Preparation of boron-containing s-nitrosothiol based on homocysteinylamides of human serum albumin for combined no-chemical and boron-neutron-capture therapy

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Дәйексөз келтіру

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Аннотация

The strategic aim of this work is to create a fluorophore-labelled, clinically relevant exogenous NO donor carrying a boron-containing compound residue on the basis of human serum albumin (HSA) for the implementation of combined NO-chemotherapy and boron-neutron-capture therapy. 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. It was found that 2 mol of NO was conjugated to 1 mol 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. 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 treating, combining chemo- and boron-neutron capture therapy.

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Авторлар туралы

T. Popova

Institute of Chemical Biology and Fundamental Medicine SB RAS; Novosibirsk National Research State University

Хат алмасуға жауапты Автор.
Email: v.silnikov@mail.ru
Ресей, Novosibirsk; Novosibirsk

M. Van

Novosibirsk National Research State University

Email: v.silnikov@mail.ru
Ресей, Novosibirsk

T. Kurochkin

Novosibirsk National Research State University

Email: v.silnikov@mail.ru
Ресей, Novosibirsk

S. Tsyrempilov

Novosibirsk National Research State University

Email: v.silnikov@mail.ru
Ресей, Novosibirsk

O. Zakharova

Institute of Chemical Biology and Fundamental Medicine SB RAS

Email: v.silnikov@mail.ru
Ресей, Novosibirsk

V. Silnikov

Institute of Chemical Biology and Fundamental Medicine SB RAS

Email: v.silnikov@mail.ru
Ресей, Novosibirsk

T. Godovikova

Institute of Chemical Biology and Fundamental Medicine SB RAS; Novosibirsk National Research State University

Email: v.silnikov@mail.ru
Ресей, Novosibirsk; Novosibirsk

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2. Fig. 1. Approaches to enhancing the effectiveness of NO therapy by exposure to exogenous (light, ultrasound, X-rays) or endogenous (glutathione, acid, glucose) stimuli [37].

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3. Fig. 2. Schematic diagram of BNCT [40].

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4. Fig. 3. Scheme of synthesis of boron-containing analogue of homocysteine ​​thiolactone (HTL-B12H11).

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5. Fig. 4. Scheme for the preparation of S-nitrosylated boron-containing homocysteinylamide albumin containing a fluorescent dye (paths a, b and c) and S-nitrosylated albumin (path d).

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6. Fig. 5. Characteristics of multifunctional conjugates of human serum albumin. (a) – Electronic absorption spectra of HSA and its homocystamides in PBS buffer, pH 7.4; (b) – MALDI-TOF mass spectra of HSA and its homocystamides; (c) – SDS-PAGE of homocystamide conjugates of HSA under Laemmli conditions followed by staining with Coomassie blue.

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7. Fig. 6. Viability of T98G cells treated with HSA, HSA-Cy5-HcyB12H11, and HSA-Cy5-HSA-Cy5-HcyB12H11-NO. The dose of conjugates was 0.02–40 μM protein equivalent. All data are presented as mean ± SD (n = 3). Two-way ANOVA was used to compare more than two data sets. **** p ≤ 0.0001.

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