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Description
Background: The widest possible range of available molecular targets and their vectors is a crucial key for targeted diagnosis and cancer therapy problems. The presented work concerns a vector – the peptidomimetic inhibitor, the molecular target of which is neuropilin-1 (NRP-1). NRP-1 is a receptor for the vascular endothelial growth factor-165 (VEGF165) playing an important role in pathological angiogenesis and in tumor development and progression. It has been observed that NRP-1 overexpression is associated with tumor aggressiveness in several types of cancers. The demonstrated involvement of VEGF165/NRP-1 complex in pathological angiogenesis has catalyzed interest in searching for inhibitors of such interaction to combat angiogenesis dependent diseases. It was shown before that a heptapeptide Ala-Thr-Trp-Leu-Pro-Pro-Arg (A7R) is a good inhibitor of the VEGF165/NRP-1 interaction.
Aim: The work involved the labeling of the Lys-(hArg)-Dab-(Ahx-DOTA)-Pro-Arg peptide (working name KM1) and preliminary physicochemical studies of obtained radiobioconjugate (Figure 1). KM1 is an analog of the A7R peptide what is stronger inhibitor of VEGF165/NRP-1 complex than A7R.
Figure 1. Structure of 68Ga-DOTA-KM1 radiobioconjugate.
Methodology: Peptide KM1 was synthesized in the Peptides Laboratory of the University of Warsaw using the SPPS method on Wang resin using the Fmoc strategy. The labeling was performed with 68Ga (95°C, 10 min) and the obtained radiobioconjugate was purified by HPLC (semi-preparative Jupiter® Proteo column). Lipophilicity (logP value) was determined in a standard biological system (PBS solution and n-octanol) and the stability of the compound was tested in human serum.
Results and discussion: The labeling yield was about 72%. The determined logP value equal to -4.16 ± 0,02 indicates that 68Ga-DOTA-KM1 radiobioconjugate is a strongly hydrophilic compound. Stability studies in human serum showed that about 85% of the radiobioconjugate remains in the free form in the serum solution (about 15% is combined with the protein present in the serum).
Conclusion: The presented studies are the first step on the new VEGF/NRP-1 radioisotopically labeled peptidomimetic inhibitors for cancer diagnostics and therapy. In the next steps the syntheses of new peptidomimetics are planned as well as the using of a long-lived isotope, e.g. 177Lu or a 43,44Sc/47Sc theragnostic pair.
