Page 14 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis

Chapter 1
(15) and typically express high levels of somatostatin receptor subtype 2 (SST2). This makes the somatostatin receptor an excellent target for diagnosis and treatment of the disease using high affinity radiolabelled peptide ligands with high affinity for the SST2. In the course of time different modifications to the original radiolabelled peptide have been made. For diagnosis and staging of the NETs [68Ga]Ga-DOTA-Tyr3-octreotate PET imaging is very often applied (16). With the same peptide sequence, it is also possible to treat the tumour cells, but instead of the radionuclide Gallium-68 a therapeutic radionuclide, such as Lutetium-177, will be applied. This represents a good example of a so-called theragnostic peptide. Upon receptor binding Lutetium-177 can eradicate tumour cells via beta decay. At Erasmus MC, NETS are being treated with [177Lu]Lu-DOTA-Tyr3-octreotate (17, 18). This treatment has a positive effect on life expectancy and improves quality of life (19). There is ongoing research conducted to even further improve this treatment by, for example, use of alpha-emitting radionuclides (20). Alpha emitters are increasingly applied because of their emission of high linear energy transfer particles with a relative short path length, causing double-strand breaks in DNA. Therefore, the cytotoxic property in cells is much greater for α-emitters than for β-emitters (21). Other improvements of PRRT can be achieved by combination therapies with e.g. chemotherapeutics to reach a synergistic effect or by adjustment of radiopeptide administration routes to be able to enhance uptake of radiopeptides in the tumour cells (22-24). The blood clearance of [177Lu]Lu- DOTA-Tyr3-octreotate in humans is rapid (<10%ID in blood at 3 h post injection) (25) and may be decreased by using a radiopeptide combined with an albumin binding strategy. In this way the tracer circulation time will be prolonged, resulting in higher tumour uptake.
NETs express the SST2 receptor, but many other receptors can be used for imaging, staging and treatment of other types of cancers. In this thesis we also investigated the gastrin-releasing peptide receptor (GRPR) as target. GRPRs are e.g. expressed at high density on the cell membranes of prostatic intraepithelial neoplasia (PIN), primary prostate cancers and invasive prostatic carcinomas (26). For diagnosis, the GRPR antagonist Sarabesin 3 (SB3) has recently been developed (27). Pre-clinically, in mice, a high tumour receptor affinity was found together with good in vivo stability and excellent targeting efficacy. In clinical PET imaging studies [68Ga]Ga-SB3 was used with success as
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