Sequence‐Defined Oligoamide Drug Conjugates of Pretubulysin and Methotrexate for Folate Receptor Targeted Cancer Therapy

• Published in: Macromolecular bioscience Vol. 17; no. 10
• Main Authors: Truebenbach, Ines, Gorges, Jan, Kuhn, Jasmin, Kern, Sarah, Baratti, Emanuele, Kazmaier, Uli, Wagner, Ernst, Lächelt, Ulrich
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.10.2017
• Subjects: Amides - chemical synthesis; Amides - chemistry; Animals; Antiangiogenics; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological Transport; Cancer; Cancer therapies; Cell Line, Tumor; combination therapy; Conjugation; Cytotoxicity; Dihydrofolate reductase; Drug Carriers; drug conjugate; Drug delivery systems; Endocytosis; Folic acid; Folic Acid - chemistry; Folic Acid - metabolism; Gene Expression; Humans; KB Cells; Ligands; Lymphocytes - drug effects; Lymphocytes - metabolism; Lymphocytes - pathology; Methotrexate; Methotrexate - chemistry; Methotrexate - pharmacology; Mice; Mice, Nude; Molecular Targeted Therapy - methods; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oligopeptides - chemistry; Oligopeptides - pharmacology; Polyethylene Glycols - chemistry; pretubulysin; Reductases; Solid phases; targeting; Tetrahydrofolate Dehydrogenase - genetics; Tetrahydrofolate Dehydrogenase - metabolism; Therapy; Toxicity; Tubulin; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Xenograft Model Antitumor Assays; combination therapy; methotrexate; targeting; pretubulysin; drug conjugate
• ISSN: 1616-5187; 1616-5195
• DOI: 10.1002/mabi.201600520

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. Several folate receptor targeted, sequence‐defined oligoamides are synthesized and evaluated for their effects on target enzyme inhibition, cellular uptake, and cell viability. Then, the antitumoral agent pretubulysin is covalently coupled to the oligoamides and the constructs are investigated for their combination therapy properties in a pretubulysin/methotrexate toxicity study.