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Sequence‐Defined Oligoamide Drug Conjugates of Pretubulysin and Methotrexate for Folate Receptor Targeted Cancer Therapy
Author(s) -
Truebenbach Ines,
Gorges Jan,
Kuhn Jasmin,
Kern Sarah,
Baratti Emanuele,
Kazmaier Uli,
Wagner Ernst,
Lächelt Ulrich
Publication year - 2017
Publication title -
macromolecular bioscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.924
H-Index - 105
eISSN - 1616-5195
pISSN - 1616-5187
DOI - 10.1002/mabi.201600520
Subject(s) - folate receptor , dihydrofolate reductase , cytotoxicity , chemistry , endocytosis , conjugate , methotrexate , targeted drug delivery , receptor , biochemistry , drug delivery , cancer cell , pharmacology , in vitro , cancer , enzyme , biology , immunology , mathematical analysis , genetics , mathematics , organic chemistry
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.