Thesis

Subcellular Targeted Radiopharmaceuticals to Unravel the Potential of Auger-Electron Cancer Therapy

• Call:

  ProtoTera Call 2023/1

• Academic Year:

  2023

• Supervisor:

  António Paulo

• Co-Supervisor:

  Célia Fernandes

• Host Institution:

  C2TN - Centro de Ciências e Tecnologias Nucleares

• Granting Degree Institution:

  Instituto Superior Técnico (Universidade de Lisboa)

• Typology:

  National

• Abstract:

  Radiopharmaceuticals offer unique opportunities to explore a theranostic approach of cancer, as one targeting biomolecule recognizing a specific molecular target can be labeled either with diagnostic and/or with therapeutic radionuclides, allowing patient-specific treatments with easier monitoring of the disease progression. In particular, Auger electron radiopharmaceutical therapy (AE-RPT) is very well suited for cancer theranostics, showing the same therapeutic efficacy in oncological small disease compared to alpha or beta therapy, with lower risks of normal tissue toxicity as the low-energy AEs deposit their energy in the immediate vicinity of their site of decay. The promise of Auger electron radiopharmaceutical therapy (AE-RPT) in cancer theranostics has not yet been realized with only a few agents evaluated in clinical trials. The highest relative biological effectiveness (RBE) of AE emitters results when these radionuclides are internalized into highly radiosensitive organelles, like the cell nucleus or mitochondria. Thus, the design of cancer specific AE-emitting radioconjugates with preferential accumulation in these organelles might lead to better therapeutic outcomes. Towards this goal, this PhD project proposes dual-targeted complexes of AE emitting trivalent radiometals (Indium-111 and Erbium-165) (Figs. 1-2), stabilized by DOTA chelators carrying: i) a PSMA-617 derivative for selective uptake by prostate (PCa) cells; ii) pharmacophores with well-recognized affinity for the cell nucleus or the mitochondria (e.g. a DNA intercalator such as an acridine orange derivative or a mitochondria-tropic moiety as a TPP or a rhodamine derivative). Unlike 111In, 165Er emits no γ-rays but X-rays, being a kind of “pure” AE emitter. This difference should contribute to further reduce the deleterious effects in non-target issues in the case of 165Er, and enable more selective radiobiological effects by the emitted short-range AEs.