title: Sequence-Defined Oligoamide Drug Conjugates of Pretubulysin and Methotrexate for Folate Receptor Targeted Cancer Therapy.
abstract: The conjugation of small molecule drugs to ligand containing carrier systems facilitates receptor targeted delivery. The folate receptor (FR) constitutes an ideal target for tumor selective therapy, being overexpressed on several tumor types. It can be targeted using the vitamin folic acid (FolA) or the structurally related drug methotrexate (MTX). Several sequence-defined oligoamides with mono- and multivalent FolA or MTX ligands and an additional thiol conjugation site are synthesized via solid-phase assisted synthesis. Their structure activity relationships are assessed in respect to dihydrofolate reductase inhibition, receptor mediated endocytosis, and cytotoxicity. Then, the tubulin-binding agent pretubulysin (PT), a highly potent drug exhibiting antitumoral, antiangiogenic, and antimetastatic properties, is conjugated via an activated mercaptane derivative to the set of FR-targeting oligoamides. In a combined PT/MTX cytotoxicity study in FR-overexpressing KB and L1210 cells, a 2-arm MTX-PT construct or the 4-arm analog displays the highest potency in the respective cell lines.
authors.affiliation: Pharmaceutical Biotechnology, Center for System-Based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, 81377, Munich, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Truebenbach
authors.affiliation: Institute of Organic Chemistry, Saarland University, P. O. Box 151150, 66041, Saarbrücken, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Gorges
authors.affiliation: Pharmaceutical Biotechnology, Center for System-Based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, 81377, Munich, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Kuhn
authors.affiliation: Pharmaceutical Biotechnology, Center for System-Based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, 81377, Munich, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kern
authors.affiliation: Pharmaceutical Biotechnology, Center for System-Based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, 81377, Munich, Germany.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Baratti
authors.affiliation: Institute of Organic Chemistry, Saarland University, P. O. Box 151150, 66041, Saarbrücken, Germany.
authors.forename: Uli
authors.initials: U
authors.lastname: Kazmaier
authors.affiliation: Pharmaceutical Biotechnology, Center for System-Based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, 81377, Munich, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.affiliation: Pharmaceutical Biotechnology, Center for System-Based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, 81377, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lächelt
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D004337:Drug Carriers; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007624:KB Cells; D008024:Ligands; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008727:Methotrexate / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008024:Ligands; D009363:Neoplasm Proteins; D009842:Oligopeptides; D050257:Tubulin Modulators; D011092:Polyethylene Glycols; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; C575012:pretubulysin; D008727:Methotrexate
keywords: combination therapy; drug conjugate; methotrexate; pretubulysin; targeting