Abstract
The biodistribution of molecular imaging probes or tracers mainly depends on the chemical nature of the probe and the preferred mET(A)bolization and excretion routes. Small molecules have rather short half-lives while antibodies reside inside the organism for a longer period of time. An excretion via kidneys and bladder is faster than a mainly hepatobiliary elimination. To manipulate the biodistribution behavior of probes, different strategies have been pursued, including utilizing serum albumin as an inherent transport mechanism for small molecules. Here, we modified an existing small molecular fluorescent probe targeted to the endothelin-A receptor (ETAR) with three different albumin-binding moieties to search for an optimal modification strategy. A diphenylcyclohexyl (DPCH) group, a p-iodophenyl butyric acid (IPBA), and a fatty acid (FA) group were attached via amino acid linkers. All three modifications result in transient albumin binding of the developed compounds, as concluded from gel electrophoresis investigations. Spectrophotometric measurements applying variable amounts of bovine, murine, and human serum albumin (BSA, MSA, and HSA) reveal distinct variations of absorption and emission intensities and shifts of their maximum wavelengths. Binding to MSA results in the weakest effects, while binding to HSA leads to the strongest. Cell-based in vitro investigations utilizing ETAR-positive HT-1080 fibrosarcoma and ETAR-negative BT-20 breast adenocarcinoma cells support a rET(A)ined specific target-binding capacity of the modified compounds and different degrees of unspecific binding. In vivo analysis of a HT-1080 xenograft model in nude mice over the course of 1 week by fluorescence reflectance imaging illustrates noticeable differences between the four examined probes. While the IPBA-modified probe shows the highest absolute signal intensity values, the FA-modified probe exhibits the most favorable tumor-to-organ ratios. In summary, reversible binding to albumin enhances the biological half-life of the designed probes substantially and enables near infrared optical imaging of subcutaneous tumors for several days in vivo. Because the unmodified probe already exhibits reasonable results, the attachment of albumin-binding moieties does not lead to a substantially improved imaging outcome in terms of target-to-background ratios. On the other hand, because the implemented transient albumin binding results in an overall higher amount of probe inside tumor lesions, this strategy might be adaptable for theranostic or therapeutic approaches in a future clinical routine.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| Fakultät: | Medizin |
| Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| ISSN: | 1543-8384 |
| Sprache: | Englisch |
| Dokumenten ID: | 99039 |
| Datum der Veröffentlichung auf Open Access LMU: | 05. Jun. 2023, 15:30 |
| Letzte Änderungen: | 17. Okt. 2023, 15:00 |
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