RESUMO
BACKGROUND: Efficient monitoring of glucose concentration in the human body necessitates the utilization of electrochemically active sensing materials in nonenzymatic glucose sensors. However, prevailing limitations such as intricate fabrication processes, lower sensitivity, and instability impede their practical application. Herein, ternary Cu-Co-Ni-S sulfides nanoporous network structure was synthesized on carbon fiber paper (CP) by an ultrafast, facile, and controllable technique through on-step cyclic voltammetry, serving as a superior self-supporting catalytic electrode for the high-performance glucose sensor. RESULTS: The direct growth of free-standing Cu-Co-Ni-S on the interconnected three-dimensional (3D) network of CP boosted the active site of the composites, improved ion diffusion kinetics, and significantly promoted the electron transfer rate. The multiple oxidation states and synergistic effects among Co, Ni, Cu, and S further promoted glucose electrooxidation. The well-architected Cu-Co-Ni-S/CP presented exceptional electrocatalytic properties for glucose with satisfied linearity of a broad range from 0.3 to 16,000 µM and high sensitivity of 6829 µA mM- 1 cm- 2. Furthermore, the novel sensor demonstrated excellent selectivity and storage stability, which could successfully evaluate the glucose levels in human serum. Notably, the novel Cu-Co-Ni-S/CP showed favorable biocompatibility, proving its potential for in vivo glucose monitoring. CONCLUSION: The proposed 3D hierarchical morphology self-supported electrode sensor, which demonstrates appealing analysis behavior for glucose electrooxidation, holds great promise for the next generation of high-performance glucose sensors.
Assuntos
Técnicas Biossensoriais , Fibra de Carbono , Cobalto , Cobre , Técnicas Eletroquímicas , Eletrodos , Níquel , Sulfetos , Cobre/química , Níquel/química , Catálise , Humanos , Cobalto/química , Técnicas Eletroquímicas/métodos , Técnicas Biossensoriais/métodos , Sulfetos/química , Fibra de Carbono/química , Glucose/análise , Glucose/química , Nanoporos , Oxirredução , Glicemia/análiseRESUMO
BACKGROUND: Although cisplatin-based chemotherapy has been used as the first-line treatment for ovarian cancer (OC), tumor cells develop resistance to cisplatin during treatment, causing poor prognosis in OC patients. Studies have demonstrated that overactivation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is involved in tumor chemoresistance and that overexpression of microRNA-497 (miR497) may overcome OC chemotherapy resistance by inhibiting the mTOR pathway. However, the low transcriptional efficiency and unstable chemical properties of miR497 limit its clinical application. Additionally, triptolide (TP) was confirmed to possess a superior killing effect on cisplatin-resistant cell lines, partially through inhibiting the mTOR pathway. Even so, the clinical applications of TP are restricted by serious systemic toxicity and weak water solubility. RESULTS: Herein, whether the combined application of miR497 and TP could further overcome OC chemoresistance by synergically suppressing the mTOR signaling pathway was investigated. Bioinspired hybrid nanoparticles formed by the fusion of CD47-expressing tumor exosomes and cRGD-modified liposomes (miR497/TP-HENPs) were prepared to codeliver miR497 and TP. In vitro results indicated that the nanoparticles were efficiently taken up by tumor cells, thus significantly enhancing tumor cell apoptosis. Similarly, the hybrid nanoparticles were effectively enriched in the tumor areas and exerted significant anticancer activity without any negative effects in vivo. Mechanistically, they promoted dephosphorylation of the overactivated PI3K/AKT/mTOR signaling pathway, boosted reactive oxygen species (ROS) generation and upregulated the polarization of macrophages from M2 to M1 macrophages. CONCLUSION: Overall, our findings may provide a translational strategy to overcome cisplatin-resistant OC and offer a potential solution for the treatment of other cisplatin-resistant tumors.
Assuntos
Exossomos , MicroRNAs , Nanopartículas , Neoplasias Ovarianas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Diterpenos , Resistencia a Medicamentos Antineoplásicos , Compostos de Epóxi , Exossomos/metabolismo , Humanos , Lipossomos/farmacologia , MicroRNAs/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Fenantrenos , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
BACKGROUND: Multidrug resistance (MDR) is a pressing obstacle in clinical chemotherapy for breast cancer. Based on the fact that the drug efflux is an important factor in MDR, we designed a codelivery system to guide the drug efflux inhibitor verapamil (VRP) and the chemotherapeutic agent novantrone (NVT) synergistically into breast cancer cells to reverse MDR. RESULTS: This co-delivery system consists of following components: the active targeting peptide RGD, an inorganic calcium phosphate (CaP) shell and an organic inner core. VRP and NVT were loaded into CaP shell and phosphatidylserine polyethylene glycol (PS-PEG) core of nanoparticles (NPs) separately to obtain NVT- and VRP-loaded NPs (NV@CaP-RGD). These codelivered NPs allowed VRP to prevent the efflux of NVT from breast cancer cells by competitively combining with drug efflux pumps. Additionally, NV@CaP-RGD was effectively internalized into breast cancer cells by precise delivery through the effects of the active targeting peptides RGD and EPR. The pH-triggered profile of CaP was also able to assist the NPs to successfully escape from lysosomes, leading to a greatly increased effective intracellular drug concentration. CONCLUSION: The concurrent administration of VRP and NVT by organic/inorganic NPs is a promising therapeutic approach to reverse MDR in breast cancer.
Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Mitoxantrona/química , Nanocápsulas/química , Verapamil/química , Animais , Fosfatos de Cálcio/química , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Quimioterapia Combinada/métodos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitoxantrona/farmacologia , Terapia de Alvo Molecular , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Fosfatidilserinas/química , Polietilenoglicóis/química , Verapamil/metabolismoRESUMO
Primary hepatocellular carcinoma (HCC) is a common malignant tumor. Surgery is the main treatment, but HCC patients have a potential risk of tumor recurrence. Besides, many limitations arise during the application of single first-line antitumor drugs. Here, we selected Pluronic F-127 and sodium alginate (SA) to prepare a thermosensitive gel (Gel). The optimal synergistic ratio of PTX and DOX on the SMMC-7721 cells was 1: 2 (w/w), calculated by the Chou-Talalay analysis. Then, PTX and DOX coloaded liposomes (PD-LPs) with such drugs ratios presented enhanced anticancer ability in vitro. Upon local injection, the PD-LPs Gel formed a nanoparticles reservoir at tumor via sol-gel transformation, while exhibiting a long-term effective anti-tumor ability in vivo. The relative tumor volume after the PD-LPs Gel treatment was reduced over 62%. Effective mitochondria related apoptosis induction was observed. Therefore, the local delivery of PD-LPs Gel can be a promising alternative method for the HCC therapy.
Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular , Doxorrubicina , Neoplasias Hepáticas Experimentais , Mitocôndrias Hepáticas , Nanocompostos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Humanos , Lipossomos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Nanocompostos/química , Nanocompostos/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In general, atherosclerosis is considered to be a form of chronic inflammation. Dexamethasone has anti-inflammatory effects in atherosclerosis, but it was not considered for long-term administration on account of a poor pharmacokinetic profile and adverse side effects. Nanoparticles in which drugs can be dissolved, encapsulated, entrapped or chemically attached to the particle surface have abilities to incorporate dexamethasone and to be used as controlled or targeted drug delivery system. Long circulatory polymeric nanoparticles present as an assisting approach for controlled and targeted release of the encapsulated drug at the atherosclerotic site. Polymeric nanoparticles combined with ultrasound (US) are widely applied in cancer treatment due to their time applications, low cost, simplicity, and safety. However, there are few studies on atherosclerosis treatment using polymeric nanoparticles combined with US. In this study, targeted dexamethasone acetate (DA)-loaded poly (lactide-glycolide)-polyethylene glycol-cRGD (PLGA-PEG-cRGD) nanoparticles (DA-PLGA-PEG-cRGD NPs) were prepared by the emulsion-evaporation method using cRGD modified PLGA-PEG polymeric materials (PLGA-PEG-cRGD) prepared as the carrier. The average particle size of DA-PLGA-PEG-cRGD NPs was 221.6 ± 0.9 nm. Morphology of the nanoparticles was spherical and uniformly dispersed. In addition, the DA released profiles suggested that ultrasound could promote drug release from the nanocarriers and accelerate the rate of release. In vitro, the cellular uptake process of fluorescein isothiocyanate (FITC)@DA-PLGA-PEG-cRGD NPs combined with US into the damaged human umbilical vein endothelial cells (HUVECs) indicated that US promoted rapid intracellular uptake of FITC@DA- PLGA-PEG-cRGD NPs. The cell viability of DA-PLGA-PEG-cRGD NPs combined with US reached 91.9% ± 0.2%, which demonstrated that DA-PLGA-PEG-cRGD NPs combined with US had a positive therapeutic effect on damaged HUVECs. Overall, DA-PLGA-PEG-cRGD NPs in combination with US may provide a promising drug delivery system to enhance the therapeutic effects of these chemotherapeutics at the cellular level.
Assuntos
Dexametasona/análogos & derivados , Portadores de Fármacos/química , Ácido Láctico/química , Nanopartículas/química , Oligopeptídeos/química , Polietilenoglicóis/química , Ácido Poliglicólico/química , Sobrevivência Celular/efeitos dos fármacos , Dexametasona/química , Dexametasona/farmacologia , Liberação Controlada de Fármacos , Fluoresceína-5-Isotiocianato/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipoproteínas LDL/toxicidade , Espectroscopia de Ressonância Magnética , Microscopia Confocal , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , SonicaçãoRESUMO
In a previous study, a novel biodegradable multiblock copolymer, monomethoxy(poly-ethylene glycol)-poly(d,l-lactide-co-glycolide)-poly(l-lysine) (PEAL), was developed as a new drug carrier material. It is imperative to study the biocompatibility and degradation behavior of PEAL to pave the way for clinical applications. Here, we systematically demonstrated that the PEAL copolymer has the appropriate hydrophilicity and biosafety. The degradation rate of the PEAL films was obtained by observing changes in mass, molecular weight (Mw), Mw distribution and degradation products. The degradation rate was observed to have a highly positive correlation with the pH of the medium and negative correlation with the ratio of lactic acid to glycolic acid (LA/GA). Cytotoxicity tests indicated that the degradation products of the copolymer were non-toxic to cells. In zebrafish embryos, the PEAL nanoparticles had no obvious impact on heart rate, production of reactive oxygen species, mortality, or cell apoptosis, and they were observed to have a long circulation time. Therefore, the PEAL copolymer has great potential for use as a drug carrier material.
Assuntos
Portadores de Fármacos/metabolismo , Poliésteres/metabolismo , Polietilenoglicóis/metabolismo , Polilisina/metabolismo , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Linhagem Celular , Ativação do Complemento/efeitos dos fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Nanopartículas/análise , Nanopartículas/química , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/toxicidade , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/toxicidade , Polilisina/química , Polilisina/farmacocinética , Polilisina/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Peixe-ZebraRESUMO
In this work, we have reported the preparation and optimization of paclitaxel (PTX) and temozolomide (TMZ) loaded monomethoxy (polyethylene glycol)-poly(D, L-lactide-co-glycolide) (mPEG-PLGA) nanocomposite which is a thermo-sensitive gel delivery system to glioblastoma. We utilized the orthogonal design and homogeneous design for the optimal drug-loaded nanoparticles (NPs) and composite gel prescription, respectively. The physicochemical characteristics of NPs and rheological properties of the gel were analyzed. Then the in vitro release of the gel was determined with a membrane-less diffusion system. Finally, the cytotoxic and apoptosis-inducing effects of the gel on the human malignant glioblastoma cell line U87 and C6 rat glioblastoma cell line were evaluated by MTT and flow cytometry apoptosis assay, respectively. The transmission electron microscopy (TEM) analysis revealed the optimized NPs with a relatively uniform diameter and distribution. The homogeneous design and rheological determination showed that the optimized gel prescription was 250 mg/mL Pluronic F127 (F127), 0.5% hydroxy propyl methylcellulose (HPMC-100M), 0.5% Pluronic F68 (F68), 0.5% sodium alginate (SA) and suitable NPs, which possessed the appropriate gelation behaviors: gelation temperature 28.01 degrees C, gelation time 127.1 s and corrosion speed 0.1892 g/cm2 x hr; and rheological properties: suitable elasticity modulus, viscosity modulus and low phase angle. The in vitro results suggested that the PTX and TMZ were sustainedly released from nanoparticles or the composite gel, and the release and elimination time greatly prolonged; and the composite gel possessed much higher growth-inhibiting effect and apoptosis-inducing rate in U87 and C6 cells than other formulations. These findings demonstrated that the optimal gel was a promising delivery system for the interstitial chemotherapy to glioblastoma.
Assuntos
Dacarbazina/análogos & derivados , Portadores de Fármacos/química , Glioblastoma/tratamento farmacológico , Nanocompostos/química , Paclitaxel/farmacologia , Animais , Linhagem Celular Tumoral , Dacarbazina/farmacologia , Humanos , Poliésteres/química , Polietilenoglicóis/química , Ratos , TemozolomidaRESUMO
The prostate specific membrane antigen (PSMA) is broadly overexpressed on prostate cancer (PCa) cell surfaces. In this study, we report the synthesis, characterization, in vitro binding assay, and in vivo magnetic resonance imaging (MRI) evaluation of PSMA targeting superparamagnetic iron oxide nanoparticles (SPIONs). PSMA-targeting polypeptide CQKHHNYLC was conjugated to SPIONs to form PSMA-targeting molecular MRI contrast agents. In vitro studies demonstrated specific uptake of polypeptide-SPIONs by PSMA expressing cells. In vivo MRI studies found that MRI signals in PSMA-expressing tumors could be specifically enhanced with polypeptide-SPION, and further Prussian blue staining showed heterogeneous deposition of SPIONs in the tumor tissues. Taken altogether, we have developed PSMA-targeting polypeptide-SPIONs that could specifically enhance MRI signal in tumor-bearing mice, which might provide a new strategy for the molecular imaging of PCa.
Assuntos
Antígenos de Superfície/química , Compostos Férricos/química , Glutamato Carboxipeptidase II/química , Nanopartículas Metálicas/química , Neoplasias da Próstata/diagnóstico , Animais , Linhagem Celular Tumoral , Meios de Contraste/química , Ferrocianetos/química , Humanos , Ácido Láctico/química , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanotecnologia , Transplante de Neoplasias , Peptídeos/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Neoplasias da Próstata/patologia , Ligação Proteica , Transdução de SinaisRESUMO
Pluronic-poly[alpha-(4-aminobutyl)-1-glycolic acid] (Pluronic-PAGA) with different types of Pluronic, the different molecule weight of PAGA, and the different molar ratios of Pluronic to PAGA were synthesized. These materials were bio-degradable, amphiphilic, could be degraded into non-toxic small molecules and could be used to carry drugs. 5-Fluorouracil (5-Fu) loaded Pluronic-PAGA micelle-like nanoparticles (5-Fu loaded P-PAGA NPs) were prepared by a simple self-assembly method, and characterized by dynamic light scattering, transmission electron microscope. The degradation and release characteristics have also been studied in this paper. With the time passing, the 5-Fu loaded P-PAGA NPs degraded into smaller ones with the similar characteristics of the original NPs. Both the types of Pluronic and the molecule weight of the PAGA affected the releasing progresses. It was found that 5-Fu loaded P-PAGA NPs exhibited high growth inhibitory effect on human gastric cancer cells by MTT assay. The cellular uptake of Rhodamine B loaded P-PAGA NPs was higher than free Rhodamine B. This study suggested that the Pluronic-PAGA with acceptable drug entrapment efficiencies, drug loading efficiencies and tunable release profiles could offer an alternative carrier for 5-Fu delivery and have the potential for the delivery of other anti-tumour drug.
Assuntos
Fluoruracila/administração & dosagem , Fluoruracila/química , Nanocápsulas/administração & dosagem , Nanocápsulas/química , Poloxâmero/química , Ácido Poliglicólico/análogos & derivados , Neoplasias Gástricas/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Difusão , Humanos , Micelas , Peso Molecular , Nanocápsulas/ultraestrutura , Tamanho da Partícula , Ácido Poliglicólico/química , Neoplasias Gástricas/patologia , Resultado do TratamentoRESUMO
Development of high-stability and efficient nonviral vectors with low cytoxicity is important for targeted tumor gene therapy. In this study, cationic polymeric liposomes (CPLs), with similar lipid bilayer structure and high thermal stability, were prepared from polymeric surfactants of quaternized (carboxymethyl)chitosan with different carbon chains (dodecyl, tetradecyl, hexadecyl, and octadecyl). By comparing different factors that influence gene delivery, tetradecyl-quaternized (carboxymethy)chitosan (TQCMC) CPLs, with suitable size (184.4 ± 17.1 nm), ζ potentials (27.5 ± 4.9 mV), and productivity for synthesis TQCMC (weight yield 13.1%), were selected for gene transfection evaluation in various cancer cell lines. Although TQCMC CPLs have lower gene transfection efficiency compared with cationic liposomes (Lipofectamine 2000) in vitro, they displayed higher reporter gene delivery ability for cancer tissues (bearing U87 and SMMC-7721 tumors) in vivo after intravenous injection. TQCMC CPLs also have lower cell cytotoxicity and lower cytokine production or liver injury for BALB/c mice. We conclude that the CPLs are promising gene delivery systems that may be used to target various cancers.
Assuntos
Quitosana/química , Técnicas de Transferência de Genes , Vetores Genéticos/farmacologia , Lipídeos/química , Lipossomos/farmacologia , Neoplasias/tratamento farmacológico , Polímeros/química , Animais , Cátions/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Vetores Genéticos/síntese química , Vetores Genéticos/química , Células Hep G2 , Humanos , Lipossomos/síntese química , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Tamanho da Partícula , Relação Estrutura-Atividade , Propriedades de SuperfícieRESUMO
Calcium phosphate (CaP) has been widely used as the vector for gene transfection in the past three decades. However, clinical application is still not popular due to the poor-controlling of DNA/CaP complexes preparation, cytotoxicity and its low transfection efficiency. In this study, a novel amphipathic octadecyl-quatemized carboxymethyl chitosan (OQCMC) derivative from chitosan was combined with calcium phosphate to synthesize CaP/OQCMC nanoparticles (CaP/OQCMC NPs). The nanoparticles were 122-177 nm in diameter exhibited neutral zeta potential (from -0.115 mV to 0.216 mV), and they were applied as DNA vectors for DNA loading and in vitro transfection. The results showed that CaP/OQCMC NPs displayed high DNA loading capacity and enhanced transfection efficiency with extremely low cytotoxicity. In addition, both CaP and OQCMC are biocompatible and biodegradable, thus the as-prepared CaP/OQCMC NPs are promising in gene delivery.
Assuntos
Fosfatos de Cálcio/química , Quitosana/análogos & derivados , Quitosana/química , Nanopartículas/química , Nanotecnologia/métodos , Transfecção , Animais , Materiais Biocompatíveis/química , Linhagem Celular , DNA/química , Técnicas de Transferência de Genes , Vetores Genéticos , Luz , Camundongos , Microscopia Eletrônica de Transmissão , Modelos Genéticos , Nanocompostos/química , Polímeros/química , Espalhamento de RadiaçãoRESUMO
The nanoparticles (NPs) provide a promising prospect for tumor therapy, and exercise is also becoming readily and accepted as a beneficial adjunct therapy to maintain or enhance quality of life in cancer patients. We investigate the antitumor efficacy of paclitaxel (PT) loaded polylactide/poly(ethylene glycol) NPs (PT-PLA/PEG NPs) under the exercise conditions. Results showed that within the first 7 days, the PT concentration in tumor maintained at a higher level in the PT-PLA/PEG NPs + exercise (PT-PLA/PEG NPs + EX) group as compared with the PT-PLA/PEG NPs group. All the phagocytosis rates of macrophages were significantly decreased below the CON in exercise group. The most significant antitumor effect was observed in PT-PLA/PEG NPs + EX group, demonstrating that the PT-PLA/PEG NPs improved the concentration of PT, and exercise could further increased its therapeutic efficiency for tumor. These researches may provide an effective means for tumor therapy.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Lewis/metabolismo , Neoplasias Pulmonares/metabolismo , Nanopartículas , Paclitaxel/farmacologia , Condicionamento Físico Animal , Poliésteres/química , Polietilenoglicóis/química , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Camundongos , Paclitaxel/administração & dosagemRESUMO
The main purpose of this study was to evaluate the targeting effect of cyclic arginine-glycine-aspartic peptide (cRGD)-modified monomethoxy (polyethylene glycol)-poly (D, L-lactide-co-glycolide)-poly (L-lysine) nanoparticles (mPEG-PLGA-PLL-cRGD NPs) for gastric cancer SGC-7901 cells. We prepared the 5-Fulorouracil (5Fu)-loaded mPEG-PLGA-PLL-cRGD (5Fu/mPEG-PLGA-PLL-cRGD) NPs that had an average particle size of 180 nm and a zeta potential 2.77 mV. The results of cytotoxicity demonstrated the mPEG-PLGA-PLL-cRGD NPs showed the ignorable cytotoxicity and the 5Fu/mPEG-PLGA-PLL-cRGD NPs could significantly enhance the cytotoxicity of 5Fu. In vitro drug release experiments showed that the release of drug was effectively prolonged and sustained. The results of confocal laser scanning microscope (CLSM) and flow cytometer analysis demonstrated that the fluorescence intensity of the SGC-7901 gastric cancer cells treated with Rb/mPEG-PLGA-PLL-cRGD NPs was significantly higher than that treated with Rb, this suggested that Rb/mPEG-PLGA-PLL-cRGD NPs could effectively be internalized by SGC-7901 gastric cancer cells. In summary, the above experimental results illustrate that mPEG-PLGA-PLL-cRGD NPs have great potential to be used as an effective delivery carriers.
Assuntos
Fluoruracila/administração & dosagem , Terapia de Alvo Molecular/métodos , Nanocápsulas/química , Poliésteres/química , Polietilenoglicóis/química , Polilisina/análogos & derivados , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Difusão , Fluoruracila/química , Humanos , Teste de Materiais , Nanocápsulas/administração & dosagem , Peptídeos Cíclicos , Polilisina/química , Resultado do TratamentoRESUMO
Degradation of mRNA by RNA interference is one of the most powerful and specific mechanisms for gene silencing. However, insufficient cellular uptake and poor stability have limited its usefulness. Here, we report efficient delivery of siRNA via the use of biodegradable nanoparticles (NPs) made from monomethoxypoly(ethylene glycol)-poly(lactic-co-glycolic acid)-poly-l-lysine (mPEG-PLGA-PLL) triblock copolymers. Various physicochemical properties of mPEG-PLGA-PLL NPs, including morphology, size, surface charge, siRNA encapsulation efficiency, and in vitro release profile of siRNA from NPs, were characterized by scanning electron microscope, particle size and zeta potential analyzer, and high performance liquid chromatography. The levels of siRNA uptake and targeted gene inhibition were detected in human lung cancer SPC-A1-GFP cells stably expressing green fluorescent protein. Examination of the cultured SPC-A1-GFP cells with fluorescent microscope and flow cytometry showed NPs loading Cy3-labeled siRNA had much higher intracellular siRNA delivery efficiencies than siRNA alone and Lipofectamine-siRNA complexes. The gene silencing efficiency of mPEG-PLGA-PLL NPs was higher than that of commercially available transfecting agent Lipofectamine while showing no cytotoxicity. Thus, the current study demonstrates that biodegradable NPs of mPEG-PLGA-PLL triblock copolymers can be potentially applied as novel non-viral vectors for improving siRNA delivery and gene silencing.
Assuntos
Materiais Biocompatíveis/química , Nanopartículas/metabolismo , Polietilenoglicóis/química , Poliglactina 910/química , RNA Interferente Pequeno/metabolismo , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/toxicidade , Carbocianinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Humanos , Lipídeos/química , Microscopia de Fluorescência , Nanopartículas/química , Nanopartículas/toxicidade , Tamanho da Partícula , Poliésteres , Polietilenoglicóis/metabolismo , Polietilenoglicóis/toxicidade , Poliglactina 910/metabolismo , Poliglactina 910/toxicidade , Interferência de RNA , RNA Interferente Pequeno/genética , TransfecçãoRESUMO
T-cell engagers (TCEs) represent a breakthrough in hematological malignancy treatment but are vulnerable to antigen escape and lack a vaccination effect. The "immunologically cold" solid tumor presents substantial challenges due to intratumor heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, a methoxy poly(ethylene glycol) (mPEG)-masked CD44×PD-L1/CD3 trispecific T-cell nanoengager loaded with the STING agonist c-di-AMP (CDA) (PmTriTNE@CDA) for the treatment of triple-negative breast cancer (TNBC) is rationally designed. PmTriTNE@CDA shows tumor-specific accumulation and is preferentially unmasked in response to a weakly acidic TME to prevent on-target off-tumor toxicity. The unmasked CD44×PD-L1/CD3 trispecific T-cell nanoengager (TriTNE) targets dual tumor-associated antigens (TAAs) to redirect CD8+ T cells for heterogeneous TNBC lysis while achieving PD-L1 blockade. PmTriTNE synergized with CDA to transform the cold tumor into a hot tumor, eradicate the large established TNBC tumor, and induce protective immune memory in a 4T1 orthotopic tumor model without causing obvious toxicity. PmTriTNE@CDA shows potent efficacy in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. This study serves as a proof-of-concept demonstration of a nanobased TCEs strategy to expand therapeutic combinations that previously could not be achieved due to systemic toxicity with the aim of overcoming TNBC heterogeneity and immunotherapy resistance.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Camundongos , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Antígeno B7-H1/uso terapêutico , Linhagem Celular Tumoral , Imunoterapia , Modelos Animais de Doenças , Fatores Imunológicos/uso terapêutico , Vacinação , Polietilenoglicóis/uso terapêutico , Microambiente TumoralRESUMO
Targeted delivery carriers are receiving considerable attention, the development of a more precise targeted delivery carrier is critical for the advancement of cancer chemotherapy. In this study, we evaluated the effects of RGD-conjugated poly (lactic acid-co-lysine)-(Arginine-Glycine-Aspartic) nanoparticles (PLA-PLL-RGD NPs) on targeted delivery to Bacp-37 breast cancer bearing mice. PLA-PLL-RGD NPs were prepared by using the emulsion-solvent evaporation method. A subsequent MTT assay indicated that the NPs were non-toxic and had good biocompatibility. In vitro, the results of Confocal Laser Scanning Microscope (CLSM) and FAC Scan flow cytometry (FACS) indicated that the PLA-PLL-RGD NPs can bind more significantly to human umbilical vein endothelial cells, compared to PLA-PLL NPs. In vivo, the results of target imaging and biodistribution showed that PLA-PLL-RGD can significantly target to tumor of Bacp-37 breast cancer bearing mice. These results demonstrated that PLA-PLL-RGD NPs can effectively enhance targeted efficiency in vivo, and have the potential to be used as targeted delivery carrier.
Assuntos
Neoplasias da Mama/patologia , Ácido Láctico/química , Lisina/química , Nanopartículas , Oligopeptídeos/química , Polímeros/química , Ensaios Antitumorais Modelo de Xenoenxerto , Materiais Biocompatíveis , Feminino , Citometria de Fluxo , Humanos , Microscopia Confocal , Oligopeptídeos/farmacocinética , Poliésteres , Distribuição TecidualRESUMO
The nano drug delivery system (NDDS) has been extensively investigated for cancer treatment because of its ability to enhance drug efficacy. However, there are only a few studies attempting NDDS for AZD9291 (Osimertinib). Here, we encapsulated AZD9291 in chitooligosaccharides (COS)-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles. COS, a cationic polymer, was used to develop positively charged nanoparticles with good biological affinity. The prepared AZD-PLGA-COS NPs exhibited a smaller particle size (176.6 ± 0.4 nm), a positively charged surface (+18.65 ± 0.38 mV), and an increased cellular uptake. The IC50 of H1975 cells was reduced by 45.90%, and the expression of p-EGFR, PARP, Bak, caspase-9, Bax, and Bcl-2 was regulated to promote cellular apoptosis. Furthermore, COS was found to inhibit the expression of immune checkpoint PD-L1. This study suggests that COS-modified PLGA nanoparticles with low toxicity and high encapsulation efficiency (EE) could potentially enhance drug efficacy.
Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Quitina/análogos & derivados , Portadores de Fármacos/química , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Antígeno B7-H1/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quitina/química , Quitosana , Liberação Controlada de Fármacos , Receptores ErbB/metabolismo , Humanos , Concentração Inibidora 50 , Microscopia Eletrônica de Transmissão , Nanopartículas/toxicidade , Nanopartículas/ultraestrutura , Oligossacarídeos , Tamanho da Partícula , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
PURPOSE: Platinum/paclitaxel-based chemotherapy is the strategy for ovarian cancer, but chemoresistance, inherent or acquired, occurs and hinders therapy. Therefore, further understanding of the mechanisms of drug resistance and adoption of novel therapeutic strategies are urgently needed. METHODS: In this study, we report that sphingosine-1-phosphate receptor-1 (S1PR1)-mediated chemoresistance for ovarian cancer. Then we developed nanoparticles with a hydrophilic PEG2000 chain and a hydrophobic DSPE and biodegradable CaP (calcium ions and phosphate ions) shell with pH sensitivity as a delivery system (CaP-NPs) to carry BAF312, a selective antagonist of S1PR1 (BAF312@CaP-NPs), to overcome the cisplatin (DDP) resistance of the ovarian cancer cell line SKOV3DR. RESULTS: We found that S1PR1 affected acquired chemoresistance in ovarian cancer by increasing the phosphorylated-signal transduction and activators of transcription 3 (P-STAT3) level. The mean size and zeta potential of BAF312@CaP-NPs were 116 ± 4.341 nm and -9.67 ± 0.935 mV, respectively. The incorporation efficiency for BAF312 in the CaP-NPs was 76.1%. The small size of the nanoparticles elevated their enrichment in the tumor, and the degradable CaP shell with smart pH sensitivity of the BAF312@CaP-NPs ensured the release of BAF312 in the acidic tumor niche. BAF312@CaP-NPs caused substantial cytotoxicity in DDP-resistant ovarian cancer cells by downregulating S1PR1 and P-STAT3 levels. CONCLUSION: We found that BAF312@CaP-NPs act as an effective and selective delivery system for overcoming S1PR1-mediated chemoresistance in ovarian carcinoma by inhibiting S1PR1 and P-STAT3.
Assuntos
Azetidinas/administração & dosagem , Compostos de Benzil/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Receptores de Esfingosina-1-Fosfato/genética , Azetidinas/farmacocinética , Compostos de Benzil/farmacocinética , Fosfatos de Cálcio/química , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosforilação/efeitos dos fármacos , Polietilenoglicóis/química , Fator de Transcrição STAT3/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Receptores de Esfingosina-1-Fosfato/metabolismoRESUMO
PURPOSE: The aim of this study is to develop novel polylactide/poly(ethylene glycol) (PLA/PEG) micelles as carrier of hydrophobic drug (paclitaxel) by direct dissolution method without using any organic solvents. The in vitro and in vivo release properties were studied in comparison with micelles prepared by dialysis. METHODS: Drug encapsulation efficiency (EE) and loading content (LC) of the micelles were evaluated by high-performance liquid chromatography. Micelle diameters and structures were determined by dynamic light scattering and transmission electron microscopy. In vitro release was performed in phosphate-buffered saline (pH 7.4) at 37 degrees C, and in vivo experiments were realized in lung cancer-bearing mice. RESULTS: Similar EE and LC values were obtained for micelles by direct dissolution method and those by dialysis. L- and D-PLA/PEG mixed micelles present higher drug encapsulation ability than separate micelles due to stereocomplexation. Micelle diameters are enlarged by drug-loading. Faster drug release was obtained for micelles by direct dissolution than those by dialysis. Compared with current clinical formulation and micelles by dialysis, paclitaxel-loaded micelles by direct dissolution showed the highest antitumor ability. CONCLUSION: The L- and D-PLA/PEG mixed micelles by direct dissolution method present many advantages such as easy formulation and absence of toxic organic solvents, which shows great potential as carrier of hydrophobic drugs.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Materiais Biocompatíveis/síntese química , Sistemas de Liberação de Medicamentos/métodos , Poliésteres/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Micelas , Poliésteres/química , Poliésteres/farmacocinética , Polietilenoglicóis/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Clinically acceptable safety and efficacy are the most important issues for the design and synthesis of iron oxide MRI contrast agents. In order to meet the practical requirements, a kind of low molecular weight PAA-coated Fe3O4 nanoparticle (CS015) with super colloidal stability and low hypersensitivity benefitting from an ultrahigh carboxyl group density was developed in this study. The composition and physicochemical properties of the particles were characterized by TEM, XRD, FTIR and TGA. The ultrahigh density of COOH on the particles (33 COOH per nm2) was verified while a core size of 5.1 nm and a dynamic diameter of 41 nm with a narrow distribution were also achieved. The particles still showed excellent dispersity and stability even after a spray-drying or freeze-drying process, exposure to high temperature sterilized conditions and long-term storage. The nanoparticles could quickly capture iron ions in bulk solution which was confirmed by ITC results, and the bioactive iron concentration of CS015 was greatly decreased (0.54 ± 0.05 mg L-1) compared to that of commercially available ferumoxytol, iron sucrose and VSOP. Free iron ion release was 1120 times lower than the toxic concentration of iron. An excellent biocompatibility of CS015 with no obvious cytotoxicity and low risk of hypersensitivity has been manifested by cytotoxicity experiments and a passive cutaneous anaphylaxis test. The T1 and T2-weighted MRI contrast effects both in vitro and in vivo have also been verified which made CS015 a potential dual MRI contrast agent. Furthermore, theoretically calculated conformation was speculated and all the advantages mentioned above were benefited from the three dimensional brush-like texture of CS015. Therefore, these merits make the CS015 nanoplatform highly suitable in diagnostic applications as a MRI contrast agent.