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EGFR-targeting peptide-coupled platinum(IV) complexes
Josef Mayr1, Sonja Hager2, Bettina Koblmüller2
1Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090, Vienna, Austria.
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.
Insights
Researchers developed novel platinum(IV) complexes targeting the epidermal growth factor receptor (EGFR) for lung cancer. However, the peptide LARLLT did not enhance targeted drug uptake in EGFR-overexpressing cancer cells.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Lung cancer has a high mortality rate, necessitating more targeted therapies.
- Epidermal growth factor receptor (EGFR) is a key target in lung cancer treatment.
- Platinum(II) drugs are standard lung cancer therapeutics, driving interest in novel platinum complexes.
Purpose of the Study:
- To synthesize and evaluate novel platinum(IV) complexes conjugated with the EGFR-targeting peptide LARLLT for lung cancer treatment.
- To investigate the specificity and efficacy of these platinum(IV) complexes in EGFR-overexpressing cancer cells.
- To assess the utility of the LARLLT peptide in directing small-molecule drugs to EGFR-positive tumors.
Main Methods:
- Synthesis of platinum(IV) complexes linked to LARLLT and a control peptide (RTALLL).
- Characterization of synthesized compounds using High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS).
- Biological evaluation including cell viability assays, clonogenic assays, and platinum uptake studies in cell lines with varying EGFR expression. Fluorophore-coupled peptides were used to track cellular uptake via flow cytometry.
Main Results:
- The synthesis yielded platinum(IV) complexes, with HPLC-MS revealing a transcyclization reaction in the linker.
- Biological assays showed no enhanced activity or EGFR-dependent uptake of the platinum(IV) complexes.
- Studies with fluorophore-labeled peptides confirmed that LARLLT does not correlate with EGFR expression levels for drug uptake.
Conclusions:
- The study successfully synthesized the first platinum(IV) complexes conjugated to an EGFR-targeting peptide.
- The LARLLT peptide was found to be unsuitable for enhancing the specific uptake of small-molecule drugs into EGFR-overexpressing cancer cells.
- This research highlights the challenges in developing targeted drug delivery systems for lung cancer, even with established targets like EGFR.