Protein modification by thiolactone homocysteine chemistry: a multifunctionalized human serum albumin theranostic

• Published in: MedChemComm Vol. 11; no. 11; pp. 1314 - 1325
• Main Authors: Popova, Tatyana V, Krumkacheva, Olesya A, Burmakova, Anna S, Spitsyna, Anna S, Zakharova, Olga D, Lisitskiy, Vladimir A, Kirilyuk, Igor A, Silnikov, Vladimir N, Bowman, Michael K, Bagryanskaya, Elena G, Godovikova, Tatyana S
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 02.04.2020; RSC
• Subjects: Albumin; Breast cancer; Cell proliferation; Chemical compounds; Chemistry; Conjugates; Cytotoxicity; Emission spectra; Fluorescence; Glioblastoma; Homocysteine; Human serum albumin; Nitroxide; NMR; Nuclear magnetic resonance; Pharmacology; Proteins; Reagents; Serum albumin; Serum proteins; Size exclusion chromatography; Spectroscopy; Tamoxifen; Thiolactone; Toxicity; Tumor cells
• ISSN: 2632-8682; 2040-2503; 2632-8682; 2040-2511
• DOI: 10.1039/c9md00516a

As the most abundant protein with a variety of physiological functions, albumin has been used extensively for the delivery of therapeutic molecules. Thiolactone chemistry provides a powerful tool to prepare spin-labeled albumin-based multimodal imaging probes and therapeutic agents. We report the synthesis of a tamoxifen homocysteine thiolactone derivative and its use in thiol-'click' chemistry to prepare multi-functionalized serum albumin. The released sulfhydryl group of the homocysteine functional handle was labeled with a nitroxide reagent to prepare a spin-labeled albumin-tamoxifen conjugate confirmed by MALDI-TOF-MS, EPR spectroscopy, UV-vis and fluorescent emission spectra. This is the basis for a novel multimodal tamoxifen-albumin theranostic with a significant (dose-dependent) inhibitory effect on the proliferation of malignant cells. The response of human glioblastoma multiforme T98G cells and breast cancer MCF-7 cells to tamoxifen and its albumin conjugates was different in tumor cells with different expression level of ERα in our experiments. These results provide further impetus to develop a serum protein for delivery of tamoxifen to cancer cells. A tamoxifen-homocysteine conjugate provides a tool to prepare a multifunctionalized albumin theranostic with a significant cytotoxicity on the malignant cells.