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Synthetic Polyglutamylation of Dual-Functional MTX Ligands for Enhanced Combined Cytotoxicity of Poly(I:C) Nanoplexes
journal contribution
posted on 2014-08-04, 00:00 authored by Ulrich Lächelt, Valentin Wittmann, Katharina Müller, Daniel Edinger, Petra Kos, Miriam Höhn, Ernst WagnerThe antifolate drug methotrexate
(MTX) can serve as a dual-functional
ligand in antitumoral drug delivery, inducing both a folate receptor
mediated cellular uptake and an intracellular cytotoxic action. Bioactivity
of MTX however changes by conjugation; the activity can be affected
by the hampered intracellular conversion to more potent poly-γ-glutamyl
derivatives. Therefore, in a cancer combination therapy approach for
the codelivery of cytotoxic dsRNA polyinosinic–polycytidylic
acid poly(I:C), a set of molecularly precise oligo(ethanamino)amides
were synthesized comprising poly(ethylene glycol) conjugated MTX ligands.
The conjugates differed in the number of additional glutamic acid
residues to investigate the effect of different degrees of synthetic
“a priori” polyglutamylation. The bioactivity of these
compounds concerning dihydrofolate reductase (DHFR) inhibition, cytotoxicity,
nucleic acid binding potency, cellular uptake of poly(I:C) polyplexes,
and combined antifolate/poly(I:C) toxicity was investigated. Synthetic
polyglutamylation had a crucial impact on several stages of efficient
poly(I:C) delivery and combined MTX cytotoxicity. DHFR inhibition
of the conjugates significantly increased with increasing polyglutamate
chain length. The library member with highest glutamylation degree
even outperformed free MTX in direct comparison. Studies in KB cells
showed the corresponding enhanced cytotoxicity by polyglutamylation.
Also poly(I:C) polyplexes of the glutamylated MTX variants exhibited
higher cellular uptake in the folate receptor positive cell line.
Finally, a synergistic combined cytotoxicity of polyglutamylated MTX
ligands and complexed poly(I:C) cargo was observed in transfected
KB cells. The present structure–activity relationship study
of MTX-based ligands pinpoints the concept of synthetic polyglutamylation
as a promising approach for optimizing bioactivity of antifolate conjugates,
which might be considered as a useful tool also in context of other
drug delivery systems.
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uptakefolate receptorintracellular cytotoxic actionpolyglutamylated MTX ligandscancer combination therapy approachantitumoral drug deliverypolyglutamate chain lengthDHFRglutamylated MTX variantspolyglutamylationantifolateconjugatedrug delivery systemscytotoxicitytransfected KB cellsacid binding potency
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