexes of Tc and Re for Biomedical Applications

“…Towards this goal, a variety of 99m Tc complexes carrying different structural motifs for a preferential uptake by the nucleus, such as nuclear localization sequences (NLS) or DNA intercalators, were designed and evaluated. [75][76][77][78][79][80][81][82][83][84][85][86][87] However, the development of strategies aiming at a selective and specific delivery of radiocomplexes to the nucleus of tumor cells is a quite demanding task, as shown by the results recently reported for AE-emitting 111 In-radioconjugates combining NLS sequences with target-specific biomolecules. [88] The presence of the NLS improved the nuclear uptake of the radioconjugates but this effect was accompanied by a loss of specificity towards the target tumor cells and poor biodistribution profiles due to the accumulation of activity in excretory non-target organs like the liver and the kidneys.…”

“…Adapted images from. [85] Figure 16. Structures of heterometallic complexes reported as potential DNA targeting agents.…”