Preparation of Boron-Containing S-Nitrosothiol Based on Homocysteinylamides of Human Serum Albumin for Combined NO-Chemical and Boron-Neutron-Capture Therapy

Abstract

Objective: The strategic aim of this work is to create a fluorophore-labelled, clinically relevant exogenous NO donor carrying a boron-containing compound residue based on human serum albumin (HSA) for the implementation of combined NO-chemotherapy and boron-neutron-capture therapy. Methods: By selective modification of the Cys34 residue of albumin with a maleimide derivative of a fluorescent dye and subsequent N-homocysteinylation with a thiolactone derivative of homocysteine containing a clozo-dodecaborate residue, a nanoconstruct for boron-neutron-capture therapy was obtained. An analogue based on the natural modifier, boron-containing homocysteine thiolactone, was synthesised by alkylation of the amino group of thiolactone with a dioxonium derivative of clozo-dodecaborate. Post-synthetic modification of the lysine residues of the protein using the boron thiolactone of homocysteine provided the introduction of SH groups into the protein and the possibility of subsequent trans-S-nitrosylation of the protein using S-nitrosoglutathione. Results and Discussion: It was found that 2 M of NO was conjugated to 1 M of boron-containing HSA. Boron-containing S-nitrosothiol based on albumin homocysteinylamide, without epithermal neutron irradiation, was demonstrated to be more cytotoxic against human glioblastoma cell lines than the boron-containing albumin conjugate. Conclusions: Thus, the approach used allows obtaining a boron-enriched structure based on a biocompatible tumor-specific protein, containing a fluorescent label and an increased number of S-nitroso groups. It is necessary for the manifestation of a chemotherapeutic effect of the construct. The practical significance of this structure lies in the possibility of a cancer treatment, combining chemo- and boron-neutron capture therapy.