Synthesis and evaluation of intercalating peptide conjugates for the endoradiotherapy

摘要

When conjugated to 'therapeutic' nuclides such as ~(90)Y,somatostatin receptor binding peptides have been shown to be successful for the therapy of receptor expressing tumors.The most successful radiotherapeutic is ~(90)Y-DOTATOC.However,the therapeutic value of this treatment is limited by the side effects in non-target tissues such as the kidneys.The effectiveness of the treatment modality might be further increased with conjugates which enable the nuclear targeting of the low energy emitting radioactive isotopes.Intercalators,planar aromatic compounds,are able to interact with DNA by sandwiching themselves between the stacked bases at right angles to the long axis of the helix.The bis-benzimidazole dyes,Haechst 33258 and 33342,have been shown to bind to the minor groove of DNA in A-T rich regions.Under certain circumstances,Auger-electron-emitting radionuclides can be extremely radiotoxic and produce extensive DNA damage.The degree of damage appears to depend upon the location of the decaying atom.Consequently,Auger electron-emitting radioisotopes,such as ~(195m)Pt,~(114m)In,~(111)In,~(99m)Tc,~(67)Ga and ~(51)Cr are known to be highly cytotoxic when localized in cell nuclei due to highly localized energy deposition by low energy Auger electrons.In addition,binding to the DNA might increase the retention in the receptor expressing tissues.