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Therapeutic application of CCK2R-targeting PP-F11: influence of particle range, activity and peptide amount
Mark W Konijnenberg1, Wout A P Breeman, Erik de Blois
1Department of Nuclear Medicine, Erasmus MC, PO Box 2040, 3000, CA, Rotterdam, The Netherlands, m.konijnenberg@erasmusmc.nl.
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 ED50 = 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.
Insights
Targeted radionuclide therapy using Yttrium-90 (90Y)-labeled PP-F11 is optimal for treating larger tumors (>200 mg), offering a promising approach for cancer treatment. This method surpasses other radionuclides in efficacy for CCK2 receptor-positive tumors.
Area of Science:
- Nuclear medicine
- Radiopharmaceutical therapy
- Oncology
Background:
- Targeted radionuclide therapy (TRT) with high-energy beta-emitters is often suboptimal for small tumors (<300 mg).
- The CCK2 receptor-binding minigastrin analogue PP-F11 shows potential for tumor targeting.
- Optimizing TRT requires careful consideration of radionuclide choice, specific activity, and absorbed tumor dose.
Purpose of the Study:
- To determine the optimal CCK2 receptor-binding peptide PP-F11 therapy for tumors using different radionuclides.
- To analyze the efficacy of PP-F11 labeled with Yttrium-90 (90Y), Lutetium-177 (177Lu), and Bismuth-213 (213Bi).
- To evaluate the impact of radionuclide specific activity, absorbed tumor dose, and tumor radiobiology on therapeutic outcomes.
Main Methods:
- Tumor uptake of Indium-111 (111In)-PP-F11 was assessed in mice bearing CCK2 receptor-transfected xenografts with escalating peptide doses.
- Absorbed tumor doses were estimated assuming comparable biodistributions for 90Y, 177Lu, and 213Bi labeled PP-F11.
- The linear-quadratic (LQ) model was used to calculate tumor control probabilities (TCP) based on tumor mass and growth.
Main Results:
- Maximum achievable specific activities (SA) were 400 MBq/nmol for 90Y, 120 MBq/nmol for 177Lu, and 40 MBq/nmol for 213Bi.
- Tumor uptake decreased logarithmically with increasing peptide mass (ED50 = 0.5 nmol).
- A curative dose (60 Gy) could be achieved with 111 MBq 90Y-PP-F11 for tumors >200 mg; 213Bi was effective for smaller tumors, while 177Lu was suboptimal for fast-growing tumors.
Conclusions:
- Therapy with 90Y-labeled PP-F11 is favored for CCK2 receptor-positive tumors, especially those larger than 300 mg, due to receptor saturation, specific activity, and absorbed dose considerations.
- Despite its longer beta-particle range, 90Y demonstrates superior efficacy.
- Predicted TCPs require validation through experimental targeted radionuclide studies.
