EGFR-targeting peptide-coupled platinum(IV) complexes

Abstract

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.

Improving the Stability of Maleimide–Thiol Conjugation for Drug Targeting

“…For conjugation a Cys‐miniPEG linker was attached to the LARLLT peptide sequence. We synthesized the transcyclization product 5a using 24 h incubation of the peptide and the maleimide‐bearing platinum complex in PB pH 7.4, [8] resulting in ∼95 % conversion to 5a . For the thiosuccinimide reference complex 5b we protected the terminal Cys via acetylation.…”

“…In ar ecent publication, we synthesized ad rug-peptide conjugatev ia reactiono famaleimide moiety and an N-terminal cysteinef or coupling. [8] High-performance liquid chromatography/mass spectrometry( HPLC-MS)m easurements revealed that the product peak converted within severalh ours into a new peak with the same exact mass. This reaction was supposed to be aM ichael-transcyclization already known from similars ystems.…”

“…For conjugation aC ys-miniPEG linker was attached to the LARLLTp eptide sequence. We synthesized the transcyclization product 5a using 24 hi ncubation of the pep-tide and the maleimide-bearing platinum complex in PB pH 7.4, [8] resulting in~95 %conversion to 5a.For the thiosuccinimider eference complex 5b we protected the terminal Cys via acetylation. All compounds (50 mm)w erei ncubated in an aqueous phosphate buffered solution (100 mm,p H7.4, 25 8C) in the presence of 10-folde xcesso fr educed GSH for 25 ha nd the reaction was monitored via HPLC-MS.T he N-acetylated, open-chain complex 5b underwent distinctt hiol-exchange reaction with GSH ( Figure 5A)w ith formation of the oxaliplatin(IV)-thiosuccinimide-GSH speciesa tm/z = 947.I nc ontrast, the transcyclization bioconjugate 5a did not show significant GSHadduct formation even after 25 h( Figure 5B).…”

Recent Advances in the Chemistry of Metal Carbamates

“…Following a different approach, the incorporation of a maleimide fragment enabled specific interactions with proteins (e.g., addition to thiol residues) for compounds showing a promising anticancer activity in vivo [261,268,369]. The conjugation with suitable targeting groups, to enhance the pharmacological performance, can be achieved via modification of either the axial carboxylato co-ligand [367,370] or the carbamato ligand itself [272,371,372]. Remarkably, all of these Pt(IV) complexes are stable for several hours or even days in physiological aqueous solutions [260,261,263,272].…”

Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs

“…20,21 This prodrug strategy has been widely used for the construction of multifunctional Pt complexes as illustrated in many studies. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] BRCA and RAD51 play essential roles in HR, and BRCA-procient tumors are usually refractory to CDDP due to effective HR. Recently, we designed two Pt IV -artesunate prodrugs, which inhibited HR via downregulating RAD51 and exhibited higher cytotoxicity against BRCA-procient cancer cells than CDDP.…”