title: Octreotide-Mediated Tumor-Targeted Drug Delivery via a Cleavable Doxorubicin-Peptide Conjugate.
abstract: Although recent methods for targeted drug delivery have addressed many of the existing problems of cancer therapy associated with undesirable side effects, significant challenges remain that have to be met before they find significant clinical relevance. One such area is the delicate chemical bond that is applied to connect a cytotoxic drug with targeting moieties like antibodies or peptides. Here we describe a novel platform that can be utilized for the preparation of drug-carrier conjugates in a site-specific manner, which provides excellent versatility and enables triggered release inside cancer cells. Its key feature is a cleavable doxorubicin-octreotide bioconjugate that targets overexpressed somatostatin receptors on tumor cells, where the coupling between the two components was achieved through the first cleavable disulfide-intercalating linker. The tumor targeting ability and suppression of adrenocorticotropic hormone secretion in AtT-20 cells by both octreotide and the doxorubicin hybrid were determined via a specific radioimmunoassay. Both substances reduced the hormone secretion to a similar extent, which demonstrated that the tumor homing peptide is able to interact with the relevant cell surface receptors after the attachment of the drug. Effective drug release was quickly accomplished in the presence of the physiological reducing agent glutathione. We also demonstrate the relevance of this scaffold in biological context in cytotoxicity assays with pituitary, pancreatic, and breast cancer cell lines.
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Lelle
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
authors.forename: Stefka
authors.initials: S
authors.lastname: Kaloyanova
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Freidel
authors.affiliation: Max Planck Institute for Psychiatry, Kraepelinstraße 2-10, 80804 Munich, Germany.
authors.forename: Marily
authors.initials: M
authors.lastname: Theodoropoulou
authors.affiliation: Institute of Molecular Biology, Ackermannweg 4, 55128 Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Musheev
authors.affiliation: Institute of Molecular Biology, Ackermannweg 4, 55128 Mainz, Germany.|Division of Molecular Embryology, DKFZ-ZMBH Alliance , 69120 Heidelberg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
authors.affiliation: Max Planck Institute for Psychiatry, Kraepelinstraße 2-10, 80804 Munich, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Stalla
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.|Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena , Lessingstrasse 8, 07743 Jena, Germany.
authors.forename: Kalina
authors.initials: K
authors.lastname: Peneva
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry*; D004337:Drug Carriers; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D015282:Octreotide / Q000008:administration & dosage / Q000737:chemistry*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry*; D017481:Receptors, Somatostatin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D010455:Peptides; D017481:Receptors, Somatostatin; D004317:Doxorubicin; D015282:Octreotide
keywords: cross-linker; doxorubicin; drug delivery; octreotide; somatostatin receptor; tumor-targeting