RESUMO
Tumor-associated macrophages (TAMs) that exist in tumor microenvironment promote tumor progression and have been suggested as a promising therapeutic target for cancer therapy in preclinical studies. Development of theranostic systems capable of specific targeting, imaging, and ablation of TAMs will offer clinical benefits. Here we constructed a theranostic probe, namely, TPE-Man, by attaching mannose moieties to a red-emissive and AIE (aggregation-induced emission)-active photosensitizer. TPE-Man can specifically recognize a mannose receptor that is overexpressed on TAMs by the sugar-receptor interaction and enables fluorescent visualization of the mannose-receptor-positive TAMs in high contrast. The histologic study of mouse tumor sections further verifies TPE-Man's excellent targeting specificity being comparable with the commercial mannose-receptor antibody. TAMs can be effectively eradicated upon exposure to white light irradiation via a photodynamic therapy effect. To our knowledge, this is the first small molecular theranostic probe for TAMs that revealed combined advantages of low cost, high targeting specificity, fluorescent light-up imaging, and efficient photodynamic ablation.
Assuntos
Compostos de Benzilideno/farmacologia , Macrófagos/efeitos dos fármacos , Manosídeos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Animais , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/efeitos da radiação , Compostos de Benzilideno/toxicidade , Manosídeos/síntese química , Manosídeos/efeitos da radiação , Manosídeos/toxicidade , Camundongos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Fármacos Fotossensibilizantes/toxicidade , Ratos Sprague-Dawley , Nanomedicina Teranóstica/métodosRESUMO
We have recently demonstrated, by employing azobenzene glycosides, that bacterial adhesion to surfaces can be switched through reversible reorientation of the carbohydrate ligands. To investigate this phenomenon further, we have turned here to more complex-that is, multivalent-azobenzene glycoclusters. We report on the synthesis of a photosensitive trivalent cluster mannoside conjugated to an azobenzene hinge at the focal point. Molecular dynamics studies suggested that this cluster mannoside, despite the conformational flexibility of the azobenzene-glycocluster linkage, offers the potential for reversibly changing the glycocluster's orientation on a surface. Next, the photoswitchable glycocluster was attached to human cells, and adhesion assays with typeâ 1 fimbriated Escherichia coli bacteria were performed. They showed marked differences in bacterial adhesion, dependent on the light-induced reorientation of the glycocluster moiety. These results further underline the importance of orientational effects in carbohydrate recognition and likewise the value of photoswitchable glycoconjugates for their study.
Assuntos
Compostos Azo/química , Aderência Bacteriana/efeitos dos fármacos , Manosídeos/química , Azidas/metabolismo , Compostos Azo/síntese química , Compostos Azo/efeitos da radiação , Aderência Bacteriana/efeitos da radiação , Engenharia Celular , Células Endoteliais/metabolismo , Escherichia coli/fisiologia , Hexosaminas/metabolismo , Humanos , Ligantes , Manosídeos/síntese química , Manosídeos/efeitos da radiação , Simulação de Dinâmica Molecular , Estereoisomerismo , Raios UltravioletaRESUMO
Two ß-cyclodextrin derivatives randomly appended on the primary face with both the nitric oxide (NO) photodonor 4-nitro-3-(trifluoromethyl)aniline and a mannose or α(1â2)mannobioside residue are reported to construct targeted NO photoreleasing nanocarriers. 2D ROESY and PGSE NMR suggested supramolecular homodimerization in water by inclusion of the nitroaniline group into the facing macrocycle cavities. Isothermal titration calorimetry on their concanavalin A lectin binding showed an exothermic binding event to the lectin and an endothermic process during the dilution of the conjugates. Both α(1â2)mannobioside and the nitroaniline moieties significantly enhanced the binding to the lectin. These effects might arise from a better fit within the carbohydrate-recognition site in the former case and a multivalent effect caused by homodimerization in the latter. Direct detection of NO by amperometric technique shows that both ß-cyclodextrin derivatives release this radical upon excitation with visible light with higher efficiency than the unfunctionalized NO photodonor.