Preparation and evaluation of tumor-targeting peptide-oligonucleotide conjugates

Enormous progress has been made in the development of antisense oligodeoxyn ucleotides (ODNs) as therapeutic agents inhibiting gene expression. Unfortu nately, the therapeutical application of ODNs is still held back because of the low cellular uptake and the lack of specific transport into particular cells. In this paper, we report a drug-targeting system using somatostatin receptors (SSTRs) which are overexpressed in various tumors. Phosphorothio ate ODNs were covalently linked to Tyr(3)-octreotate, an analogue of somato statin. The peptide was assembled by solid-phase synthesis, oxidized to for m the cyclic disulfide, and subsequently derivatized with a N-terminal male imido functionality. 5'-Thiol derivatized phosphorothioate-ODNs directed ag ainst the protooncogene bcl-2 were conjugated to this maleimido-modified pe ptide. Binding studies revealed that the conjugates retain specific binding with nanomolar affinities to SSTRs (IC50-values between 1.83 and 2.52 nM). Furthermore, melting studies with complementary DNA revealed that the term inal conjugation of the ODNs did not significantly affect their hybridizati on affinity.