Abstract
As the most abundant protein with a variety of physiological functions, human serum albumin (HSA) has been used extensively for the delivery and improvement of therapeutic molecules. Thiolactone chemistry provides a powerful tool to prepare albumin-based multimodal imaging probes and agents for boron neutron capture therapy (BNCT). For this purpose, boron containing 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dye was designed and synthesized. BODIPY dyes are photostable neutral derivatives of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene. These are widely used as chemosensors, laser materials and molecular probes. At the same time, BODIPY dyes, like most other fluorophores, have small or moderate Stokes shifts. Large Stokes shifts are preferred for fluorophores because of higher sensitivity of such probes and sensors. We succeeded in performing an annulation of pyrrole ring with coumarin heterocyclic system and achieved a remarkable difference in absorption and emission maximum of obtained fluorophore up to 100 nm. Moreover, this BODIPY dye was equipped with a linker arm and was functionalized with a maleimide residue specifically reactive towards thiol groups of proteins. The released sulfhydryl groups of the homocysteine functional handle in thiolactone modified HSA was labeled with BODIPY dye to prepare a labeled albumin-BODIPY dye conjugate confirmed by MALDI-TOF-MS, UV-vis and fluorescent emission spectra. The cytotoxicity of HSA conjugate was evaluated by MTT assay in cell lines MCF-7 and T98G. This is the basis for a novel BODIPY dye -albumin theranostic for BNCT. These results provide further impetus to develop derivatives of HSA for delivery of boron to cancer cells.
Highlights
Boron neutron capture therapy (BNCT) is a promising cancer treatment modality based on the nuclear capture of slow neutrons by stable 10B atoms followed by charged particle emission that have a cell killing effect within 10 μm-range. [1] Successful Boron Neutron Capture Therapy (BNCT) mainly depends on the selective accumulation of 10B including agents in tumor cells
The released sulfhydryl groups of the homocysteine functional handle in thiolactone modified human serum albumin (HSA) was labeled with BODIPY dye to prepare a labeled albuminBODIPY dye conjugate confirmed by MALDI-TOF-MS, UV-vis and fluorescent emission spectra
The cytotoxicity of HSA conjugate was evaluated by MTT assay in cell lines MCF-7 and T98G
Summary
Boron neutron capture therapy (BNCT) is a promising cancer treatment modality based on the nuclear capture of slow neutrons by stable 10B atoms followed by charged particle emission that have a cell killing effect within 10 μm-range. [1] Successful BNCT mainly depends on the selective accumulation of 10B including agents in tumor cells. Nowadays only two boron agents, boronophenylalanine (BPA) and borocaptate sodium (BSH), have been used clinically [2,3,4]. Both compounds do not correspond all the required criteria. We report synthesis and spectral study of a new non-symmetric BODIPY dye having 7dimethylaminochromeno[4,3-b]pyrrol-4-one and pyrrole equipped with a linker arm carrying a carboxyl group for biopolymer labelling. Conjugation of this new dye to human serum albumin (HSA) and some physico-chemical and biological properties of the conjugate are described
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