Speaker
Description
Due to the high variation in surface receptor expression, breast cancer (BCa) is a highly heterogeneous disease presenting significant challenges for early detection and treatment. Four molecular subtypes have been identified including estrogen receptor (ER)- and progesterone receptor (PR)-positive BCa. ER and PR are overexpressed in ≈ 80% of all BCa which promotes cell proliferation. The expression of PR in target tissues is highly dependent on the presence of ER conducting in less than 1% of ER-negative/PR-positive BCa. Estradiol, an estrogen steroid and the major female sex hormone, possesses a high affinity for ER. Katzenellenbogen and coworkers have developed the clinically approved radiotracer 16α-[18F]fluoro-17β-estradiol ([18F]FES) for BCa diagnostic by positron emission tomography (PET). However, due to its high lipophilicity, [18F]FES is rapidly metabolised in the liver resulting in a high hepatic uptake and background signal preventing its use in targeted radionuclide therapy (TRT). This group has proposed derivates of estradiol and progesterone radiolabelled with fluorine-18, technetium-99m and rhenium-188 for theranostics but their high lipophilicity has prevented further studies. This project aims to develop steroid-based ligands suitable for radiotheranostics applications in ER/PR-expressing BCa. For this purpose, versatile DOTA chelator was selected for complexation of various diagnostic and therapeutic radionuclides. DOTA-lysine-estradiol has been synthesised on solid phase with a yield of 15% and purity of >95%. Coupling of estradiol was achieved by Copper(I)-catalysed Azide-Alkyne Cycloaddition (CuAAC) between ethynylestradiol and lysine-resin. DOTA was then coupled using classic amidation method. The synthesis of other DOTA-estradiol and DOTA-progesterone derivatives are currently ongoing. These derivatives will be radiolabelled using [177Lu]LuCl3 (~5 MBq, 0.4 M NaOAc pH 5, 95°C, 30 min). Internalisation assays of 177Lu-conjugates will be performed on ER/PR-positive and -negative cell lines with the aim to validate radioligands targeting ER and PR to improve the early detection and stratification of BCa patients followed by TRT.
| Research type | Basic research |
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