RESUMEN
Nitric oxide (NO) molecular messenger can reverse the multidrug resistance (MDR) effect of cancer cells through reducing P-glycoprotein (P-gp) expression, beneficial for creating a favorable microenvironment for the treatment of doxorubicin (Dox)-resistant cancer cells. Development of sophisticated nanosystems to programmably release NO and Dox becomes an efficient strategy to overcome the MDR obstacles and achieve promising therapeutic effects in Dox-resistant cancer. Herein, a NO stimulated nanosystem was designed to engineer a significant time gap between NO and Dox release, promoting MDR cancer therapy. A o-phenylenediamine-containing lipid that can hydrolyze in response to NO was embedded in the phospholipid bilayer structure of liposome to form NO-responsive liposome, which could further encapsulate l-arginine (l-Arg)/Dox-loaded gold@copper sulfide yolk-shell nanoparticls (ADAu@CuS YSNPs) to form ADLAu@CuS YSNPs. Under 808 nm laser irradiation, the unique resonant energy transfer (RET) process and reactive oxygen species (ROS) generation in the confined space of ADLAu@CuS YSNPs could effectively convert l-Arg into NO, regionally destabilizing the phospholipid bilayer structure, as a result of NO release. However, at this early stage Dox could not be released from YSNPs due to the molecular scaffold limit. As the NO release progressed, the NO-responsive liposome layer was deteriorated more severely, allowing Dox to escape. This NO and Dox sequential release of ADLAu@CuS YSNPs could significantly inhibit P-gp expression and enhance Dox accumulation in Dox-resistant MCF-7/ADR cells, leading to promising in vitro and in vivo therapeutic effects and presenting their great potential for MDR cancer therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Preparaciones de Acción Retardada/metabolismo , Doxorrubicina/administración & dosificación , Óxido Nítrico/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Liberación de Fármacos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Femenino , Humanos , Liposomas/metabolismo , Células MCF-7 , Nanopartículas/metabolismoRESUMEN
Tumor immunotherapy is a promising strategy to activate the immune system and eliminate tumors. Major histocompatibility complex I (MHC-I) is usually applied to potentiate antigen presentation, but it is associated with upregulation of programmed death ligand 1 (PD-L1) expression, which is unfavorable for activation of immune responses. Moreover, poor permeability of various therapeutic antibodies results in the limited immune response rates of most patients. It is necessary to develop combined small molecule drug delivery systems for simultaneous upregulation of MHC-I expression and downregulation of PD-L1 expression, promoting effective tumor treatment. A moderate dose of doxorubicin hydrochloride (DOX) can induce upregulation of MHC-I expression, while deferasirox (DFX) can inhibit the PI3K-Akt pathway, which potentially downregulates PD-L1 expression. In the present study, we designed a pH-sensitive liposome to incorporate DOX in the hydrophilic cavity and embed DFX in the hydrophobic shell, forming a dual delivery system (DOX-DFXL). In a B16F10 melanoma-bearing mouse model, DOX and DFX were released in acidic tumor microenvironment, which further lead to enhanced antigen presentation and infiltration of T cells into tumor tissues as a result of tumor remission. This codelivery system holds great potential for clinical applications of tumor immunotherapy.
Asunto(s)
Melanoma , Nanopartículas , Animales , Antígeno B7-H1 , Línea Celular Tumoral , Deferasirox , Regulación hacia Abajo , Doxorrubicina , Inmunoterapia/métodos , Liposomas , Complejo Mayor de Histocompatibilidad , Ratones , Nanopartículas/química , Fosfatidilinositol 3-Quinasas , Microambiente Tumoral , Regulación hacia ArribaRESUMEN
Tumor-associated macrophages (TAMs) of M2 phenotype have mediated the immunosuppression in a tumor microenvironment, facilitating the escape of tumor cells from immunosurveillance. Reprograming the immunosuppressive M2 TAMs to immunostimulatory M1 phenotype can activate the antitumor immune responses for cancer immunotherapy. Herein, hollow iron oxide (Fe3O4) nanoparticles (NPs) were employed to reprogram M2 TAMs toward M1 TAMs, aiming to release proinflammatory cytokines and recruit T cells to kill tumor cells. After loaded with l-arginine (l-Arg) and sealed with poly(acrylic acid) (PAA), hollow Fe3O4 NPs were fabricated into LPFe3O4 NPs, which could release l-Arg based on pH-responsive PAA and produce nitric oxide (NO) with the help of nitric oxide synthase (iNOS) overexpressed by M1 TAMs, as a result of additional tumor elimination for gas therapy. In vitro and in vivo studies demonstrate that LPFe3O4 NPs could effectively reprogram M2 to M1 macrophages, activating T cells, releasing TNF-α, and producing high levels of NO, leading to synergistic tumor therapy.
Asunto(s)
Arginina/administración & dosificación , Gases/química , Inmunoterapia/métodos , Macrófagos/inmunología , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapéutico , Neoplasias/tratamiento farmacológico , Microambiente Tumoral , Resinas Acrílicas/química , Animales , Humanos , Macrófagos/enzimología , Macrófagos/metabolismo , Ratones , Neoplasias/inmunología , Neoplasias/patología , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Photochemotherapy is currently an effective anticancer therapy. Recently, it has been reported that cancer cells pretreated with epidermal growth factor receptor (EGFR) inhibitor erlotinib (Erl) can significantly synergize its apoptosis against the DNA damaging agent doxorubicin (Dox). As a result, we designed two gold nanocages (Au NCs) microcontainers covered with different smart polymer shell-PAA (pH responsive) and p (NIPAM-co-AM) (temperature responsive) containing Erl and Dox respectively. The acidic tumor microenvironment and NIR light irradiation can selectively activate the release of Erl and Dox. Time staggered release of Erl and Dox and photothermal therapy enhance the apoptotic signaling pathways, resulting in improved tumor cell killing in both MCF-7 (low EGFR expression) and A431 (very high EGFR expression) tumor cells, but more efficient in the latter. The photochemotherapy strategy controls the order and duration of drug exposure precisely in spatial and temporal, and significantly improves the therapeutic efficacy against high EGFR expressed tumors.
Asunto(s)
Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Clorhidrato de Erlotinib/farmacología , Oro/química , Hipertermia Inducida , Nanopartículas del Metal/química , Fototerapia , Polímeros/química , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Receptores ErbB/metabolismo , Femenino , Humanos , Concentración de Iones de Hidrógeno , Rayos Infrarrojos , Células MCF-7 , Nanopartículas del Metal/ultraestructura , Ratones Endogámicos BALB C , Ratones Desnudos , Temperatura , Factores de TiempoRESUMEN
A novel recognition element of molecularly imprinted films (MIFs) was synthesized by wet phase inversion (WPI) on the surface of Ti/TiO2 electrode for highly selective and sensitive electrochemical detection of bisphenol A (BPA). The Ti/TiO2/MIFs sensor was constructed by casting the precursor poly(acrylonitrile-co-acrylic acid) (p(AN-co-AA)) in dimethyl sulfoxide containing template molecule BPA onto the electrode and then immersing into water, resulting in simultaneous p(AN-co-AA) precipitation and BPA imprinting via the facile WPI. The imprinted sites could selectively rebind BPA through hydrogen bonding and hence lead to the equalizing current increase in amperometric detection, by which the BPA could be sensed electrochemically. Accordingly, the Ti/TiO2/MIFs sensor offered a favorable linearity within the wide range over five orders of magnitude (4.4nM-0.13mM), and a low detection limit down to 1.3nM. Excellent recognition selectivity for BPA was also attained over its analogues. Furthermore, this sensor was successfully applied to detect BPA in seawater and paper cup samples, and high recoveries were 86-110% with low relative standard deviations of 1.3-3.2%. By using BPA as a model, the MIFs-based method may provide a facile, rapid, and cost-effective way for ultrasensitive electrochemical measurements of various targeted compounds with good applicability to WPI.
Asunto(s)
Compuestos de Bencidrilo/análisis , Fenoles/análisis , Contaminantes Químicos del Agua/análisis , Resinas Acrílicas/química , Compuestos de Bencidrilo/química , Técnicas Electroquímicas , Embalaje de Alimentos , Enlace de Hidrógeno , Impresión Molecular , Papel , Fenoles/química , Agua de Mar/análisis , Titanio/química , Contaminantes Químicos del Agua/químicaRESUMEN
Zipper-like thermoresponsive molecularly imprinted polymers (MIPs) were prepared based on interpolymer complexation via the synergy of dual functional monomers of acrylamide (AAm) and 2-acrylamide-2-methyl propanesulfonic acid (AMPS) for selective recognition and extraction of estradiol (E2) by temperature regulation. The resulting E2-MIPs attained controlled adsorption and release of E2 in response to temperature change, with higher adsorption capacity (8.78mg/g) and stronger selectivity (imprinting factor was 3.18) at 30°C compared with that at 20 and 40°C; the zipper-like interpolymer interaction between poly(AAm) and poly(AMPS) enabled switchable molecular recognition. The adsorption processes obeyed Langmuir isotherm and pseudo-second-order kinetic models. High recognition selectivity of the MIPs toward E2 was achieved over its structural analogues, and good reusability was displayed over 86% recovery after six adsorption-desorption cycles. Accordingly, the E2-MIPs were empolyed as new adsorbents for selective dispersive solid-phase extraction of E2, and offered low limits of detection and quantification of 4.81 and 16.03µg/L, respectively. Recoveries from goat milk samples ranged from 76.2% to 89.7% with the precisions (relative standard deviations, n = 3, %) of 2.8-3.7% at 30°C. The intelligent E2-MIPs combining good adsorption, special recognition and temperature sensitivity proved to be a promising alternative to the selective identification and controlled extraction/removal of E2 in complicated samples by simple temperature-responsive regulation.
Asunto(s)
Resinas Acrílicas/química , Estradiol/análisis , Impresión Molecular , Polímeros/química , Ácidos Sulfónicos/química , Adsorción , Animales , Estradiol/química , Cabras , Leche/química , Extracción en Fase Sólida , TemperaturaRESUMEN
Novel multi-template molecularly imprinted polymers (mt-MIPs) with six phenolic compounds as the template, namely phenol, 4-chlorophenol (4-CP), 2,4,6-trichlorophenol (2,4,6-TCP), 2,4-dichlorophenol (2,4-DCP), 2-chlorophenol (2-CP) and 2,6-dichlorophenol (2,6-DCP), were prepared by precipitation polymerization and used as the adsorbents of solid-phase extraction (SPE), and coupled with capillary electrophoresis (CE) for the simultaneous selective extraction, separation and determination of trace phenolic compounds in water samples. The resultant mt-MIPs exhibited uniform spherical morphology, large specific surface area and high thermal stability, and offered high selectivity towards the six template phenolic compounds. Various parameters affecting the molecularly imprinted SPE (MISPE) efficiency were investigated in detail, and excellent CE separation was realized within 7min. Good linearity was obtained in the range of 1-200µgL-1 for phenol and 4-CP, and 1-300µgL-1 for 2,4,6-TCP, 2,4-DCP, 2-CP and 2,6-DCP. High sensitivity was attained with low limits of detection and quantification ranging from 0.17 to 0.31µgL-1 and 0.57 to 1.03µgL-1, respectively. Satisfactory recoveries for spiked reservoir water, river water, tannery wastewater and tap water samples were achieved in the range of 82.13-105.63% with relative standard deviations within 1.68-6.96%. The developed MISPE-CE method proved practically feasible for simultaneous selective extraction/enrichment, separation and sensitive determination of multiple targets in complicated aqueous matrices.
Asunto(s)
Electroforesis Capilar/métodos , Impresión Molecular/métodos , Fenoles/aislamiento & purificación , Polímeros/química , Extracción en Fase Sólida/métodos , Agua/química , Adsorción , Precipitación Química , Cromatografía Líquida de Alta Presión/métodos , Concentración de Iones de Hidrógeno , Microscopía Electrónica de Rastreo , Fenoles/análisis , Polimerizacion , Solventes , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Novel nano-sized dummy-surface molecularly imprinted polymers (DSMIPs) on a magnetic graphene oxide (GO-Fe3O4) surface were developed as substrates, using propionamide as a dummy template molecule for the selective recognition and rapid pre-concentration and removal of acrylamide (AM) from food samples. These products showed rapid kinetics, high binding capacity (adsorption at 3.68mg·g-1), and selectivity (imprinting factor α 2.83); the adsorption processes followed the Langmuir-Freundlich isotherm and pseudo-second-order kinetic models. Excellent recognition selectivity toward acrylamide was achieved compared to structural analogs, such as propionic and acrylic acids (selectivity factor ß 2.33, and 2.20, respectively). Moreover, DSMIPs-GO-Fe3O4 was used to quantify acrylamide in food samples, yielding satisfactory recovery (86.7-94.3%) and low relative standard deviation (<4.85%). Thus, our DSMIPs-GO-Fe3O4-based procedure was demonstrated to be a convenient and practical method for the separation, enrichment, and removal of acrylamide from food samples.
Asunto(s)
Acrilamida/análisis , Grafito/química , Calor , Impresión Molecular/métodos , Polímeros/química , Adsorción , Manipulación de AlimentosRESUMEN
Versatile molecularly imprinted polymers (MIPs) have been widely applied to various sample matrices, however, molecular recognition in aqueous media is still difficult. Stimuli-responsive MIPs have received increasing attentions due to their unique feature that the molecular recognition is regulated by specific external stimuli. Herein, water-compatible temperature and magnetic dual-responsive MIPs (WC-TMMIPs) with hydrophilic brushes were prepared via reversible addition-fragmentation chain transfer precipitation polymerization for reversible and selective recognition and extraction of bisphenol A (BPA). Transmission electron microscopy (TEM), Fourier transform infrared spectrometer (FT-IR) and vibrating sample magnetometry (VSM) as characterization methods were used to examine the successful synthesis of polymers, and the resultant WC-TMMIPs showed excellent thermosensitivity and simple rapid magnetic separation. Controlled adsorption and release of BPA by temperature regulation were investigated systematically, and the maximum adsorption and removal efficiency toward BPA in aqueous solutions were attained at 35 °C and 45 °C, respectively, as well as a good recoverability was exhibited with the precision less than 5% through five adsorption-desorption cycles. Phenolic structural analogs were tested and good recognition specificity for BPA was displayed. Accordingly, the WC-TMMIPs were employed as adsorbents for magnetic solid-phase extraction (MSPE) and packed SPE of BPA from seawater samples. Using the two modes followed by HPLC-UV determination, excellent linearity was attained in the range of 0.1-14.5 µM and 1.3-125 nM, with low detection limits of 0.02 µM and 0.18 nM, respectively. Satisfactory recoveries for spiked seawater samples were achieved ranging from 86.3-103.5% and 96.2-104.3% with RSD within 2.12-4.33%. The intelligent WC-TMMIPs combining water-compatibility, molecular recognition, magnetic separation, and temperature regulation proved potentially applicable for selective identification, controlled adsorption/release and high-efficiency enrichment/removal of trace targets in complicated aqueous media.