title: Isostructural Re(I)/(99m)Tc(I) tricarbonyl complexes for cancer theranostics.
abstract: Merging classical organic anticancer drugs with metal-based compounds in one single molecule offers the possibility of exploring new approaches for cancer theranostics, i.e. the combination of diagnostic and therapeutic modalities. For this purpose, we have synthesized and biologically evaluated a series of Re(I)/(99m)Tc(I) tricarbonyl complexes (Re1–Re4 and Tc1–Tc4, respectively) stabilized by a cysteamine-based (N,S,O) chelator and containing 2-(4′-aminophenyl)benzothiazole pharmacophores. With the exception of Re1, all the Re complexes have shown a moderate cytotoxicity in MCF7 and PC3 cancer cells (IC50 values in the 15.9–32.1 μM range after 72 h of incubation). The cytotoxic activity of the Re complexes is well correlated with cellular uptake that was quantified using the isostructural (99m)Tc congeners. There is an augmented cytotoxic effect for Re3 and Re4 (versusRe1 and Re2), and the highest cellular uptake for Tc3 and Tc4, which display a long ether-containing linker to couple the pharmacophore to the (N,S,O)-chelator framework. Moreover, fluorescence microscopy clearly confirmed the cytosolic accumulation of the most cytotoxic compound (Re3). Biodistribution studies of Tc1–Tc4 in mice confirmed that these moderately lipophilic complexes (logDo/w = 1.95–2.32) have a favorable bioavailability. Tc3 and Tc4 presented a faster excretion, as they undergo metabolic transformations, in contrast to complexes Tc1 and Tc2. In summary, our results show that benzothiazole-containing Re(I)/(99m)Tc(I) tricarbonyl complexes stabilized by cysteamine-based (N,S,O)-chelators have potential to be further applied in the design of new tools for cancer theranostics.
authors: Centro de Ciências e Tecnologias e Nucleares, IST, Universidade de Lisboa, Estrada Nacional 10, 2695-066 Bobadela LRS, Portugal. apaulo@ctn.ist.utl.pt.
authors: Patrique
authors: P
authors: Nunes
authors: Goreti Ribeiro
authors: GR
authors: Morais
authors: Elisa
authors: E
authors: Palma
authors: Francisco
authors: F
authors: Silva
authors: Maria Cristina
authors: MC
authors: Oliveira
authors: Vera F C
authors: VF
authors: Ferreira
authors: Filipa
authors: F
authors: Mendes
authors: Lurdes
authors: L
authors: Gano
authors: Hugo
authors: H
authors: Vicente Miranda
authors: Tiago F
authors: TF
authors: Outeiro
authors: Isabel
authors: I
authors: Santos
authors: António
authors: A
authors: Paulo
mesh_terms: D006801:Humans; D009369:Neoplasms / Q000175:diagnosis* / Q000628:therapy*; D015609:Organotechnetium Compounds / Q000737:chemistry*; D012211:Rhenium / Q000737:chemistry*; D000068936:Theranostic Nanomedicine
chemical_list: D015609:Organotechnetium Compounds; D012211:Rhenium