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.
Keywords: combination therapy; drug conjugate; methotrexate; pretubulysin; targeting.
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