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1.
ACS Nano ; 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32203665

RESUMO

Systemic lupus erythematosus (SLE), a common lethal autoimmune disease, is characterized by effector/regulatory T cells imbalance. Current therapies are either inefficient or have severe side effects. MicroRNA-125a (miR-125a) can stabilize Treg-mediated self-tolerance by targeting effector programs, but it is significantly downregulated in peripheral T cells of patients with SLE. Therefore, overexpression of miR-125a may have therapeutic potential to treat SLE. Considering the stability and targeted delivery of miRNA remains a major challenge in vivo, we constructed a monomethoxy (polyethylene glycol)-poly(d,l-lactide-co-glycolide)-poly(l-lysine) (mPEG-PLGA-PLL) nanodelivery system to deliver miR-125a into splenic T cells. Results demonstrate that miR-125a-loaded mPEG-PLGA-PLL (PEALmiR-125a) nanoparticles (NPs) exhibit good biocompatibility and protect miR-125a from degradation, thereby prolonging the circulatory time of miRNA in vivo. In addition, PEALmiR-125a NPs are preferentially enriched in a pathological spleen and efficiently deliver miR-125a into the splenic T cells in SLE mice models. The PEALmiR-125a NPs treatment significantly alleviates SLE disease progression by reversing the imbalance of effector/regulatory T cells. Collectively, the PEALmiR-125a NPs show excellent therapeutic efficacy and safety, which may provide an effective treatment for SLE.

2.
J Nanobiotechnology ; 17(1): 125, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870362

RESUMO

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/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-31637008

RESUMO

Hepatocellular carcinoma (HCC) is a malignancy with a poor prognosis. Surgery combined with chemotherapy has been recommended as a curative regimen for HCC. Nevertheless, the anticancer mechanisms of chemicals in hepatocellular carcinoma remain unclear. Pyroptosis is a type of programmed necrosis, and its mechanism in hepatocellular carcinoma is poorly understood. The efficacy and mechanism of arsenic trioxide nanoparticles in the treatment of HCC were explored in this research. Arsenic trioxide alone and arsenic trioxide nanoparticles were conveniently administered to mice intratumorally using a needle. Compared with As2O3, As2O3 nanoparticles (As2O3-NPs) showed better inhibition, promoted greater LDH release, and induced cell morphology indicative of pyroptosis in vitro. Compared with the free drug, As2O3-NPs increased GSDME-N expression and decreased Dnmt3a, Dnmt3b, and Dnmt1 expression in Huh7 cells. In vivo, As2O3-NPs induced a significant decrease in the expression of Dnmt3a, Dnmt3b and Dnmt1, but significantly upregulated the expression of GSDME-N (gasdermin E (GSDME) was originally found to be related to deafness; recently, it has been defined as a gasdermin family member associated with pyroptosis). As2O3-NPs inhibited tumor growth more strongly than As2O3 or control, a finding likely attributed to the downregulation of PCNA and DNMT-related proteins and the upregulation of GSDME-N.

4.
ACS Appl Mater Interfaces ; 11(42): 38417-38428, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31556584

RESUMO

Triple negative breast cancer (TNBC) is insensitive to either chemotherapy or endocrine therapy because of the powerful DNA reparation and the negative expression of surface antigens, which urgently claims for an effective approach to improve the prognosis. Herein, DNA repair blocker BRCA1 small interfering RNA (siRNA) was introduced with cisplatin (Pt) into the elaborately designed pH-sensitive shell-core platform to enhance the chemotherapeutic treatment effect by silencing the DNA repair related gene. In this platform, BRCA1 siRNA and Pt prodrug (Pro-Pt) were separately encapsulated in the porous outer shell and hydrophobic inner core with extremely high encapsulation efficiency and stability effectively preventing them from degradation during circulation. Suitable size and urokinase plasminogen activator analogues (uPA) with high affinity for the uPA receptor (uPAR) realized an excellent dual passive and active tumor targeting ability. Moreover, the exposed PEG hydrophilic chain prevented the nanoparticles (NPs) from precipitating by serum protein or inactivating by nuclease in the blood cycle. Most importantly, the degradable CaP (calcium ions and phosphate ions) shell with smart pH sensitivity would dissipate from NPs in the lysosomes to burst the lysosome membranes so as to guarantee the lysosomal escape and the sequential release of the siRNA and Pro-Pt where the BRCA1 siRNA blocked the DNA repairing pathway followed by reducing Pro-Pt to Pt for irreversible DNA damage. Hence, the uPA-SP@CaP NPs provided a promising strategy for high-efficiency treatment of TNBC along with bringing new hope for more patients.

5.
Biomaterials ; 222: 119442, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31491561

RESUMO

Polyelectrolyte modified iron oxide nanoparticles have great potential applications for clinical magnetic resonance imaging (MRI) and anemia treatments, however, possible associated heart toxicity is rarely reported. Here, polyacrylic acid (PAA)-coated Fe3O4 nanoparticles (PION) were synthesized and lethal reactions appeared when it was applied in vivo. The investigation of underlying mechanism showed that PION could break electrolyte balance and further resulted in serious heart failure, which was observed under color doppler ultrasound and dynamic vector blood flow technique. The results demonstrated that PION had a strong absorption tendency for divalent ions and the maximum tolerated dose (MTD) was lower than 100 mg/kg. From electrocardiography (ECG), PION presented an obvious impact on CaV1.2 ion channel, which leading to fatal arrhythmia. An appropriate solution for preventing this deadly effect was pre-chelation Ca2+ (n (Ca): n (COOH) = 3: 8) to PION (PION-Ca), which displayed much higher cardiac and electrophysiological safety when sealing the binding point of divalent cation ions with PAA. The injection in Beagle dogs further confirmed the safety of PION-Ca. This study explored the mechanism and offered a solution for cardiac toxicity induced by PAA-coated nanoparticles, which guides for enhancing the safety of such polyelectrolyte decorated nanoparticles and provides assurance for clinical applications.

6.
Chem Commun (Camb) ; 55(73): 10940-10943, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31441920

RESUMO

Different from traditional "always on" photothermal therapy (PTT) agents, tumor microenvironment responsive agents showed more tumor specificity and lower photo-toxicity to normal tissues. Herein, a photo-stable and reversible pH responsive phenazine dye (PIOH) was synthesized and assembled with liposomes forming nanoparticles (PIOH-NPs), which exhibited a strong NIR absorption in a weak acid environment and were successfully utilized for photoacoustic (PA) imaging-guided photothermal therapy in mice.


Assuntos
Antineoplásicos/uso terapêutico , Corantes Fluorescentes/uso terapêutico , Fenazinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Colesterol/química , Feminino , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/toxicidade , Concentração de Íons de Hidrogênio , Hipertermia Induzida/métodos , Lecitinas/química , Lipossomos/química , Camundongos Endogâmicos BALB C , Nanopartículas/química , Tamanho da Partícula , Fenazinas/síntese química , Fenazinas/química , Fenazinas/toxicidade , Técnicas Fotoacústicas/métodos , Fototerapia/métodos , Microambiente Tumoral/fisiologia
7.
Nanomedicine ; 21: 102062, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31344501

RESUMO

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.

8.
Biomed Res Int ; 2019: 2595801, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240207

RESUMO

Triptolide has been proven to possess anticancer efficacy; however, its application in the clinical practice was limited by poor water solubility, hepatotoxicity, and nephrotoxicity. In this study, a triptolide-loaded exosomes delivery system (TP-Exos) was constructed and its effects on the proliferation and apoptosis of SKOV3 cells in vitro and in vivo were observed. SKOV3-exosomes (SK-Exos) were collected by ultracentrifugation and ultrafiltration centrifugation. TP-Exos was constructed by sonication and ultrafiltration centrifugation. SK-Exos and TP-Exos were characterized by transmission electron microscopy, western blotting, nanoparticle-tracking analysis, and high-performance liquid chromatography. Cellular uptake of exosomes, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, bromodeoxyuridine (BrdU) cell proliferation assay, and cell apoptosis experiment were used to study the effect of TP-Exos on ovarian cancer in vitro. Tumor-targeting study of exosomes, monitoring the tumor volume of mice, and TdT-mediated dUTP Nick-End labeling (TUNEL) assay were used to evaluate the effect of TP-Exos on ovarian cancer in vivo. The toxicity of TP-Exos in vivo was evaluated by liver and kidney function and histopathology of major organs (heart, liver, spleen, lung, kidney, and ovary). The results revealed that TP-Exos not only have the general characteristics of exosomes but also have high drug encapsulation efficiency. Besides, PKH26 labeled exosomes (PKH26-Exos) could be uptaken by SKOV3 cells, and Dir labeled exosomes (Dir-Exos) could be enriched to the tumor site of tumor bearing mice. Furthermore, the cytotoxic and apoptotic effects on SKOV3 cells of TP-Exos were weaker than those of free TP, and tumor cell proliferation inhibition and tumor growth inhibition were stronger than that of free TP. Moreover, TP-Exos have toxic effect on liver and spleen. In conclusion, the TP-Exos could be a promising strategy for ovarian cancer, but they need to be further optimized to attenuate the damage to liver and spleen.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Exossomos/metabolismo , Neoplasias Ovarianas/metabolismo , Fenantrenos/farmacologia , Animais , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Diterpenos/uso terapêutico , Sistemas de Liberação de Medicamentos , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Ovário , Fenantrenos/uso terapêutico , Coelhos , Testes de Toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Biomaterials ; 212: 73-86, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108274

RESUMO

Given that there is no effective treatment method for lethality androgen-resistant prostate cancers (ARPC), herein we report a multifunctional gold-caged nanoparticle (PTX-PP@Au NPs) against ARPC through integrating functional organic/inorganic materials to exploit the superiors of gold particles such as photothermal effects (PTT), generating reactive oxygen species (photodynamic effects, PDT), carrying chemotherapeutic agents (chemotherapy effects, CT), and inhibiting ion channel. This synergistic PTT/PDT/CT platform consists of three components: i) the Pluronic-polyethylenimine assembling into micelles to encapsulate drugs and providing reduction sites for gold cage formation through a "green" method, ii) the gold cage with surface plasmon resonance peak at near-infrared (NIR) region in a broad window qualifying the PTT/PDT potentiality, iii) a chemotherapeutic agent paclitaxel (PTX) arresting the tumor cell cycle. As demonstrated, the system has remarkable performance on controlling drug release, blocking TRPV6 cation channel, enhancing cell cycle arrest, elevating temperature and generating ROS, thus improving cellular toxicity along with apoptosis, enhancing tumor targeting, and achieving the therapy to ARPC with low toxicity on liver function and minimal side effects to normal organs. Notably, both PTT and PDT effect are generated under single irradiation situation because of the broad absorbance window, along with limited skin damages. As a specific synergistic platform creatively integrating multiple treatment protocols with negative toxicity, PTX-PP@Au NPs provide a facile, effective, and broadly applicable strategy to deadly ARPC.

10.
Theranostics ; 9(4): 1047-1065, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867815

RESUMO

Background: Platinum (II) (Pt(II))-based anticancer drugs dominate the chemotherapy field of ovarian cancer. However, the patient's quality of life has severely limited owing to dose-limiting toxicities and the advanced disease at the time of diagnosis. Multifunctional tumor-targeted nanosized ultrasound contrast agents (glutathione (GSH)-sensitive platinum (IV) (Pt(IV)) prodrug-loaded phase-transitional nanoparticles, Pt(IV) NP-cRGD) were developed for precise theranostics against ovarian cancer. Methods: Pt(IV) NP-cRGD were composed of a perfluorohexane (PFH) liquid core, a hybrid lipid-polymer shell with PLGA12k-PEG2k and DSPE-PEG1k-Pt(IV), and an active targeting ligand, the cRGD peptide (PLGA: poly(lactic-co-glycolic acid), PEG: polyethylene glycol, DSPE: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, cRGD: cyclic Arg-Gly-Asp). Pt(IV), a popular alternative to Pt(II), was covalently attached to DSPE-PEG1k to form the prodrug, which fine-tuned lipophilicity and improved cellular uptake. The potential of Pt(IV) NP-cRGD as contrast agents for ultrasound (US) imaging was assessed in vitro and in vivo. Moreover, studies on the antitumor efficiency and antitumor mechanism of Pt(IV) NP-cRGD assisted by US were carried out. Results: Pt(IV) NP-cRGD exhibited strong echogenic signals and excellent echo persistence under an US field. In addition, the GSH-sensitive and US-triggered drug delivery system maximized the therapeutic effect while reducing the toxicity of chemotherapy. The mechanistic studies confirmed that Pt(IV) NP-cRGD with US consumed GSH and enhanced reactive oxy gen species (ROS) levels, which further causes mitochondria-mediated apoptosis. Conclusion: A multifunctional nanoplatform based on phase-transitional Pt(IV) NP-cRGD with US exhibited excellent echogenic signals, brilliant therapeutic efficacy and limited side effect, suggesting precise theranostics against ovarian cancer.


Assuntos
Antineoplásicos/administração & dosagem , Terapia de Alvo Molecular/métodos , Nanocompostos/administração & dosagem , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Compostos de Platina/administração & dosagem , Ultrassonografia/métodos , Animais , Meios de Contraste/administração & dosagem , Modelos Animais de Doenças , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Feminino , Lipídeos/administração & dosagem , Camundongos Nus , Nanocompostos/química , Transplante de Neoplasias , Peptídeos Cíclicos/administração & dosagem , Polímeros/administração & dosagem , Pró-Fármacos/administração & dosagem , Nanomedicina Teranóstica/métodos , Transplante Heterólogo , Resultado do Tratamento
11.
J Biomed Nanotechnol ; 15(2): 261-271, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30596549

RESUMO

Microwave ablation is emerging as an effective local treatment for solid tumors. The efficiency of microwave ablation in treating hepatocellular carcinoma is evidently limited by the incomplete ablation of large tumors and tumors in high-risk locations. Microwave ablation in conjunction with localized chemotherapy is a promising strategy for cancer therapy. In this study, we prepared As2O3-mPEG-PLGA-PLL nanoparticles by double emulsion method and investigated their efficacy to eliminate residual cancer cells and inhibit lung metastasis after microwave ablation of hepatic VX2 tumor. As2O3 formulations were administered into the residual tumor area for four times over four weeks after microwave ablation (As2O3 equivalent to 1 mg/kg body weight). Both As2O3 treatments showed good therapeutic effects, including inhibiting lung metastasis and decreasing the stiffness of the residual tumors. Additionally, As2O3-mPEG-PLGA-PLL nanoparticles had better anti-cancer efficacy than did the As2O3 treatment. Compared with As2O3 alone, As2O3-mPEG-PLGA-PLL nanoparticles could increase the expression of epithelial marker E-cadherin, decrease the expression of mesenchymal markers N-cadherin and snail, as well as down-regulate the expressions of PCNA (proliferation marker), CD34 (angiogenesis marker). The As2O3-mPEG-PLGA-PLL nanoparticles are an effective formulation for preventing lung metastasis through reversing EMT progress after incomplete ablation, thus it has the potential to be a new therapy strategy for HCC patients.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pulmonares , Humanos , Micro-Ondas , Neoplasia Residual
12.
J Biomed Nanotechnol ; 15(2): 329-339, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30596555

RESUMO

Bufalin has significant antitumor effects on various kinds of tumors. However, bufalin's clinical utility is severely limited because of its side effects, toxicity, and fast metabolism. We made bufalin-loaded, targeted nanospheres with the aim of overcoming bufalin's limitations. Epidermal growth factor (EGF)-modified nanospheres with encapsulated bufalin showed increased toxicity in colorectal cancer cells, inhibition of cell proliferation, and induction of apoptosis relative to the non-EGF-modified nanospheres. The average particle size of the nanospheres was 171 nm and the encapsulation efficiency was 83.2%. In vitro release data showed that bufalin loaded in calcium phosphate/DPPE-PEG-EGF hybrid porous nanospheres was released more slowly from dialysis membranes than free bufalin. According to our results, EGF-modified nanospheres containing bufalin show improved anti-tumor effects on colon cancer in nude mice, but without severe side effects.


Assuntos
Nanosferas , Animais , Antineoplásicos , Bufanolídeos , Linhagem Celular Tumoral , Fator de Crescimento Epidérmico , Camundongos , Camundongos Nus , Fosfatidiletanolaminas , Polietilenoglicóis
13.
Biomater Sci ; 6(10): 2667-2680, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30209483

RESUMO

microRNA-122 (miR-122) is a kind of non-coding RNA expressed specifically in the liver and accumulating evidence elucidates its relationship with HCV virus replication. The utilization of anti-miRNA oligonucleotide (antimiR) offers tremendous potential for future HCV infection therapy. However, multiple existing problems, such as targeting and stability, impede in vivo application of antimiR. To overcome them, we synthesized monomethoxy (polyethylene glycol)-poly (d,l lactide-co-glycolide)-poly (l-lysine) (mPEG-b-PLGA-b-PLL) materials to deliver miR-122 antagomir (AN), and formed stable and well-distributed AN-loaded mPEG-b-PLGA-b-PLL nanoparticles (NP-AN). NP-AN showed a high degree of miR-122 inhibition after 72 h in vitro. In vivo results showed an NP-AN "leak" through a hepatic sinusoid to reach hepatocytes and over 90% reduction of miR-122 after being injected with NP-AN for 72 h. Besides, the inhibition of miR-122 lasted for 28 days with limited dosage in vivo. This study strongly suggests that the silencing of miR-122 was enhanced and the reduction of miR-122 expression could be extended by utilizing an mPEG-b-PLGA-b-PLL nano-platform, which potentially facilitate further studies on miRNA function loss and related RNAi therapy for HCV infection.


Assuntos
Fígado/efeitos dos fármacos , Nanopartículas , Oligonucleotídeos , Poliésteres , Polietilenoglicóis , Polilisina/análogos & derivados , Animais , Antagomirs , Linhagem Celular , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Feminino , Hepatite C , Humanos , Fígado/metabolismo , Camundongos Endogâmicos BALB C , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Nanopartículas/administração & dosagem , Nanopartículas/química , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/química , Poliésteres/administração & dosagem , Poliésteres/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polilisina/administração & dosagem , Polilisina/química
14.
Nanoscale ; 10(37): 17663-17670, 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30206611

RESUMO

Zinc oxide (ZnO) often serves as protein microarray substrates owing to its outstanding fluorescence enhancement effect. However, the integration of functional substrates with microfluidic technology to detect cancer biomarkers still needs to be optimized and promoted, for example, the optimization of micro/nanostructure and hydrophilic modification strategies for fluorescence immunoassays. Here, ZnO nanorod arrays were constructed on the inner wall of glass capillaries through a microfluidic chemical method, and the electrostatic layer by layer self-assembly was applied to modify the nanorod array with hydrophilic polyelectrolyte-polyacrylic acid (PAA). The effects of the flow rate and the reagent concentration on the morphology of the ZnO nanorod array were investigated. The ZnO nanorod array-based glass capillary, prepared at 25 µL min-1 for 4 min with 50 mM Zn2+ in solution, showed a remarkable enhancement in fluorescence performance. In addition, the introduction of PAA suppressed the interference of nonspecific protein and improved the antibody loading capacity effectively. In the detection of carcinoembryonic antigen, the limit of detection reached 100 fg mL-1, which indicated that the ZnO@PAA nanorod array-based microfluidic device exhibits remarkable fluorescence detection performance towards protein markers and possesses potential to be applied to point-of-care diagnostics and high throughput cancer biomarker detection.


Assuntos
Resinas Acrílicas/química , Imunofluorescência , Dispositivos Lab-On-A-Chip , Nanotubos , Óxido de Zinco/química , Antígeno Carcinoembrionário/análise , Nanoestruturas
15.
J Biomed Nanotechnol ; 14(10): 1761-1772, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30041722

RESUMO

Triptolide has proven to possess anticancer potential and been widely used for anti-cancer research. However, the liver and kidney toxicity has limited its application in cancer treatment. In this study, a drug delivery system based on mPEG-DPPE/calcium phosphate was developed to co-load triptolide and curcumin (TP and Curc-NPs). The coefficient of drug interaction (CDI) was calculated to determine the optimal concentration of the two drugs. When the concentration of triptolide was 25.22 ng/mL and the concentration of curcumin was 6.62 µg/mL, the two drugs reached the maximum synergistic killing effects on SKOV-3 tumor cells. The TP and Curc-NPs was prepared using ultrasonic emulsification. Flow cytometry results revealed that the TP and Curc-NPs arrested cell-cycle in the S and G2/M phases and exhibited a strong ability to induce apoptosis. Intracellular reactive oxygen species (ROS) results indicated that curcumin could reduce the intracellular ROS level caused by triptolide. The mRNA levels of heat shock protein (HSP) were detected by qTR-PCR and the results showed that the TP and Curc-NPs could lower the HSP70 mRNA level while could not reduce the HSP90 mRNA level. The animal experiments demonstrated the favorable curative effects of the TP and Curc-NPs, and the tumor inhibition rate reached 68.78%. The results of the pathological examinations demonstrated that the nanoparticles had no significant toxic effects on important organs. In conclusion, the TP and Curc-NPs exerted synergistic effects on ovarian cancer in vitro and in vivo, and the toxicity caused by triptolide may be reduced by curcumin through anti-oxidative stress effects. The TP and Curc-NPs could be a promising strategy for ovarian cancer.


Assuntos
Nanopartículas , Neoplasias Ovarianas , Animais , Apoptose , Fosfatos de Cálcio , Linhagem Celular Tumoral , Curcumina , Diterpenos , Compostos de Epóxi , Feminino , Fenantrenos , Éteres Fenílicos , Polietilenoglicóis
16.
J Biomed Nanotechnol ; 14(10): 1816-1825, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30041727

RESUMO

Short interfering RNA (siRNA)-based therapy has a high potential for application in cancer gene therapy. However, delivery of siRNA to target cells is limited by many factors such as serum ribonuclease (RNase) degradation, off-target effects, and inadequate cellular uptake. In this study, an enzyme-response PEG/Lipids/calcium phosphate hybrid delivery system was constructed for siRNA. The nearly neutral charged siRNA@NP2 was resistant to serum-induced degradation. Compared with the non-enzyme-response siRNA@NP1, siRNA@NP2 had efficient delivery in both SMMC-7721 cell lines and SMMC-7721-bearing nude mice. Moreover, safety evaluation of the nanoparticles revealed that they had no significant toxicity both in vitro and in vivo. The developed siRNA@NP2 delivery system presents an efficient tool for siRNA-based cancer gene therapy in vivo.


Assuntos
Nanopartículas , Microambiente Tumoral , Animais , Fosfatos de Cálcio , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , RNA Interferente Pequeno
17.
ACS Appl Mater Interfaces ; 10(9): 7821-7831, 2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29411964

RESUMO

Chemotherapy-induced activation of cell survival pathways leads to drug resistance. MicroRNAs (miRNAs) post-transcriptionally regulate gene expression in many biological pathways. Paclitaxel (PTX) is one of the first-line chemotherapy drugs for ovarian cancer, and it induces the activation of the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) pathway that leads to tumor cell proliferation, survival, invasion, and drug resistance. MicroRNA-7 (miR-7) has the ability to suppress the EGFR/ERK pathway. To sensitize chemotherapy, we developed monomethoxy(poly(ethylene glycol))-poly(d,l-lactide- co-glycolide)-poly(l-lysine) nanoparticles for the simultaneous co-delivery of PTX and miR-7. The resulting PTX/miR-7 nanoparticles (P/MNPs) protect miRNA from degradation, possess a sequential and controlled release of drugs, improve the transfection efficiency of miRNA, decrease the half-maximal inhibitory concentration of PTX, and increase the apoptosis of ovarian cancer cells. The chemotherapeutic efficacy of PTX is prominently enhanced in vitro and in vivo via the inhibition of PTX-induced EGFR/ERK pathway activation by miR-7. Our studies in P/MNPs reveal a novel paradigm for a dual-drug-delivery system of chemotherapeutics and gene therapy in treating cancers.


Assuntos
Nanopartículas , Antineoplásicos Fitogênicos , Linhagem Celular Tumoral , Receptores ErbB , MAP Quinases Reguladas por Sinal Extracelular , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , MicroRNAs , Neoplasias Ovarianas , Paclitaxel
18.
Theranostics ; 7(18): 4424-4444, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29158837

RESUMO

Gold nanoparticle-coated Pluronic-b-poly(L-lysine) nanoparticles (Pluronic-PLL@Au NPs) were synthesized via an easy one-step method and employed as carriers for the delivery of paclitaxel (PTX) in chemo-photothermal therapy, in which Pluronic-PLL acts as the reductant for the formation of AuNPs without the need for an additional reducing agent. METHODS: The deposition of AuNPs on the surface of Pluronic-PLL micelles and the thermal response of the system were followed via ultraviolet-visible spectroscopy and dynamic light scattering. Calcein-AM and MTT assays were used to study the cell viability of MDA-MB-231 cells treated with PTX-loaded Pluronic-PLL@Au NPs, and we then irradiated the cells with NIR light. RESULTS: An obvious temperature response was observed for the Pluronic-PLL@Au NPs. Blood compatibility and in vitro cytotoxicity assays confirmed that the Pluronic-PLL@Au NPs have excellent biocompatibility. Compared to Taxol, the PTX-loaded Pluronic-PLL@Au NPs exhibited higher cytotoxicity in MDA-MB-231 cells. All of these results and confocal laser scanning microscopy analysis results suggest that Pluronic-PLL@Au NPs greatly enhance the cellular uptake efficiency of the drug. CONCLUSION: As confirmed by in vitro and in vivo studies, the combination of chemotherapy and photothermal therapy can cause more damage than chemo- or photothermal therapy did alone, demonstrating the synergistic effect of chemo-photothermal treatment. Thus, the as-prepared Pluronic-PLL@Au NPs are promising for chemo-photothermal therapy.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Poloxâmero/química , Polilisina/química , Animais , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Feminino , Fluoresceínas/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Paclitaxel/química , Paclitaxel/farmacologia , Coelhos , Temperatura Ambiente
19.
J Biosci ; 42(2): 299-309, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28569253

RESUMO

We investigated the efficacy and safety of ultrasound (US)-targeted microbubble (MB) destruction (UTMD)-enhanced delivery of monomethoxypoly(ethylene glycol)-poly(lactic-co-glycolic acid)-poly-L-lysine (mPEG-PLGA-PLL) nanoparticles (NPs) loading Cy3-labelled platelet-derived growth factor BB (PDGF-BB) siRNA to rat retina in vivo. Eighty Wistar rats were divided into five groups (G). The right eyes, respectively, received an intravitreal injection as follows: normal saline (NS) (G1), NPs and NS (G2), NPs and MBs (G3), NPs and NS (G4) and NPs and MBs (G5). In G4 and G5, the eyes were exposed to US for 5 mins. Twenty-four hours after transfection, the uptake and distribution of Cy3-labelled siRNA in rat retina were observed by fluorescent microscope. The percentage of Cy3- labelled siRNA-positive cells was evaluated by flow cytometer. The levels of PDGF-BB mRNA in retinal pigment epithelium (RPE) cells and secreted PDGF-BB proteins were also measured. Hematoxylin and eosin staining and frozen sections were used to observe tissue damage. Our results showed that the number of Cy3-labelled siRNApositive cells in G5 was significantly higher than those of the other groups (P less than 0.05 for all comparisons). The maximum efficiency of siRNA uptake in neural retina was 18.22 +/_ 1.67%. In G4 and G5, a small number of Cy3- labelled siRNA-positive cells were also detected in the pigmented cell layer of the retina. NPs loading siRNA delivered with UTMD could more effectively down-regulate the mRNA and protein expression of PDGF-BB than NPs plus US (P=0.014 and P=0.007, respectively). Histology showed no evident tissue damage after UTMDmediated NPs loading siRNA transfection. UTMD could be used safely to enhance the delivery of mPEG-PLGAPLL NPs loading siRNA into rat retina.


Assuntos
Carbocianinas/química , Ácido Láctico/química , Nanopartículas/química , Polietilenoglicóis/química , Ácido Poliglicólico/química , Polilisina/química , Proteínas Proto-Oncogênicas c-sis/metabolismo , Animais , Becaplermina , Materiais Biocompatíveis , Sistemas de Liberação de Medicamentos , Masculino , Microbolhas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , RNA Interferente Pequeno , Ratos , Ratos Wistar , Retina , Ultrassom
20.
Autophagy ; 13(7): 1176-1190, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28594260

RESUMO

Although the treatments of malignant glioma include surgery, radiotherapy and chemotherapy by oral drug administration, the prognosis of patients with glioma remains very poor. We developed a polyethylene glycol-dipalmitoylphosphatidyle- thanoiamine (mPEG-DPPE) calcium phosphate nanoparticles (NPs) injectable thermoresponsive hydrogel (nanocomposite gel) that could provide a sustained and local delivery of paclitaxel (PTX) and temozolomide (TMZ). In addition, the proportion of PTX and TMZ for the optimal synergistic antiglioma effect on C6 cells was determined to be 1:100 (w/w) by the Chou and Talalay method. Our results clearly indicated that the autophagy induced by PTX:TMZ NPs plays an important role in regulating tumor cell death, while autophagy inhibition dramatically reverses the antitumor effect of PTX:TMZ NPs, suggesting that antiproliferative autophagy occurs in response to PTX:TMZ NPs treatment. The antitumor efficacy of the PTX:TMZ NP-loaded gel was evaluated in situ using C6 tumor-bearing rats, and the PTX:TMZ NP-loaded gel exhibited superior antitumor performance. The antitumor effects of the nanocomposite gel in vivo were shown to correlate with autophagic cell death in this study. The in vivo results further confirmed the advantages of such a strategy. The present study may provide evidence supporting the development of nanomedicine for potential clinical application.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Autofagia , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Nanocompostos , Paclitaxel/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Sinergismo Farmacológico , Glioma/patologia , Hidrogéis , Masculino , Nanopartículas , Paclitaxel/uso terapêutico , Ratos , Ratos Wistar , Temozolomida , Temperatura Ambiente
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