Preparation and evaluation of tumor-targeting peptide−oligonucleotide conjugates

• Verfasst von: Mier, Walter [VerfasserIn]
• Verfasst von: Haberkorn, Uwe [VerfasserIn]
• Verfasst von: Eisenhut, Michael [VerfasserIn]
• Titel: Preparation and evaluation of tumor-targeting peptide−oligonucleotide conjugates
• Verf.angabe: Walter Mier, Ramon Eritja, Ashour Mohammed, Uwe Haberkorn, and Michael Eisenhut
• E-Jahr: 2000
• Jahr: October 28, 2000
• Umfang: 6 S.
• Fussnoten: Gesehen am 09.02.2021
• Titel Quelle: Enthalten in: Bioconjugate chemistry
• Ort Quelle: Columbus, Ohio : American Chemical Society, 1990
• Jahr Quelle: 2000
• Band/Heft Quelle: 11(2000), 6, Seite 855-860
• ISSN Quelle: 1520-4812
• DOI: doi:10.1021/bc000041k
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1747887668

Abstract

Enormous progress has been made in the development of antisense oligodeoxynucleotides (ODNs) as therapeutic agents inhibiting gene expression. Unfortunately, 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. Phosphorothioate ODNs were covalently linked to Tyr3−octreotate, an analogue of somatostatin. The peptide was assembled by solid-phase synthesis, oxidized to form the cyclic disulfide, and subsequently derivatized with a N-terminal maleimido functionality. 5‘-Thiol derivatized phosphorothioate-ODNs directed against the protooncogene bcl-2 were conjugated to this maleimido-modified peptide. 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 terminal conjugation of the ODNs did not significantly affect their hybridization affinity.