PhD | Development of chelators for Ac-225 based radiopharmaceuticals

Updated: about 1 month ago
Job Type: FullTime
Deadline: 31 Mar 2021

Radionuclide based targeted therapy is mainly focused on the use of β- -emitters bound to targeting molecules such as small molecules, peptides or monoclonal antibodies. This is due to the availability and the favourable characteristics of many β- -emitting nuclides. Other therapeutic particle emissions are Auger electrons, α-particles and conversion electrons. Despite the limited availability of α-particle emitters that are relevant for clinical use, targeted α-radionuclide therapy (TAT) is gaining more and more attention in preclinical and clinical studies [1]. Due to the short path length and high linear energy transfer (LET) of α-particles, the DNA damage caused by α-particles is much more difficult to repair than the DNA damage caused by β- -particles. Furthermore, because of the limited range of the α-particle, toxicity to the healthy surrounding cells is expected to be quite low. TAT is envisioned as being more potent than targeted radionuclide therapy with β- -emitters for the treatment of metastases, in particular small ones, or residual tumours after surgery. On the other hand, β- -emitters are considered more suitable for the eradication of larger solid tumours because radiopharmaceuticals are often not homogeneously distributed within the tumour. An additional advantage of TAT is that the cytocidal efficacy is generally considered to be independent of dose fractionation, dose rate, or hypoxia and it can reverse resistance to chemotherapy or conventional external beam radiotherapy [2]. It is generally accepted that there is no effective resistance to α-particle lethality.

The α-emitting radionuclide 225 Ac can be obtained, besides other routes, from the decay of 229 Th (T1/2 = 7880 years). SCK CEN has a very limited quantity of 229 Th originating from the historical Actinium Programme, but which will suffice for the needs of this project. 225 Ac possesses nuclear properties that are highly promising for use in TAT. A key factor, however, that may hinder the clinical use of 225 Ac is the poor understanding of its coordination chemistry, which creates challenges for the development of suitable chelation strategies for this actinide. Metal-ligand bonding in actinium complexes is driven primarily by electrostatic interactions and steric constraints. Because the stability of electrostatic interactions scales as the ratio of charge over distance, the large ionic radius of the Ac3+ ion gives rise to the formation of kinetically labile complexes. Furthermore, the lack of significant ligand-field stabilization energy effects for this actinide ion afford a high degree of structural diversity in Ac-ligand complexes that is limited only by the coordinative saturation of the Ac3+ ion and ligand–ligand steric interactions. Due to the lack of polarizability, Ac3+ is classified as a hard Lewis acid according to the Hard and Soft Acids and Bases theory and thus is predicted to have a higher affinity for hard Lewis bases, for instance oxyanions and nitrogens, in the form of tertiary amines. Based on this premise we have designed 2 classes of compounds which will afford actinium complexes with strong oxygen- and nitrogen-actinium bonds.

In this project we will develop chelators which are designed for the coordination chemistry of 225 Ac. In addition to this we will synthesize ligands which are bifunctional chelators that not only form strong and stable bonds with 225 Ac, but also allow to easily couple the actinium complex to a vector molecule. The new bifunctional chelators should overcome the difficult and lengthy labeling chemistry of the currently applied chelators. Development of these bifunctional chelators will enable fast and facile radiolabeling of biomolecules (small proteins, antibodies, nanobodies, …) targeting of any kind of tumor with 225 Ac. In this way we aim to improve current practice in radiolabeling radiopharmaceuticals using 225 Ac.

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