<p>The optimal way to detect and treat cancer is to target cancer cells exclusively without affecting the surrounding tissue. One promising approach is to use radiolabelled molecules to target receptors that are overexpressed in cancer cells. Since the epidermal growth factor receptor (EGFR) family is overexpressed in many types of cancer, it is an attractive target for both diagnostic and therapeutic applications.</p><p>This thesis can be divided into two parts. In part one (paper I), studies were conducted to modulate radionuclide uptake in tumour cells. The results showed that it was possible to modulate the cellular uptake of ¹²⁵I delivered by trastuzumab (targeting HER2) by adding EGF (targeting EGFR).</p><p>In part two (papers II-V) a high affinity EGFR-targeting affibody molecule (Z_EGFR:955)₂ was selected and analysed both <i>in vitro</i> and <i>in vivo</i>. In papers II, III and V, the results obtained when using (Z_EGFR:955)₂ were compared with those obtained with the two EGFR-binding molecules, EGF and cetuximab. These studies demonstrated that the affibody molecule bound specifically to EGFR (probably to subdomain III) with high affinity (~50 nM in biosensor analysis and ~1 nM in cellular studies) and produced intracellular signalling changes similar to those with cetuximab. In paper IV, <i>in vivo</i> studies were made, demonstrating that [¹¹¹In](Z_EGFR:955)₂ gave a tumour-specific ¹¹¹In uptake of 3.8±1.4% of injected dose per gram tumour tissue, 4 h post-injection. The tumours could be easily visualized with a gamma camera at this time-point. </p><p>The results of these studies indicated that the affibody molecule (Z_EGFR:955)₂ is a possible candidate for radionuclide-based imaging of EGFR-expressing tumours. The biological effects of (Z_EGFR:955)₂ might be of interest for therapy applications.</p>

Radiolabeled somatostatin analogues based on octreotide have proven useful in the management of somatostatin receptor subtype 2 (sstr2)-positive tumours in clinical trials. The aim was to compare the potency and evaluate the combination of 111In- and 177Lu-DOTATOC with a double-deleted version of vaccinia virus (ddVV), an oncolytic virus for inhibiting the growth of sstr2-expressing human embryonic kidney (HEK-293) cells or MC-38 murine colon cancer cells grown as monolayers or as spheroids. Cytotoxicity studies were carried out using ddVV, 111In-DOTATOC and 177Lu-DOTATOC, individually or in combination on MC-38 spheroids, HEK-293 cells and spheroids. HEK-293 cell growth in spheroids was reduced to 17.2 ± 4.9% and 26.5 ± 6.3 % with 111In-DOTATOC and 177Lu-DOTATOC alone and 13.1 ± 7.1% and 0% in combination, respectively. MC-38 spheroids showed greater toxicity in combination treatment. Combination of ddVV with 111In- or 177Lu-DOTATOC is only advantageous in monolayer culture. No advantage was observed in spheroid models.

Radiolabeled somatostatin analogues based on octreotide have proven useful in the management of somatostatin receptor subtype 2 (sstr2)-positive tumours in clinical trials. The aim was to compare the potency and evaluate the combination of 111In- and 177Lu-DOTATOC with a double-deleted version of vaccinia virus (ddVV), an oncolytic virus for inhibiting the growth of sstr2-expressing human embryonic kidney (HEK-293) cells or MC-38 murine colon cancer cells grown as monolayers or as spheroids. Cytotoxicity studies were carried out using ddVV, 111In-DOTATOC and 177Lu-DOTATOC, individually or in combination on MC-38 spheroids, HEK-293 cells and spheroids. HEK-293 cell growth in spheroids was reduced to 17.2 ± 4.9% and 26.5 ± 6.3 % with 111In-DOTATOC and 177Lu-DOTATOC alone and 13.1 ± 7.1% and 0% in combination, respectively. MC-38 spheroids showed greater toxicity in combination treatment. Combination of ddVV with 111In- or 177Lu-DOTATOC is only advantageous in monolayer culture. No advantage was observed in spheroid models.

The optimal way to detect and treat cancer is to target cancer cells exclusively without affecting the surrounding tissue. One promising approach is to use radiolabelled molecules to target receptors that are overexpressed in cancer cells. Since the epidermal growth factor receptor (EGFR) family is overexpressed in many types of cancer, it is an attractive target for both diagnostic and therapeutic applications. This thesis can be divided into two parts. In part one (paper I), studies were conducted to modulate radionuclide uptake in tumour cells. The results showed that it was possible to modulate the cellular uptake of 125I delivered by trastuzumab (targeting HER2) by adding EGF (targeting EGFR). In part two (papers II-V) a high affinity EGFR-targeting affibody molecule (ZEGFR:955)2 was selected and analysed both in vitro and in vivo. In papers II, III and V, the results obtained when using (ZEGFR:955)2 were compared with those obtained with the two EGFR-binding molecules, EGF and cetuximab. These studies demonstrated that the affibody molecule bound specifically to EGFR (probably to subdomain III) with high affinity (~50 nM in biosensor analysis and ~1 nM in cellular studies) and produced intracellular signalling changes similar to those with cetuximab. In paper IV, in vivo studies were made, demonstrating that [111In](ZEGFR:955)2 gave a tumour-specific 111In uptake of 3.8±1.4% of injected dose per gram tumour tissue, 4 h post-injection. The tumours could be easily visualized with a gamma camera at this time-point. The results of these studies indicated that the affibody molecule (ZEGFR:955)2 is a possible candidate for radionuclide-based imaging of EGFR-expressing tumours. The biological effects of (ZEGFR:955)2 might be of interest for therapy applications.