A “two birds with one stone” approach to the targeted treatment and imaging of tumors: vitamin B12-functionalized metallotheranostic agents
Fotopoulou, Eirini
Fotopoulou, Eirini
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http://hdl.handle.net/10379/16863
https://doi.org/10.13025/17525
https://doi.org/10.13025/17525
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Publication Date
2021-06-04
Type
Thesis
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Abstract
Vitamin B12 (aka cyanocobalamin) is a vital nutrient characterized by very low bioavailability. Owing to their extremely high proliferation rates, tumor cells show increased demand for nutrients compared with healthy ones, including the greater uptake of vitamin B12. Such avidity of cyanocobalamin can thus be exploited for the site-specific delivery of drugs directly into the tumor by conjugating vitamin B12 (carrier) to either anticancer (chemotherapeutics) or imaging (fluorophores) agents. Accordingly, this research project includes the rational design and synthesis of vitamin B12-based metallotheranostics of the type [{B12–Co–C≡C–Ph–Inp–dtc–M}] and [{FLUO-B12–Co–C≡C–Ph–Inp–dtc–M}]. As such, cyanocobalamin is functionalized at the 5'-hydroxo group of the ribose unit with a fluorophore (FLUO), whereas the cyano (CN) group is replaced with phenylacetylide-containing metal-dithiocarbamato complexes ({M(dtc)}; M = Au(III)/Pt(II), dtc = various dithiocarbamates). The rationale behind the proposed designing approach is based on the evidence that vitamin B12 converted into its cofactors (methylcobalamin or adenosylcobalamin) inside the cell through the reduction of Co(III) to Co(II) and the subsequent release of the cyano group. Therefore, by binding metal-containing scaffolds to the cyanocobalamin Co(III)-CN moiety, should the overall bioconjugate accumulate preferentially in the tumor cells, the cytotoxic metal complexes are expected to be released directly into the diseased site where it can exert its anticancer activity without affecting healthy tissues. At the same time, the fluorophore attached at the 5'-ribose moiety would allow the transport and biodistribution to be followed and assessed by fluorescence spectroscopy. Therefore, the goal is to take advantage of the increased demand of cyanocobalamin in tumor cells by exploiting its carrier properties to design selective "Trojan Horse"-type theranostics in which the structural features of vitamin B12 conceal both the attached imaging agent and the metallodrug, to achieve a better therapeutic outcome and reduce side-effects. Additionally, considering the role of amino acids in tumor metabolism as nutrients, inhibitors, and epigenetic regulators, we designed four novel naturally fluorescent metal-dithiocarbamato L-tyrosine ester complexes. Furthermore, four new platinum(II) glycomimetic analogs were synthesized and fully characterized. Notably, all of the novel platinum(II)-glycoconjugates proved cytotoxic against the A2780 ovarian cancer cell line, and three of them against the resistant cell line A2780cis, with GI50 values lower than 20μM.
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NUI Galway
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Attribution-NonCommercial-NoDerivs 3.0 Ireland