RESUMEN
Targeted drug delivery systems that combine imaging and therapeutic functions in a single structure have become very popular in nanomedicine. Near-infrared (NIR) emitting Ag2S quantum dots (QDs) are excellent candidates for this task. Here, we have developed PEGylated Ag2S QDs functionalized with Cetuximab (Cet) antibody and loaded with an anticancer drug, 5-fluorouracil (5FU). These theranostic QDs were used for targeted NIR imaging and treatment of lung cancer using low (H1299) and high (A549) Epidermal Growth Factor Receptor (EGFR) overexpressing cell lines. The Cet conjugated QDs effectively and selectively delivered 5FU to A549 cells and provided significantly enhanced cell death associated with apoptosis. Interestingly, while treatment of cells with free 5FU activated autophagy, a cellular mechanism conferring resistance to cell death, these EGFR targeting multimodal QDs significantly overcame drug resistance compared to 5FU treatment alone. The improved therapeutic outcome of 5FU delivered to A549 cells by Cet conjugated Ag2S QDs is suggested as the synergistic outcome of enhanced receptor mediated uptake of nanoparticles, and hence the drug, coupled with suppressed autophagy even in the absence of addition of an autophagy suppressor.
Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos , Fluorouracilo/administración & dosificación , Neoplasias Pulmonares/metabolismo , Compuestos de Plata/química , Células A549 , Autofagia , Muerte Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cetuximab/administración & dosificación , Receptores ErbB/genética , Humanos , Imidazoles/química , Neoplasias Pulmonares/tratamiento farmacológico , Polietilenglicoles/química , Puntos Cuánticos , Nanomedicina TeranósticaRESUMEN
AIM: N-acetyl-L-cysteine (NAC) is a free radical scavenger. We developed NAC-coated Ag2S (NAC-Ag2S) quantum dot (QD) as an optical imaging and therapeutic agent. MATERIALS & METHODS: QDs were synthesized in water. Their optical imaging potential and toxicity were studied in vitro. RESULTS: NAC-Ag2S QDs have strong emission, that is tunable between 748 and 840 nm, and are stable in biologically relevant media. QDs showed significant differences both in cell internalization and toxicity in vitro. QDs were quite toxic to breast and cervical cancer cells but not to lung derived cells despite the higher uptake. NAC-Ag2S reduces reactive oxygen species (ROS) but causes cell death via DNA damage and apoptosis. CONCLUSION: NAC-Ag2S QDs are stable and strong signal-generating theranostic agents offering selective therapeutic effects.
Asunto(s)
Acetilcisteína/química , Antineoplásicos/química , Depuradores de Radicales Libres/química , Sustancias Luminiscentes/química , Puntos Cuánticos/química , Compuestos de Plata/química , Apoptosis/efectos de los fármacos , Transporte Biológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Humanos , Rayos Infrarrojos , Luminiscencia , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Especies Reactivas de Oxígeno/metabolismo , Propiedades de SuperficieRESUMEN
AIM: We aim to develop folic acid (FA)-conjugated cationic Ag2S near-infrared quantum dots (NIRQDs) for the delivery of doxorubicin (DOX) selectively to folate receptor (FR)-positive cancer cells to achieve enhanced drug efficacy and optical tracking in the NIR region. MATERIALS & METHODS: Cationic Ag2S NIRQDs were decorated with FA using a PEG bridge and loaded with DOX. In vitro studies were performed on FR-positive human cervical carcinoma cells and FR-negative A549 cells. RESULTS: Significantly higher uptake of DOX by human cervical carcinoma cells cells and a greater therapeutic effect along with a strong intracellular optical signal were obtained with DOX-loaded FA-conjugated Ag2S NIRQDs. CONCLUSION: These Ag2S NIRQDs are promising theranostic nanoparticles for receptor-mediated delivery of DOX with enhanced drug efficacy combined with optical imaging.
Asunto(s)
Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Ácido Fólico/química , Nanoconjugados/química , Puntos Cuánticos/química , Compuestos de Plata/química , Células A549 , Antineoplásicos/química , Apoptosis , Técnicas de Cultivo de Célula , Supervivencia Celular , Doxorrubicina/química , Portadores de Fármacos/química , Liberación de Fármacos , Colorantes Fluorescentes/química , Células HeLa , Humanos , Imagen Óptica/métodos , Tamaño de la Partícula , Polietilenglicoles/química , Propiedades de SuperficieRESUMEN
The development of non-toxic theranostic nanoparticles capable of delivering a therapeutic cargo and providing a means for diagnosis is one of the most challenging tasks in nano-biotechnology. Gene therapy is a very important mode of therapy and polyethyleneimine (PEI) is one of the most successful vehicles for gene transfection, yet poses significant toxicity. Optical imaging utilizing quantum dots is one of the newer but fast growing diagnostic modalities, which requires non-toxic, highly luminescent materials, preferentially active in the near infrared region. Ag2S NIRQDs fit to this profile perfectly. Here, we demonstrate the aqueous synthesis of cationic Ag2S NIRQDs with a mixed coating of 2-mercaptopropionic acid (2MPA) and PEI (branched, 25 kDa), which are highly luminescent in the NIR-I window (λem = 810-840 nm) as new theranostic nanoparticles. Synergistic stabilization of the QD surface via the simultaneous use of a small molecule and a polymeric material provided the highest quantum yield, 150% (with respect to LDS 798 at pH 7.4), reported in the literature for Ag2S. These cationic particles show a dramatic improvement in cytocompatibility even without PEGylation, a strong optical signal easily detected by confocal laser microscopy and effective conjugation and transfection of the green fluorescence protein plasmid (pGFP) to HeLa and MCF-7 cell lines (40% efficiency). Overall, these Ag2S NIRQDs show great potential as new theranostics.