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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  90 Y,  177 Lu or  213 Bi, accounting for the radionuclide specific activities (SAs), the tumour absorbed doses and tumour (radio) biology.    Methods  Tumour uptake of  111 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  90 Y,  177 Lu or  213 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  90 Y and  177 Lu were 400 MBq  90 Y/nmol and 120 MBq 177 Lu/nmol. Both the large elution volume from the 220 MBq  225 Ac generator used and reaction kinetics diminished the maximum achieved  213 Bi SA in practice: 40 MBq  213 Bi/nmol. Tumour uptakes decreased rapidly with increasing peptide amounts, following a logarithmic curve with ED 50  = 0.5 nmol. At 0.03 nmol peptide, the (300 mg) tumour dose was 9 Gy after 12 MBq  90 Y-PP-F11, and for  111 In and  177 Lu, this was 1 Gy. A curative dose of 60 Gy could be achieved with a single administration of 111 MBq  90 Y labelled to 0.28 nmol PP-F11 or with 4 × 17 MBq  213 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  90 Y-PP-F11; the other radionuclides perform better in smaller tumours. Furthermore,  177 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  90 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.

Therapeutic application of CCK2R-targeting PP-F11: influence of particle range, activity and peptide amount