RESUMEN
Cisplatin continues to be one of the frontline cytotoxic drugs. However, cisplatin-induced acute kidney injury (AKI) remains a major unmet medical need without any approved pharmacological interventions. The involvement of reactive oxygen species generation and activation of inflammatory and apoptotic pathways in the pathogenesis of cisplatin-induced AKI prompts the use of natural anti-inflammatory compounds. In this context, resolution of inflammation using natural antioxidant and anti-inflammatory such as urolithin A (UA) could prove beneficial. In the end, testing such combinations in models to eliminate the possibility that UA stimulates tumor growth or compromises the potency of cisplatin could prove useful for clinical translation of adjuvant therapies.
Asunto(s)
Lesión Renal Aguda , Nanopartículas , Humanos , Cisplatino/efectos adversos , Riñón/patología , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Antiinflamatorios/uso terapéutico , Apoptosis , Estrés OxidativoRESUMEN
Here we report that reactive oxygen species (ROS) can reprogram cancer cells to increase the expression of specific receptors and modulate the delivery of nanomaterials. Gold and γ-polyglutamic acid (γ-PGA) hybrid nanoparticles (PGANP) were prepared via a facile single-step process. Gold nanoclusters in PGANP were dispersed within the tangled γ-PGA matrix of the nanoparticles. The condensed assembly of gold nanoclusters in γ-PGA matrix enabled the interparticle plasmon coupling effect, which lacks in single gold nanoparticles. Compared with gold nanoparticles of the similar sizes, PGANP showed significantly higher absorbance at near infrared (NIR) wavelength and light-to-heat converting ratios, resulting in greater temperature increase upon NIR light irradiation. Pretreatment of HeLa cancer cells with methylene blue (MB) generated reactive oxygen species. The ROS reprogrammed the cancer cells to express higher cell membrane levels of gamma glutamyl transferase (GGT), which is known to bind to γ-PGA of PGANP. MB pretreatment significantly enhanced delivery of PGANP to cancer cells. Cancer cells internalized PGANP to a greater extent and, were highly susceptible to irradiation with NIR light, which reduced cell viability to near zero. In vivo, MB pretreatment of HeLa xenograft mice increased the expression of GGT in tumor tissues. In mice pretreated with MB and exposed to NIR irradiation, PGANP treatment resulted in complete tumor ablation. The strategy of actively reprogramming tumor membrane levels of target receptors could be widely applied to overcome the heterogeneity of cancer cells. Although we used interparticle plasmon coupling effect-based PGANP for proving the concept of receptor-modulated delivery, this strategy could be broadly applicable to the active modulation of the receptor-mediated delivery of anticancer nanomaterials.
Asunto(s)
Hipertermia Inducida , Nanopartículas del Metal , Nanopartículas , Nanoestructuras , Animales , Línea Celular Tumoral , Oro , Células HeLa , Humanos , RatonesRESUMEN
Tissue-specific delivery of therapeutic RNAi has great potential for clinical applications. Receptor-mediated endocytosis plays a crucial role in targeted delivery of biotherapeutics including short interfering RNA (siRNA). Previously we reported a novel Curdlan-based nanoparticle for intracellular delivery of siRNA. Here we designed a nanoparticle based on ligand-functionalized Curdlan. Disaccharides were site-specifically conjugated to 6-deoxy-6-amino Curdlan, and the cell line specificity, cellular uptake, cytotoxicity, and siRNA delivery efficiency of the corresponding disaccharide-modified 6-deoxy-6-amino-Curdlan were investigated. Observation by fluorescence microscopy as well as flow cytometry showed that galactose-containing Curdlan derivatives delivered fluorescently labeled short nucleic acid to HepG2 cells expressing ASGPR receptor but not in other cells lacking surface ASGPR protein. Moreover, highly galactose-substituted Curdlan derivatives delivered siRNA specifically to ASGPR-expressing cells and induced RNAi activities, silencing endogenous GAPDH gene expression. Our data demonstrated that galactose-functionalized 6-deoxy-6-amino-Curdlan is a promising carrier for short therapeutic nucleic acids for clinical applications.
Asunto(s)
Receptor de Asialoglicoproteína/metabolismo , Técnicas de Transferencia de Gen , Nanopartículas/química , Interferencia de ARN , beta-Glucanos/química , Tampones (Química) , Espectroscopía de Resonancia Magnética con Carbono-13 , Muerte Celular , Ensayo de Cambio de Movilidad Electroforética , Citometría de Flujo , Células Hep G2 , Humanos , Ligandos , Microscopía Fluorescente , Nanopartículas/toxicidad , Tamaño de la Partícula , ARN Interferente Pequeño/metabolismo , Electricidad Estática , beta-Glucanos/toxicidadRESUMEN
Lanreotide is an octapeptide analog of endogenous somatostatin, specifically binding with tumors over-express somatostatin receptor 2 (SSTR2). In this study, we conjugated lanreotide to 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (poly-(ethylene glycol))-2000] (PEG-DSPE), constructed active targeted micelles (lanreotide-PM), characterized their in vitro and in vivo targeting effect, and explored the receptor mediated transportion. The uptake of lanreotide-PM was found to be related to the expression level of SSTR2 in different cell lines and the competitive inhibition phenomenon indicated that the cellular uptake of lanreotide-PM was via a receptor meditated mechanism. In vivo, more lanreotide-PM accumulated in SSTR2 high expression tumor xenografts, endocytosed by the tumor cells, induced more apoptosis of tumor cells, and suppressed tumor growth efficiently. In conclusion, lanreotide-modified micelles containing antitumor drugs provide a promising strategy for the treatment of SSTR-expressing tumors.