Background: Targeted radionuclide therapy with high-energy beta-emitters is generally considered suboptimal to cure small tumours (<300 mg). Tumour targeting of the CCK2 receptor-binding minigastrin analogue PP-F11 was determined in a tumour-bearing mouse model at increasing peptide amounts. The optimal therapy was analysed for PP-F11 labelled with <sup>90</sup>Y, <sup>177</sup>Lu or <sup>213</sup>Bi, accounting for the radionuclide specific activities (SAs), the tumour absorbed doses and tumour (radio) biology. Methods: Tumour uptake of <sup>111</sup>In-PP-F11 was determined in nude mice bearing CCK2 receptor-transfected A431 xenografts at 1 and 4 h post-injection for escalating peptide masses of 0.03 to 15 nmol/mouse. The absorbed tumour dose was estimated, assuming comparable biodistributions of the <sup>90</sup>Y, <sup>177</sup>Lu or <sup>213</sup>Bi radiolabelled peptides. The linear-quadratic (LQ) model was used to calculate the tumour control probabilities (TCP) as a function of tumour mass and growth. Results: Practically achievable maximum SAs for PP-F11 labelled with <sup>90</sup>Y and <sup>177</sup>Lu were 400 MBq <sup>90</sup>Y/nmol and 120 MBq<sup>177</sup>Lu/nmol. Both the large elution volume from the 220 MBq <sup>225</sup>Ac generator used and reaction kinetics diminished the maximum achieved <sup>213</sup>Bi SA in practice: 40 MBq <sup>213</sup>Bi/nmol. Tumour uptakes decreased rapidly with increasing peptide amounts, following a logarithmic curve with ED<inf>50</inf> = 0.5 nmol. At 0.03 nmol peptide, the (300 mg) tumour dose was 9 Gy after 12 MBq <sup>90</sup>Y-PP-F11, and for <sup>111</sup>In and <sup>177</sup>Lu, this was 1 Gy. A curative dose of 60 Gy could be achieved with a single administration of 111 MBq <sup>90</sup>Y labelled to 0.28 nmol PP-F11 or with 4 × 17 MBq <sup>213</sup>Bi (0.41 nmol) when its α-radiation relative biological effectiveness (RBE) was assumed to be 3.4. Repeated dosing is preferable to avoid complete tumour receptor saturation. Tumours larger than 200 mg are curable with <sup>90</sup>Y-PP-F11; the other radionuclides perform better in smaller tumours. Furthermore, <sup>177</sup>Lu is not optimal for curing fast-growing tumours. Conclusions: Receptor saturation, specific radiopharmaceutical activities and absorbed doses in the tumour together favour therapy with the CCK2 receptor-binding peptide PP-F11 labelled with <sup>90</sup>Y, despite its longer β-particle range in tissue, certainly for tumours larger than 300 mg. The predicted TCPs are of theoretical nature and need to be compared with the outcome of targeted radionuclide experiments.

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Psychonomic Bulletin and Review
Department of Radiology

Konijnenberg, M., Breeman, W., de Blois, E., Chan, H. S., Boerman, O., Laverman, P., … de Jong, M. (2014). Therapeutic application of CCK2R-targeting PP-F11: influence of particle range, activity and peptide amount. Psychonomic Bulletin and Review, 4(1). doi:10.1186/s13550-014-0047-1