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

Truebenbach, Ines; Gorges, Jan; Kuhn, Jasmin; Kern, Sarah; Baratti, Emanuele; Kazmaier, Uli; Wagner, Ernst; Lächelt, Ulrich

doi:10.1002/mabi.201600520

Cited by 16 publications

(16 citation statements)

References 29 publications

(77 reference statements)

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“…PEG obviously can interfere with this direct cationic membrane destabilization. Consistently, bioreversible PEGylation was introduced to resolve this dilemma and also the disulfide conjugation of oligomer and PEG used in the present work could possibly be cleaved off by intracellular glutathion (GSH) as demonstrated in other work …”

Section: Resultsmentioning

confidence: 56%

EGFR Targeting and Shielding of pDNA Lipopolyplexes via Bivalent Attachment of a Sequence‐Defined PEG Agent

Morys

Urnauer

Spitzweg

et al. 2017

Macromolecular Bioscience

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For successful nonviral gene delivery, cationic polymers are promising DNA carrier, which need to comprise several functionalities. The current work focuses on the postincorporation of epidermal growth factor receptor (EGFR) targeted PEGylation agents onto lipopolyplexes for pDNA delivery. T‐shaped lipo‐oligomers are previously found to be effective sequence‐defined carriers for pDNA and siRNA. Here, the bis‐oleoyl‐oligoaminoethanamide 454 containing tyrosine trimer–cysteine ends is applied for complex formation with pDNA coding for luciferase or sodium iodide symporter (NIS). In a second step, the lipopolyplexes are modified via disulfide formation with sequence‐defined monovalent or bivalent PEGylation agents containing one or two 3‐nitro‐2‐pyridinesulfenyl (NPys)‐activated cysteines, respectively. For targeting, the polyethylene glycol (PEG) agents comprise the EGFR targeting peptide GE11. In comparison of all transfection complexes, 454 lipopolyplexes modified with the bidentate PEG–GE11 agent show the best, EGFR‐dependent uptake as well as luciferase and NIS gene expression into receptor‐positive tumor cells.

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Section: Resultsmentioning

confidence: 56%

EGFR Targeting and Shielding of pDNA Lipopolyplexes via Bivalent Attachment of a Sequence‐Defined PEG Agent

Morys

Urnauer

Spitzweg

et al. 2017

Macromolecular Bioscience

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“…Based on a previous experiment with the novel microtubule inhibitor pretubulysin (PT) conjugated with methotrexate (MTX)‐containing oligomers, the same drug combination was chosen in this study. By combining PT with the well‐established chemotherapeutic drug MTX, we aimed to further increase the great antitumoral potency of PT.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it displays remarkable antitumoral potency in the subnanomolar region . PT not only leads to reduced tumor cell growth of different cell lines and inhibits cancer cell migration in vitro, it also shows great potential in vivo: PT inhibits tumor growth and metastasis and also significantly reduces angiogenesis …”

Section: Introductionmentioning

confidence: 99%

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Combined antitumoral effects of pretubulysin and methotrexate

Kern

Truebenbach

Höhn

et al. 2019

Pharmacology Res & Perspec

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Pretubulysin (PT), a potent tubulin‐binding antitumoral drug, and the well‐established antimetabolite methotrexate (MTX) were tested separately or in combination (PT+MTX) for antitumoral activity in L1210 leukemia cells or KB cervix carcinoma cells in vitro and in vivo in NMRI‐nu/nu tumor mouse models. In cultured L1210 cells, treatment with PT or MTX displays strong antitumoral effects in vitro, and the combination PT+MTX exceeds the effect of single drugs. PT also potently kills the MTX resistant KB cell line, without significant MTX combination effect. Cell cycle analysis reveals the expected arrest in G1/S by MTX and in G2/M by PT. In both cell lines, the PT+MTX combination induces a G2/M arrest which is stronger than the PT‐triggered G2/M arrest. PT+MTX does not change rates of apoptotic L1210 or KB cells as compared to single drug applications. Confocal laser scanning microscopy images show the microtubule disruption and nuclear fragmentation induced by PT treatment of L1210 and KB cells. MTX changes the architecture of the F‐actin skeleton. PT+MTX combines the toxic effects of both drugs. In the in vivo setting, the antitumoral activity of drugs differs from their in vitro cytotoxicity, but their combination effects are more pronounced. MTX on its own does not display significant antitumoral activity, whereas PT reduces tumor growth in both L1210 and KB in vivo models. Consistent with the cell cycle effects, MTX combined at moderate dose boosts the antitumoral effect of PT in both in vivo tumor models. Therefore, the PT+MTX combination may present a promising therapeutic approach for different types of cancer.

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“…The first research article in this section is contributed by Ulrich Lächelt and describes the development of sequence‐defined oligoamide drug conjugates of pretubulysin and methotrexate for folate receptor‐targeted cancer therapy. The authors could nicely demonstrate the development of a polymeric material with defined sequence and its in vitro and in vivo validation for the therapy of folate receptor‐positive tumors in mice …”

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confidence: 99%