RESUMO
Potential boron neutron capture therapy (BNCT) agents have been designed on the basis of the evidence about translocator protein (TSPO) overexpression on the outer mitochondrial membrane of tumor cells. The structure of the first TSPO ligand bearing a carborane cage (compound 2d) has been modified in order to find a suitable candidate for in vivo studies. The designed compounds were synthesized and evaluated for their potential interaction with TSPO and tumor cells. In vitro biological evaluation showed in the case of fluoromethyl derivative 4b a nanomolar TSPO affinity very similar to that of 2d, a significantly lower cytotoxicity, and a slightly superior performance as boron carrier toward breast cancer cells. Moreover, compound 4b could be used as a ¹9F magnetic resonance imaging (MRI) agent as well as labeled with ¹¹C or ¹8F to obtain positron emission tomography (PET) radiotracers in order to apply the "see and treat" strategy in BNCT.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Boro , Encéfalo/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Mitocôndrias/efeitos dos fármacos , Quinolinas , Receptores de GABA-A/metabolismo , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Animais , Sítios de Ligação , Boranos/síntese química , Boranos/farmacologia , Boranos/uso terapêutico , Boro/química , Boro/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Proteínas de Transporte/química , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Neoplasias do Colo/radioterapia , Cristalografia por Raios X , Feminino , Radioisótopos de Flúor , Expressão Gênica , Imageamento por Ressonância Magnética , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Modelos Moleculares , Tomografia por Emissão de Pósitrons , Ligação Proteica , Quinolinas/síntese química , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Ratos , Receptores de GABA-A/química , Receptores de GABA-A/genética , Relação Estrutura-AtividadeRESUMO
The effect of neutron boron capture therapy (BNCT) was studied in rat tumor liver cells after induction of the liver metastases by splenic inoculation of cells from DHA/K12/TRb line. Ten days following the treatment, the BPA was injected into rats and therefore the animals were sacrificed, the liver was exposed to neutron irradiation and processed. In some experiments the liver was reimplanted (after irradiation) in syngenic animals and studied 3 days later, following sacrifice. Samples of tissue obtained from metastasised and non-metastasised areas of the liver parenchyma, before and after the neutron irradiation, were examined in light microscopy and electron microscopy. The analysis pointed out damages induced by the neutron treatment in single tumor cells mostly localised in the synusoidal blood stream. Debris and apoptotic cells were sometimes observed in the neoplastic nodules before treatment, while the tumor cell death (apoptosis) increased in the tumor cells following BNCT treatment. An intense scavenger activity of Kupffer cells after irradiation was accompanied by a strong acid phosphatase reaction detectable in wide cytoplasmic areas. In the liver parenchyma of reimplanted animals, the presence of large collagen bundles spread among the hepatocytes was observed at electron microscopy.
Assuntos
Adenocarcinoma/radioterapia , Terapia por Captura de Nêutron de Boro , Neoplasias do Colo/radioterapia , Neoplasias Hepáticas/radioterapia , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Células de Kupffer/patologia , Células de Kupffer/efeitos da radiação , Células de Kupffer/ultraestrutura , Fígado/patologia , Fígado/efeitos da radiação , Fígado/ultraestrutura , Neoplasias Hepáticas/secundário , Masculino , Microscopia Eletrônica , Ratos , Ratos Endogâmicos , Resultado do TratamentoRESUMO
The aim of this study is to optimize targeted boron delivery to cancer cells and its tracking down to the cellular level. To this end, we describe the design and synthesis of novel nanovectors that double as targeted boron delivery agents and fluorescent imaging probes. Gold nanoparticles were coated with multilayers of polyelectrolytes functionalized with the fluorescent dye (FITC), boronophenylalanine and folic acid. In vitro confocal fluorescence microscopy demonstrated significant uptake of the nanoparticles in cancer cells that are known to overexpress folate receptors.