title: Therapeutic application of CCK2R-targeting PP-F11: influence of particle range, activity and peptide amount.
abstract: 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.
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, PO Box 2040, 3000, CA, Rotterdam, The Netherlands, m.konijnenberg@erasmusmc.nl.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Konijnenberg
authors.forename: Wout A P
authors.initials: WA
authors.lastname: Breeman
authors.forename: Erik
authors.initials: E
authors.lastname: de Blois
authors.forename: Ho Sze
authors.initials: HS
authors.lastname: Chan
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.forename: Peter
authors.initials: P
authors.lastname: Laverman
authors.forename: Petra
authors.initials: P
authors.lastname: Kolenc-Peitl
authors.forename: Marleen
authors.initials: M
authors.lastname: Melis
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong