RESUMO
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.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Preparações de Ação Retardada/metabolismo , Doxorrubicina/administração & dosagem , Óxido Nítrico/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Lipossomos/metabolismo , Células MCF-7 , Nanopartículas/metabolismoRESUMO
Poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers were synthesized and characterized for tumor localization in vivo as a theranostic scaffold for cancer imaging and anticancer drug delivery targeting tumor angiogenesis. Tumor localization of the poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers was visualized in mice bearing human prostate cancer xenografts by positron emission tomography (PET) using a microPET scanner. PET quantitative analysis demonstrated that tumor 64Cu radioactivity (2.75 ± 0.34 %ID/g) in tumor-bearing mice 3 hours following intravenous injection of the poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers was significantly higher than the tumor 64Cu radioactivity (1.29 ± 0.26 %ID/g) in tumor-bearing mice injected with the nontargeted poly(HPMA)-DOTA-64Cu copolymers (p = .004). The poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers hold potential as a theranostic scaffold for cancer imaging and radiochemotherapy of prostate cancer targeting tumor angiogenesis by noninvasive tracking with PET.
Assuntos
Radioisótopos de Cobre/química , Compostos Heterocíclicos com 1 Anel/química , Metacrilatos/química , Neovascularização Patológica/diagnóstico , Polímeros/síntese química , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico , Animais , Humanos , Masculino , Camundongos , Polímeros/químicaRESUMO
We compared the use of bovine serum albumin (BSA) and pluronic F108 (PF108) as dispersants for multiwalled carbon nanotubes (MWCNTs) in terms of tube stability as well as profibrogenic effects in vitro and in vivo. While BSA-dispersed tubes were a potent inducer of pulmonary fibrosis, PF108 coating protected the tubes from damaging the lysosomal membrane and initiating a sequence of cooperative cellular events that play a role in the pathogenesis of pulmonary fibrosis. Our results suggest that PF108 coating could serve as a safer design approach for MWCNTs.
Assuntos
Materiais Revestidos Biocompatíveis/química , Lisossomos/efeitos dos fármacos , Lisossomos/patologia , Nanotubos de Carbono/toxicidade , Poloxâmero/química , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , Administração por Inalação , Animais , Camundongos , Fibrose Pulmonar/patologiaRESUMO
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.
Assuntos
Melanoma , Nanopartículas , Animais , Antígeno B7-H1 , Linhagem Celular Tumoral , Deferasirox , Regulação para Baixo , Doxorrubicina , Imunoterapia/métodos , Lipossomos , Complexo Principal de Histocompatibilidade , Camundongos , Nanopartículas/química , Fosfatidilinositol 3-Quinases , Microambiente Tumoral , Regulação para CimaRESUMO
Immunotherapy efficacy has been limited by tumor-associated macrophages (TAMs), which are the most abundant immune regulatory cells infiltrating around tumor tissues. The repolarization of pro-tumor M2 TAMs to anti-tumor M1 TAMs is a very promising immunotherapeutic strategy for cancer therapy. In this manuscript, multifunctional 2D iron-based nanosheets (FeNSs) are synthesized via a simple hydrothermal method for the first time, which not only possess photothermal and photodynamic properties, but also can repolarize TAMs from M2 to M1. After modifying with polyethylene glycol and loading with bioreductive prodrug banoxantrone (AQ4N), abbreviated as AP FeNSs, it can effectively repolarize TAMs from M2 to M1 and deliver AQ4N to tumor microenvironment (TME). Moreover, the repolarized M1 TAMs overexpress inducible nitric oxide synthase, which can convert nontoxic AQ4N to cytotoxic AQ4 under hypoxic TME, enabling immunomodulation-activated chemotherapy. A series of in vitro and in vivo results corroborate that AP FeNSs effectively exert photothermal and photodynamic effects and repolarize M2 TAMs to M1 TAMs, releasing inflammatory factors and activating the chemotherapeutic effect, thereby realizing synergistic tumor therapy.
Assuntos
Neoplasias , Pró-Fármacos , Antraquinonas , Humanos , Fatores Imunológicos/farmacologia , Imunoterapia/métodos , Ferro/farmacologia , Macrófagos , Neoplasias/tratamento farmacológico , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/farmacologia , Fototerapia , Polietilenoglicóis/farmacologia , Pró-Fármacos/farmacologia , Microambiente TumoralRESUMO
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.
Assuntos
Arginina/administração & dosagem , Gases/química , Imunoterapia/métodos , Macrófagos/imunologia , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Neoplasias/tratamento farmacológico , Microambiente Tumoral , Resinas Acrílicas/química , Animais , Humanos , Macrófagos/enzimologia , Macrófagos/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Silver (Ag)-based nanoparticles (NPs) with a high potential of Ag+ release have been known to be capable of promoting bacteria inactivation and the wound healing process; however, keeping a steady flux of high levels of Ag+ in Ag-based NPs is still challenging. Herein, a novel strategy in terms of altering the intrinsic electronic structure of Ag NPs was attempted to facilitate Ag oxidation and boost the Ag+ flux, as results of improved antibacterial and wound healing performance of Ag NPs. Gold (Au), platinum (Pt), and palladium (Pd) were doped into Ag NPs to tune their d band centers to upshift toward the Fermi level, and the formed Pd-Ag alloy NPs showed the largest shift, followed by Pt-Ag and Au-Ag NPs, as determined by density function theory calculation and ultraviolet photoemission spectroscopy measurement. Further X-ray photoelectron spectroscopy analysis indicates that a larger upshift could induce less electron filling in the antibonding orbital and a higher Ag oxidation level, leading to the more remarkable Ag+ release as determined by inductively coupled plasma optical emission spectrometry. All these alloy Ag NPs could more efficiently inhibit bacterial growth and accelerate the wound healing process than pure Ag NPs, and their antibacterial activity and wound healing performance were progressively proportional to the upshift values of the d band center. Taken together, tuning the d band center to upshift toward the Fermi level becomes a feasible strategy for designing therapeutic Ag-based NPs with a promising antibacterial and wound healing performance.
Assuntos
Ligas , Antibacterianos , Nanopartículas Metálicas , Prata , Cicatrização/efeitos dos fármacos , Ligas/química , Ligas/farmacocinética , Ligas/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Feminino , Ouro/química , Ouro/farmacologia , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Paládio/química , Paládio/farmacologia , Prata/química , Prata/farmacocinética , Prata/farmacologiaRESUMO
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.
Assuntos
Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Cloridrato de Erlotinib/farmacologia , Ouro/química , Hipertermia Induzida , Nanopartículas Metálicas/química , Fototerapia , Polímeros/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Receptores ErbB/metabolismo , Feminino , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Células MCF-7 , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Nus , Temperatura , Fatores de TempoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) elicits a dense stromal response that blocks vascular access because of pericyte coverage of vascular fenestrations. In this way, the PDAC stroma contributes to chemotherapy resistance in addition to causing other problems. In order to improve the delivery of gemcitabine, a first-line chemotherapeutic agent, a PEGylated drug-carrying liposome was developed, using a transmembrane ammonium sulfate gradient to encapsulate the protonated drug up to 20% w/w. However, because the liposome was precluded from entering the xenograft site due to the stromal interference, we developed a first-wave nanocarrier that decreases pericyte coverage of the vasculature through interference in the pericyte recruiting TGF-ß signaling pathway. This was accomplished using a polyethyleneimine (PEI)/polyethylene glycol (PEG)-coated mesoporous silica nanoparticle (MSNP) for molecular complexation to a small molecule TGF-ß inhibitor, LY364947. LY364947 contains a nitrogen atom that attaches, through H-bonding, to PEI amines with a high rate of efficiency. The copolymer coating also facilitates systemic biodistribution and retention at the tumor site. Because of the high loading capacity and pH-dependent LY364947 release from the MSNPs, we achieved rapid entry of IV-injected liposomes and MSNPs at the PDAC tumor site. This two-wave approach provided effective shrinkage of the tumor xenografts beyond 25 days, compared to the treatment with free drug or gemcitabine-loaded liposomes only. Not only does this approach overcome stromal resistance to drug delivery in PDAC, but it also introduces the concept of using a stepwise engineered approach to address a range of biological impediments that interfere in nanocancer therapy in a spectrum of cancers.
Assuntos
Desoxicitidina/análogos & derivados , Nanomedicina/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Colágeno/química , Desoxicitidina/administração & dosagem , Desoxicitidina/química , Portadores de Fármacos , Combinação de Medicamentos , Células Endoteliais/citologia , Feminino , Humanos , Laminina/química , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Transplante de Neoplasias , Polietilenoglicóis/química , Polietilenoimina/química , Proteoglicanas/química , Transdução de Sinais , Dióxido de Silício/química , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/antagonistas & inibidores , GencitabinaRESUMO
Three-dimensional (3D) cellular assays closely mimic the in vivo milieu, providing a rapid, inexpensive system for screening drug candidates for toxicity or efficacy in the early stages of drug discovery. However, 3D culture systems may suffer from mass transfer limitations, particularly in delivery of large polypeptide or nucleic acid compounds. Nucleic acids (e.g., genes, silencing RNA) are of particular interest both as potential therapeutics and due to a desire to modulate the gene-expression patterns of cells exposed to small-molecule pharmacological agents. In the present study, polyethylenimine (PEI)-coated superparamagnetic nanoparticles (SPMNs) were designed to deliver interfering RNA and green fluorescent protein (GFP) plasmids through a collagen-gel matrix into 3D cell cultures driven by an external magnetic field. The highest transfection efficiency achieved was 64% for siRNA and 77% for GFP plasmids. Delivery of an shRNA plasmid against GFP by PEI-coated SPMNs silenced the GFP expression with 82% efficiency. We further demonstrated that this delivery approach could be used for screening interfering RNA constructs for therapeutic or toxic effects for cells grown in 3D cultures. Four known toxic shRNA plasmids were delivered by PEI-coated SPMNs into 3D cell cultures, and significant toxicities (41-51% cell death) were obtained.