Session 2. Cells, materials and biochemistry I
Diagnosis and therapy of prostate cancer increasingly concentrates on approaches with prostate-specific membrane antigen (PSMA)-specific peptides like PSMA-11 or PSMA-617. The pharmacokinetics of these substances are relevant for development and optimization of those peptides as well as for modelling the metabolic processes in planning of individualized molecular radiotherapy. Reliable and reproducible pharmacokinetic data of substances obtained by easy-to-handle methods would be advantageous
... d be advantageous for all aspects. To determine the association and dissociation rate constants of the PSMA-specific peptides PSMA-11 (ABX) and GaPSMA-11 (ABX), surface plasmon resonance (SPR) spectroscopy using a Biacore X100 was performed. This technique allows the real-time analysis of the interaction between ligand and receptor without necessity of labelling and the influence of confounding side effects as in cell-based assays. In comparison to previously published binding affinity values obtained using cell assays, for PSMA-11 a 100-fold lower dissociation constants were determined using SPR spectroscopy. In contrast to most cell binding studies performed at 4°C, SPR spectroscopy facilitates physiological conditions with temperatures of 25°C or 37°C. These data can be implemented to model the binding and internalization processes of PSMA-11 to optimize application dose and biodistribution. The determination of the binding kinetics for PSMA-11 and GaPSMA-11 yielded (0.07±0.02) nM and (0.04±0.02) nM at 25°C, and (0.07±0.04) nM and (0.10±0.08) nM at 37°C. These values are significantly lower compared to most published data (about 12 nM). No significant difference between the equilibrium dissociation constants KD measured at 25°C and at 37°C has been observed. Molecular interaction data can be determined by highly reproducible and non-influenced SPR measurements. These data are of great value for peptide development and optimization: Implemented into a physiologicallybased pharmacokinetic (PBPK) model, the binding and internalization processes can be successfully described and used for individualized treatment planning of molecular radiotherapy.