Supervisors info:
Πιρμεττής Ι., Ερευνητής Α’, Ε.Κ.Ε.Φ.Ε. «Δημόκριτος»
Τσοτίνης Α., Καθηγητής, Τμήμα Φαρμακευτικής Ε.Κ.Π.Α.
Χιωτέλλης Α., Ερευνητής Γ’, ΕΚΕΦΕ «Δημόκριτος»
Summary:
Prostate cancer is the most common cancer in men worldwide and the 5th in terms of mortality. It is especially common in developed countries, and varies substantially according to geographic region and race/ethnicity. A major percentage of patients is older than 60 years, smaller number of cases involve young men.
Prostate cancer cells can show an overexpression of PSMA (prostate specific membrane antigen) and/or GRPr (gastrin-releasing peptide receptor). These two biomarkers can be associated with different level of expression on cell’s surface. Heterogeneity of tumor target can represent a limit in cancer diagnosis and/or therapy. For this reason, in recent years research has been oriented towards molecules that target two points.
In this master thesis the focus was on the evaluation of heterodimer PSMA-DOTA-RM2, whose structure combine the two monomers PSMA-617 and DOTA-RM2, enabling binding to PSMA and GRPr, respectively. The in vitro evaluation of PSMA-DOTA-RM2 was performed by a comparison with the two monomers (reference compounds). All molecules were radiolabeled with diagnostic radionuclide 68Ga. DOTA was used as chelator, as it is predominantly applicable for the complexation of trivalent metals.
Serum stability of the molecule, internalization capacity of the molecule, and finally biodistribution studies were performed in animals with tumors. For the internalization study as well as for the biodistribution study, two different prostate cancer cell lines were used: LNCaP (positive for PSMA) and PC3 (positive for GRPr). These cells were used to mimic the conditions of the human body, and simulate the heterogeneous expression of biomarkers in cancerous tissues.
All the compounds tested show good radiolabeling efficacy with 68Ga. PSMA-DOTA-RM2 showed a promising radiolabeling capability and could be an example of a diagnostic-therapeutic compound (theranostic) if it is also labelled with a therapeutic isotope, such as 177Lu.
According to the results of our study, PSMA-DOTA-RM2 appears to have good internalization capacity and high target selectivity. Heterodimer is useful for the specialized detection of tumors and / or metastases (which is characterized by high heterogeneity in the expression of biological markers). This is also supported from the results of biodistribution studies.
This heterodimer could be considered a promising binary targeting compound, capable of detecting heterogeneous tumors and metastases. The ability to bind to more than one target at the same time is an advantage, as patients are subjected to less drug administration and lower radiation exposure. Future objectives are to study the behaviour of the heterodimer after 177Lu labelling, as well as to obtain PET imaging for initial disease staging and assessment of therapeutic response.
Keywords:
Gallium, heterodimer, labelling, radiopharmaceuticals
