RESUMEN
In the present study, a pH/redox-responsive cationic polymer dot (CD) was successfully prepared for a near-infrared (NIR)-mediated, simultaneously controllable photothermal temperature guided imaging off/on system to monitor therapeutic delivery. Carbonized disulfide cross-linked branched polyethyleneimine (bPEI) was conjugated with folic acid (FA) as a targeting moiety and partially formed an ionic complex with anionic indocyanine green (ICG) to afford a bPEI-based CD (ICG-CD). This was responsive to mild reductive (glutathione, GSH) and acidic tumor conditions, which enabled the simultaneous biodegradation of those hydrophobic and complex sites. The ICG-CD internalized readily into the cytoplasm of cancer cells by a FA receptor and cationic-mediated endocytosis in the off state, whereas if ICG-CD met intracellular GSH at high concentrations, GSH contributed partially to the recovery of fluorescence and was then internalized into acidic endosomes to induce complete restoration of fluorescence. This tumor-sensitive degradability of the CD not only facilitated ICG release in the tumor location but also allowed controllable photothermal therapy effects of nanoparticles under NIR irradiation, which resulted in improved cancer therapy. Taken together, the results indicate great potential in tumor targeting, intracellular imaging, and controllable therapeutic delivery through a fluorescence off/on assay under the pH/redox conditions of cancer cells.
Asunto(s)
Antineoplásicos/farmacología , Colorantes Fluorescentes/farmacología , Verde de Indocianina/farmacología , Puntos Cuánticos/química , Animales , Antineoplásicos/química , Carbono/química , Línea Celular Tumoral , Perros , Endocitosis/fisiología , Endosomas/metabolismo , Fluorescencia , Colorantes Fluorescentes/química , Colorantes Fluorescentes/metabolismo , Receptores de Folato Anclados a GPI/metabolismo , Ácido Fólico/química , Ácido Fólico/metabolismo , Glutatión/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Hipertermia Inducida/métodos , Verde de Indocianina/química , Verde de Indocianina/metabolismo , Rayos Infrarrojos , Células de Riñón Canino Madin Darby , Oxidación-Reducción , Fototerapia/métodos , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Polietileneimina/química , Polietileneimina/metabolismo , Puntos Cuánticos/efectos de la radiación , Nanomedicina Teranóstica/métodosRESUMEN
Herein we describe fluorescence resonance energy transfer (FRET) for a pH/redox-activatable fluorescent carbon dot (FNP) to realize "off-on" switched imaging-guided controllable photothermal therapy (PTT). The FNP is a carbonized self-crosslinked polymer that allows IR825 loading (FNP[IR825]) via hydrophobic interactions for cancer therapy. Fluorescence bioimaging was achieved by the internalization of FNP(IR825) into tumor cells, wherein glutathione (GSH) disulfide bonds are reduced, and benzoic imine groups are cleaved under acidic conditions. The release of IR825 from the FNP core in this system may be used to efficiently control PTT-mediated cancer therapy via its photothermal conversion after near-infrared (NIR) irradiation. In vitro and in vivo cellular uptake studies revealed efficient uptake of FNP(IR825) by tumor cells to treat the disease site. In this way we demonstrated in mice that our smart nanocarrier can effectively kill tumor cells under exposure to a NIR laser, and that the particles are biocompatible with various organs. This platform responds sensitively to the exogenous environment inside the cancer cells and may selectively induce the release of PTT-mediated cytotoxicity. Furthermore, this platform may be useful for monitoring the elimination of cancer cells through the fluorescence on/off switch, which can be used for various applications in the field of cancer cell therapy and diagnosis.
Asunto(s)
Benzoatos/uso terapéutico , Colorantes/uso terapéutico , Preparaciones de Acción Retardada/química , Indoles/uso terapéutico , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Puntos Cuánticos/química , Animales , Benzoatos/administración & dosificación , Carbono/química , Línea Celular Tumoral , Colorantes/administración & dosificación , Perros , Femenino , Transferencia Resonante de Energía de Fluorescencia/métodos , Humanos , Concentración de Iones de Hidrógeno , Hipertermia Inducida/métodos , Indoles/administración & dosificación , Rayos Infrarrojos , Células de Riñón Canino Madin Darby , Ratones Endogámicos BALB C , Ratones Desnudos , Imagen Óptica/métodos , Oxidación-Reducción , Fototerapia/métodosRESUMEN
We developed nanoparticles comprising a photothermal dye (IR825)-loaded carbonized zwitterionic polymer [FNP-I] as "switch-on" pH-responsive fluorescence probes to sense intracellular cancer cells and for near-infrared (NIR) controllable photothermal therapy (PTT) in vivo and in vitro. The fluorescent "off" of FNP-I was activated after reaching the cancer cell environment, where the zwitterionic compartment of FNP lost its hydrophobicity to induce PTT-mediated heat release of IR825 under NIR irradiation in the tumor. Approximately 100% of the IR825 was released from the FNP core to generate high thermal conversion to completely kill the cancer cells. Furthermore, after intravenous treatment of FNP-I into MDAMB-231-cell bearing mice, pH-responsive photothermal therapy was observed, achieving marked ablation of tumor cells with release of IR825 under tumor environment conditions. In addition, fluorescent signals were clearly found at the tumor site after 3 h, decreasing at the 6 h time point. The in vitro and in vivo detection system demonstrated good cellular uptake and biocompatibility as a potential imaging-guided photothermal therapy nanotool for cancer treatment. Interestingly, the synergism of the biosensor and PTT in single FNP-I platform led to more effective cancer cell killing than either monotherapy, providing a new approach for cancer treatment.