An albumin-based tumor-targeted oxaliplatin prodrug with distinctly improved anticancer activity in vivo

Mayr, Josef; Heffeter, Petra; Groza, Diana; Galvez, Luis; Koellensperger, Gunda; Roller, Alexander; Alte, Beatrix; Haider, Melanie; Berger, Walter; Kowol, Christian R.; Keppler, Bernhard K.

doi:10.1039/c6sc03862j

Cited by 117 publications

(123 citation statements)

References 49 publications

(53 reference statements)

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“…Subsequent oxidation with hydrogen peroxide was carried out either in methanol [31] or acetic acid [32] to yield the hydroxidomethoxidoplatinum(IV) species or the acetatohydroxidoplatinum(IV) species, respectively. The maleimide-functionalized platinum precursors 1 and 2 were synthesized in absolute DMF under inert conditions with subsequent chromatographic purification, as published recently [33]. Additionally, a succinimide-functionalized oxaliplatin compound 2 ref was prepared analogously, which was used as the platinum(IV) reference compound.…”

Section: Resultsmentioning

confidence: 99%

“…Hydrogen peroxide (50%) was used for oxidation of the complexes in either methanol [31] or acetic acid [32] as a solvent, yielding the unsymmetrically oxidized platinum(IV) precursors. Thereafter, the ligands with the maleimide or succinimide moiety were coupled to yield compounds 1, 2 and 2 Ref as recently published [33, 45]. Cys-MiniPEG-LARLLT and Cys-MiniPEG-RTALLL (MiniPEG = 2-(2-(2-aminoethoxy)ethoxy)acetic acid, both TFA salts, >95% purity) were purchased from Biomatik Corporation (Cambridge, Canada).…”

Section: Methodsmentioning

confidence: 99%

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EGFR-targeting peptide-coupled platinum(IV) complexes

et al. 2017

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The high mortality rate of lung cancer patients and the frequent occurrence of side effects during cancer therapy demonstrate the need for more selective and targeted drugs. An important and well-established target for lung cancer treatment is the occasionally mutated epidermal growth factor receptor (EGFR). As platinum(II) drugs are still the most important therapeutics against lung cancer, we synthesized in this study the first platinum(IV) complexes coupled to the EGFR-targeting peptide LARLLT (and the shuffled RTALLL as reference). Notably, HPLC–MS measurements revealed two different peaks with the same molecular mass, which turned out to be a transcyclization reaction in the linker between maleimide and the coupled cysteine moiety. With regard to the EGFR specificity, subsequent biological investigations (3-day viability, 14-day clonogenic assays and platinum uptake) on four different cell lines with different verified EGFR expression levels were performed. Unexpectedly, the results showed neither an enhanced activity nor an EGFR expression-dependent uptake of our new compounds. Consequently, fluorophore-coupled peptides were synthesized to re-evaluate the targeting ability of LARLLT itself. However, also with these molecules, flow cytometry measurements showed no correlation of drug uptake with the EGFR expression levels. Taken together, we successfully synthesized the first platinum(IV) complexes coupled to an EGFR-targeting peptide; however, the biological investigations revealed that LARLLT is not an appropriate peptide for enhancing the specific uptake of small-molecule drugs into EGFR-overexpressing cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s00775-017-1450-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

EGFR-targeting peptide-coupled platinum(IV) complexes

et al. 2017

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“…In virtue of different structures and mechanisms, polynuclear platinum complexes demonstrate great favorable properties as compared with mononuclear ones . Recently, targeted platinum drugs have witnessed improved tumor selectivity, reduced side effects and enhanced drug efficacy . However, the design and application of targeted polynuclear platinum complexes for osteosarcoma are quite rare due to the lack of effective methods for preparation.…”

Section: Introductionmentioning

confidence: 99%

Dinuclear Platinum(II) Complexes with Bone‐Targeting Groups as Potential Anti‐Osteosarcoma Agents

Zhang

Wang

Luo

et al. 2017

Chemistry An Asian Journal

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“…HSA as the most abundant protein in blood plays key roles in the transport and storage of exogenous drugs, and thus influencing their metabolism, toxicities and clearance in vivo , . In view of this, the binding properties of naphthalimide platinum(IV) complex 5 with HSA were tested by UV/Vis and fluorescence spectrum.…”

Section: Resultsmentioning

confidence: 99%

Naphthalimide Platinum(IV) Compounds as Antitumor Agents with Dual DNA Damage Mechanism to Overcome Cisplatin Resistance

Wang

Liu

et al. 2018

Eur J Inorg Chem

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A new series of naphthalimide platinum(IV) compounds with dual DNA damage mechanism were designed, synthesized and evaluated for antitumor activities. The platinum(IV) compounds could combine with DNA and cause DNA damage via naphthalimide fragment. Then the platinum(II) complexes released in reductive microenvironment would cause remarkable secondary DNA lesions. Some title compounds exhibit good antitumor activities and are of great potential in overcoming the drug resistance of cisplatin. Furthermore, naphthalimide platinum(IV) complexes could effectively combine with HSA by electrostatic force, which would influence the drug distribution and bioactivities in vivo. Moreover, the accumulation of the tested platinum(IV) compounds in whole cells and DNA is remarkably enhanced in comparison with cisplatin and oxaliplatin.

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An albumin-based tumor-targeted oxaliplatin prodrug with distinctly improved anticancer activity in vivo

Abstract: An oxaliplatin-based platinum(iv) drug which specifically binds to albumin after i.v. application led to several complete responses in tumor-bearing mice.

Cited by 117 publications

References 49 publications

EGFR-targeting peptide-coupled platinum(IV) complexes

EGFR-targeting peptide-coupled platinum(IV) complexes

Dinuclear Platinum(II) Complexes with Bone‐Targeting Groups as Potential Anti‐Osteosarcoma Agents

Naphthalimide Platinum(IV) Compounds as Antitumor Agents with Dual DNA Damage Mechanism to Overcome Cisplatin Resistance

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