RESUMO
Metastatic cancers have historically been difficult to treat. However, metastatic tumors have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antimetastatic therapy. In this study, prodrug 7 was designed to be activated by H2O2-mediated boronate oxidation, resulting in activation of the fluorophore for detection and release of the therapeutic agent, SN-38. Drug release from prodrug 7 was investigated by monitoring fluorescence after addition of H2O2 to the cancer cells. Prodrug 7 activated by H2O2, selectively inhibited tumor cell growth. Furthermore, intratracheally administered prodrug 7 showed effective antitumor activity in a mouse model of metastatic lung disease. Thus, this H2O2-responsive prodrug has therapeutic potential as a novel treatment for metastatic cancer via cellular imaging with fluorescence as well as selective release of the anticancer drug, SN-38.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Pró-Fármacos/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Camptotecina/química , Camptotecina/metabolismo , Camptotecina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Células HeLa , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Irinotecano , Neoplasias Pulmonares/metabolismo , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/secundário , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A new theranostic strategy is described. It is based on the use of an "all in one" prodrug, namely the biotinylated piperazine-rhodol conjugate 4 a. This conjugate, which incorporates the anticancer drug SN-38, undergoes self-immolative cleavage when exposed to biological thiols. This leads to the tumor-targeted release of the active SN-38 payload along with fluorophore 1 a. This release is made selective as the result of the biotin functionality. Fluorophore 1 a is 32-fold more fluorescent than prodrug 4 a. It permits the delivery and release of the SN-38 payload to be monitored easily inâ vitro and inâ vivo, as inferred from cell studies and exâ vivo analyses of mice xenografts derived from HeLa cells, respectively. Prodrug 4 a also displays anticancer activity in the HeLa cell murine xenograft tumor model. On the basis of these findings we suggest that the present strategy, which combines within a single agent the key functions of targeting, release, imaging, and treatment, may have a role to play in cancer diagnosis and therapy.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Pró-Fármacos/farmacologia , Compostos de Sulfidrila/química , Animais , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/farmacocinética , Camptotecina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Diagnóstico por Imagem , Corantes Fluorescentes , Humanos , Irinotecano , Camundongos , Imagem Molecular , Pró-Fármacos/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We present here, the design, synthesis, spectroscopic characterization, and in vitro biological assessment of a gemcitabine-coumarin-biotin conjugate (5). Probe 5 is a multifunctional molecule composed of a thiol-specific cleavable disulfide bond, a coumarin moiety as a fluorescent reporter, gemcitabine (GMC) as a model active drug, and biotin as a cancer-targeting unit. Upon addition of free thiols that are relatively abundant in tumor cells, disulfide bond cleavage occurs as well as active drug GMC release and concomitantly fluorescence intensity increases. Confocal microscopic experiments reveal that 5 is preferentially taken up by A549 cells rather than WI38 cells. Fluorescence-based colocalization studies using lysosome- and endoplasmic reticulum-selective dyes suggest that thiol-induced disulfide cleavage of 5 occur in the lysosome possibly via receptor-mediated endocytosis. The present drug delivery system is a new theranostic agent, wherein both a therapeutic effect and drug uptake can be readily monitored at the subcellular level by two photon fluorescence imaging.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacocinética , Biotina/química , Cumarínicos/química , Desoxicitidina/análogos & derivados , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/química , Desoxicitidina/farmacocinética , Desoxicitidina/farmacologia , Sistemas de Liberação de Medicamentos , Corantes Fluorescentes/química , Humanos , Neoplasias/tratamento farmacológico , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacologia , Compostos de Sulfidrila/química , GencitabinaRESUMO
An iron-catalyzed intramolecular alkyne-aldehyde metathesis strategy of the alkynyl ether of salicylaldehyde derivatives has been developed which works under mild reaction conditions to produce the functionalized 2H-chromene derivatives. This protocol is compatible toward a wide range of functional groups, such as methoxy, fluoro, chloro, bromo, and phenyl groups. This method provides an atom-economical and environmentally friendly approach for the synthesis of a series of substituted 2H-chromenes.
Assuntos
Aldeídos/química , Alcinos/química , Benzopiranos/química , Benzopiranos/síntese química , Química Verde/métodos , Ferro/química , CatáliseRESUMO
A simple, convenient, and multicomponent coupling strategy for the synthesis of highly functionalized pyrroles catalyzed by iron(III) salts has been developed. This strategy demonstrated four-component coupling reactions of 1,3-dicarbonyl compounds, amines, aromatic aldehydes, and nitroalkanes without an inert atmosphere. This methodology provides an alternative approach for easy access of highly substituted pyrroles in moderate to very good yields using four simple and readily available building blocks via one-pot tandem reaction. Notably, this method is very cheap, straightforward, and environmentally friendly compared to the existing methods.
Assuntos
Aldeídos/química , Alcanos/química , Aminas/química , Reagentes de Ligações Cruzadas/química , Ferro/química , Pirróis/síntese química , Catálise , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Nitrocompostos , Pirróis/químicaRESUMO
Biotin-disulfide-coumarin conjugates are designed and synthesized as novel fluorescent sensors for cancer targeted intracellular thiol imaging in living organisms. In vitro experiments disclose that probe 6 is preferentially taken up by biotin receptor-positive A549 tumor cells through receptor mediated endocytosis.
Assuntos
Biotina , Cumarínicos , Dissulfetos , Corantes Fluorescentes , Neoplasias/diagnóstico , Biotina/análogos & derivados , Biotina/metabolismo , Linhagem Celular Tumoral , Cumarínicos/química , Cumarínicos/metabolismo , Dissulfetos/química , Dissulfetos/metabolismo , Endocitose , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Humanos , Sondas Moleculares/química , Sondas Moleculares/metabolismo , Neoplasias/metabolismo , Imagem Óptica/métodos , Receptores de Fatores de Crescimento/análise , Receptores de Fatores de Crescimento/metabolismoRESUMO
We present the design, synthesis, optical properties and in vitro biological assessments of the theranostic prodrug in which a near IR fluorophore is conjugated with a cancer cell-directing biotin unit; further it is linked with the anti-cancer drug gemcitabine via a self-immolative spacer, a disulfide bond. The prodrug is able to monitor drug delivery and cellular imaging.