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

Background: Targeted radionuclide therapy with high-energy beta-emitters is generally considered suboptimal to cure small tumours (90Y, 177Lu or 213Bi, accounting for the radionuclide specific activities (SAs), the tumour absorbed doses and tumour (radio) biology. Methods: Tumour uptake of 111In-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 90Y, 177Lu or 213Bi 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 90Y and 177Lu were 400 MBq 90Y/nmol and 120 MBq177Lu/nmol. Both the large elution volume from the 220 MBq 225Ac generator used and reaction kinetics diminished the maximum achieved 213Bi SA in practice: 40 MBq 213Bi/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 90Y-PP-F11, and for 111In and 177Lu, this was 1 Gy. A curative dose of 60 Gy could be achieved with a single administration of 111 MBq 90Y labelled to 0.28 nmol PP-F11 or with 4 × 17 MBq 213Bi (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 90Y-PP-F11; the other radionuclides perform better in smaller tumours. Furthermore, 177Lu 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 90Y, 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

Comparison of the binding and internalization properties of 12 DOTA-coupled and ¹¹¹In-labelled CCK2/gastrin receptor binding peptides: a collaborative project under COST Action BM0607

Specific overexpression of cholecystokinin 2 (CCK2)/gastrin receptors has been demonstrated in several tumours of neuroendocrine origin. In some of these cancer types, such as medullary thyroid cancer (MTC), a sensitive diagnostic modality is still unavailable and therapeutic options for inoperable lesions are needed. Peptide receptor radionuclide therapy (PRRT) may be a viable therapeutic strategy in the management of these patients. Several CCK2R-targeted radiopharmaceuticals have been described in recent years. As part of the European Union COST Action BM0607 we studied the in vitro and in vivo characteristics of 12 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CCK2R binding peptides. In the present study, we analysed binding and internalization characteristics. Stability, biodistribution and imaging studies have been performed in parallel by other centres involved in the project

Highly improved metabolic stability and pharmacokinetics of indium-111-DOTA-gastrin conjugates for targeting of the gastrin receptor

The development of metabolically stable radiolabeled gastrin analogues with suitable pharmacokinetics is a topic of recent research activity. These imaging vectors are of interest because the gastrin/CCK2 receptor is highly overexpressed in different tumors such as medullary thyroid cancer, neuroendocrine tumors, and SCLC. The drawback of current targeting agents is either their metabolic instability or their high kidney uptake. We present the synthesis and in vitro and in vivo evaluation of 11 (111)In-labeled DOTA-conjugated peptides that differ by their spacer between the peptide and the chelate. We introduced uncharged but hydrophilic spacers such as oligoethyleneglycol, serine, and glutamine. The affinity of all radiopeptides was high with IC(50) values between 0.5 and 4.8 nM. The improvement of human serum stability is 500-fold within this series of compounds. In addition the kidney uptake could be lowered distinctly and the tumor-to-kidney ratio improved almost 60-fold if compared with radiotracers having charged spacers such as glutamic acid