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Spontaneous and Ionizing Radiation-Induced Aggregation of Human Serum Albumin: Dityrosine as a Fluorescent Probe.

ABSTRACT: The use of spectroscopic techniques has shown that human serum albumin (HSA) undergoes reversible self-aggregation through protein-protein interactions. It ensures the subsequent overlapping of electron clouds along with the stiffening of the conformation of the interpenetrating network of amino acids of adjacent HSA molecules. The HSA oxidation process related to the transfer of one electron was investigated by pulse radiolysis and photochemical methods. It has been shown that the irradiation of HSA solutions under oxidative stress conditions results in the formation of stable protein aggregates. The HSA aggregates induced by ionizing radiation are characterized by specific fluorescence compared to the emission of non-irradiated solutions. We assume that HSA dimers are mainly responsible for the new emission. Dityrosine produced by the intermolecular recombination of protein tyrosine radicals as a result of radiolysis of an aqueous solution of the protein is the main cause of HSA aggregation by cross-linking. Analysis of the oxidation process of HSA confirmed that the reaction of mild oxidants (Br2•-, N3•, SO4•-) with albumin leads to the formation of covalent bonds between tyrosine residues. In the case of ^•OH radicals and partly, Cl2•-, species other than DT are formed. The light emission of this species is similar to the emission of self-associated HSA.

SUBMITTER: Radomska K

PROVIDER: S-EPMC9331647 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The biodistribution of medical imaging probes depends on the chemical nature of the probe and the preferred metabolization and excretion routes. Especially targeted probes, which have to reach a certain (sub)cellular destination, have to be guided to the tissue of interest. Therefore, small molecular probes need to exhibit a well-balanced polarity and lipophilicity to maintain an advantageous bioavailability. Labelled antibodies circulate for several days due to their size. To alter the biodistribution behavior of probes, different strategies have been pursued, including utilizing serum albumin as an inherent transport mechanism for small molecules. We describe here the modification of an existing fluorescent RGD mimetic probe targeted to integrin αvβ3 with three different albumin binding moieties (ABMs): a diphenylcyclohexyl (DPCH) group, a p-iodophenyl butyric acid (IPBA) and a fatty acid (FA) group with the purpose to identify an optimal ABM for molecular imaging applications. All three modifications result in transient albumin binding and a preservation of the target binding capability. Spectrophotometric measurements applying variable amounts of bovine serum albumin (BSA) reveal considerable differences between the compounds concerning their absorption and emission characteristics and hence their BSA binding mode. In vivo the modified probes were investigated in a murine U87MG glioblastoma xenograft model over the course of 1 wk by fluorescence reflectance imaging (FRI) and fluorescence mediated tomography (FMT). While the unmodified probe was excreted rapidly, the albumin-binding probes were accumulating in tumor tissue for at least 5 days. Considerable differences between the three probes in biodistribution and excretion characteristics were proved, with the DPCH-modified probe showing the highest overall signal intensities, while the FA-modified probe exhibits a low but more specific fluorescent signal. In conclusion, the modification of small molecular RGD mimetics with ABMs can precisely fine-tune probe distribution and offers potential for future clinical applications.

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Spontaneous and Ionizing Radiation-Induced Aggregation of Human Serum Albumin: Dityrosine as a Fluorescent Probe.

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