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1.
Chemosphere ; 246: 125820, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31918111

RESUMO

[Background] Melamine and phthalates have been reported to damage renal function in children. This association is scarce in general adults. [Method] A cross-sectional subsample population of 611 adults participating in the 2012 Shanghai Food Consumption Survey (SHFCS) was analyzed for urinary biomarkers of melamine, metabolites of phthalates, and renal function parameters. The correlations between renal function parameters and chemical exposure (either independently or interactively) were explored by linear regression models. To simplify the analysis, phthalate metabolites were dimensionally reduced using principal component analysis (PCA) method. [Result] Urinary melamine was positively associated with renal function parameters of both albumin-to-creatinine ratio (ACR) and ß2-microglobulin (B2M) in multivariate linear regression models (P < 0.05). A PCA pattern characterized by high-molecular-weight phthalates (HMWP) was positively associated with all three parameters of renal function (ACR, B2M, and N-acetyl-ß-d-glucosaminidase (NAG)). The co-exposure to melamine and HMWP presented an additive effect on increasing these parameters (ACR, B2M, and NAG). [Conclusion] Impaired renal function in Shanghai adults was associated with exposure to both melamine and HMWP.

2.
Oncol Lett ; 18(5): 5549-5554, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31612063

RESUMO

MicroRNA-34a (miR-34a) serves as a tumor suppressor in a number of different types of cancer. The present study was performed to investigate the involvement of miR-34a in bladder cancer. In the present study, miR-34a was downregulated in patients with bladder cancer compared with the healthy controls in bladder biopsies and plasma. Downregulation of miR-34a distinguished between patients with bladder cancer and the healthy controls. miR-34a expression was associated with tumor metastasis; however, not with tumor size. Transfection of miR-34a mimics upregulated the expression of phosphatase and tensin homolog (PTEN) in bladder cancer cells, and decreased cell migration and invasion. miR-34a may inhibit bladder cancer cell migration and invasion by upregulating PTEN. miR-34a may additionally serve as a potential therapeutic target for bladder cancer.

3.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 492-500, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484611

RESUMO

To compare the accuracy of SHA.LIN,S.T.O.N.E.nephrolithometry scoring system,and Clinical Research Office of the Endourological Society(CROES)nephrolithometry nomogram in predicting percutaneous nephrolithotomy(PCNL)outcomes including stone free rate(SFR)and perioperative status. Methods The clinical data of 90 patients with nephrolithiasis undergoing PCNL in department of urology,China-Japan Friendship Hospital from January 2015 to March 2018 were retrospectively analyzed.The general data,stone characteristics,operation approaches,and perioperative variables were recorded.SHA.LIN,S.T.O.N.E.score,and CROES nomogram were assigned according to the computed tomography(CT)findings before surgery.Stone free status was evaluated by kidney-ureter-bladder one month after PCNL.The relationships of SHA.LIN score,S.T.O.N.E.score,and CROES score with SFR,postoperative complications,operation time(OT),length of hospital stay(LOS),estimated blood loss(EBL),and decrease of hemoglobin was evaluated.Receiver operating characteristic(ROC)curves were used to analyze the predictive accuracy. Results The SFR was 72.2%(65/90)and postoperative complications occurred in 33 cases(36.7%).The mean OT was(103.1±39.6)min,the mean EBL was(46.1±53.0)ml,the mean LOS was(15.3±5.2)d,the mean postoperative LOS was(8.5±3.4)d,and the mean decrease of hemoglobin was(16.1±10.2)g/L.Stone-free patients had significantly lower SHA.LIN score(8.23 vs. 10.36,P=0.000)and S.T.O.N.E.score(7.05 vs.8.16,P=0.000)and significantly higher CROES score(188.50 vs. 143.89,P=0.000)compared to patients with residual fragments.All these scores were not significantly associated with complications(P>0.05).On the other hand,all these scores were significantly correlated with OT,EBL,and decrease of hemoglobin(SHA.LIN:POT=0.006,PEBL=0.028,Pdecrease of hemoglobin=0.014;S.T.O.N.E.:POT=0.012,PEBL=0.047,Pdecrease of hemoglobin=0.011;and CROES:POT=0.040,PEBL=0.045,Pdecrease of hemoglobin=0.013).SHA.LIN(P=0.001)and S.T.O.N.E.(P=0.005)scores were associated with LOS.Logistic regression analysis revealed that SHA.LIN(OR=2.491),S.T.O.N.E.(OR=3.030),and CROES(OR=0.973)scores were significantly associated with stone-free status.ROC curves in predicting SFR showed that there was significant difference in the areas under the curves(AUC)for the SHA.LIN vs. S.T.O.N.E.score [0.808(95% CI=0.711-0.905)vs. 0.748(95% CI=0.632-0.864),P=0.047].AUC for the CROES score [0.770(95% CI=0.664-0.877)] showed no significantly different for the SHA.LIN score or the S.T.O.N.E.score(P>0.05). Conclusions All these three scoring systems have good predictive accuracy for SFR.SHA.LIN is more precise than S.T.O.N.E.in predicting SFR.However,they can not predict postoperative complications.


Assuntos
Cálculos Renais/cirurgia , Nefrolitotomia Percutânea , Nomogramas , China , Hemoglobinas/análise , Humanos , Tempo de Internação , Duração da Cirurgia , Complicações Pós-Operatórias , Prognóstico , Recidiva , Estudos Retrospectivos , Resultado do Tratamento
4.
Plant Cell ; 31(2): 430-443, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30712008

RESUMO

Leaf senescence is governed by a complex regulatory network involving the dynamic reprogramming of gene expression. Age-dependent induction of senescence-associated genes (SAGs) is associated with increased levels of trimethylation of histone H3 at Lys4 (H3K4me3), but the regulatory mechanism remains elusive. Here, we found that JMJ16, an Arabidopsis (Arabidopsis thaliana) JmjC-domain containing protein, is a specific H3K4 demethylase that negatively regulates leaf senescence through its enzymatic activity. Genome-wide analysis revealed a widespread coordinated upregulation of gene expression and hypermethylation of H3K4me3 at JMJ16 binding genes associated with leaf senescence in the loss-of-function jmj16 mutant as compared with the wild type. Genetic analysis indicated that JMJ16 negatively regulates leaf senescence, at least partly through repressing the expression of positive regulators of leaf senescence, WRKY53 and SAG201 JMJ16 associates with WRKY53 and SAG201 and represses their precocious expression in mature leaves by reducing H3K4me3 levels at these loci. The protein abundance of JMJ16 gradually decreases during aging, which is correlated with increased H3K4me3 levels at WRKY53 and SAG201, suggesting that the age-dependent downregulation of JMJ16 is required for the precise transcriptional activation of SAGs during leaf senescence. Thus, JMJ16 is an important regulator of leaf senescence that demethylates H3K4 at SAGs in an age-dependent manner.

5.
J Cell Biochem ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30426560

RESUMO

AIM: To explore the molecular mechanism of nonmuscle invasive bladder cancer (NMIBC), matched normal, and cancer tissues of 10 NMIBC were examined for RNA sequencing. METHODS: We profiled the messenger RNA (mRNA) and long noncoding RNA (lncRNA) expression of patients with NMIBC. Differentially expressed mRNAs and lncRNAs were screened between cancer and normal tissues and validated by quantitative polymerase chain reaction (qPCR), and lncRNA-mRNA-miRNA interaction network was constructed. RESULTS: A total of 91 upregulated and 190 downregulated genes and 34 upregulated and 58 downregulated lncRNAs were screened from the sequencing result. The differentially expressed mRNAs were enriched in focal adhesion, rap1 signaling pathway, Hippo signaling pathway, PI3K-Akt signaling pathway, extracellular matrix (ECM)-receptor interaction, Ras signaling pathway, and mitogen-activated protein kinases signaling pathway, of which some pathways were involved in the cancer development. In the RNA sequencing, KIT and laminin subunitγ γ3 (LAMC3) were significantly downregulated in the NMIBC group compared with the normal group. The results of quantitative reverse transcription PCR showed that the expression of LAMC3 and KIT were significantly decreased in the NMIBC group compared with the normal group. The lncRNA-mRNA-miRNA interaction network was constructed by Cytoscape software to further investigate the interaction correlations. The results implied that KIT and LAMC3 might regulate the lncRNAs (such as ENST00000445707, ENST00000501122, ENST00000505254, ENST00000528986, ENST00000557661, ENST00000602964, ENST00000614517, ENST00000620864, and ENST00000623414) by the miRNAs (such as hsa-let-7f-2-3p, hsa-miR-125a-3p, hsa-miR-134-3p, hsa-miR-191-5p, hsa-miR-210-5p, hsa-miR-30a-5p, hsa-miR-30d-5p, hsa-miR-30e-5p, hsa-miR-92a-2-5p, and hsa-miR-95-3p), and finally played a role in the development of NMIBC cancer. CONCLUSION: Altogether, our study preliminarily indicated that KIT and LAMC3 might play a crucial role in the development of NMIBC cancer via a complex mRNA-lncRNA-miRNA regulatory network.

6.
Chin Med Sci J ; 33(1): 64-68, 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-29620517

RESUMO

We herein reported a 27-year-old woman with a right renal mass for two years. She underwent laparoscopic partial nephrectomy. Immunohistochemical examination of the specimen confirmed the diagnosis of solitary fibrous tumor by revealing its positive staining for cluster of differentiation (CD)34, epithelial membrane antigen (EMA), B-cell lymphoma-2 (Bcl-2) and CD99 in the tumor cells. No adjuvant treatment was carried out. The patient was in good health without local recurrence or metastasis during 2 years of follow-up. Laparoscopic partial nephrectomy for renal solitary fibrous tumor is an alternative treatment to radical nephrectomy. It can provide a good outcome. However, further follow-up and more cases of renal solitary fibrous tumor treated with laparoscopic partial nephrectomy are necessary to compare the oncological outcome with radical nephrectomy.


Assuntos
Neoplasias Renais/cirurgia , Rim/patologia , Rim/cirurgia , Nefrectomia/métodos , Tumores Fibrosos Solitários/cirurgia , Adulto , Feminino , Humanos
7.
J Control Release ; 268: 198-211, 2017 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-29061511

RESUMO

Malignant proliferation and metastasis in non-small cell lung carcinoma (NSCLC) are great challenges for effective clinical treatment through conventional chemotherapy. The combinational therapy strategy of RNA interfering (RNAi) technology and chemotherapeutic agents have been reported to be promising for effective cancer therapy. In this study, based on multifunctional nanoparticles (NPs), the simultaneous delivery of etoposide (ETP) and anti-Enhancer of Zeste Homologue 2 (EZH2) siRNA for the effective treatment of orthotopic lung tumor was achieved. The NPs exhibited pH/redox dual sensitivity verified by particle size changes, morphological changes, and in vitro release of drugs. Confocal microscopy analysis confirmed that the NPs exhibited endosomal escape property and on-demand intracellular drug release behavior, which can protect siRNA from degradation and facilitate the chemotherapeutic effect respectively. In vitro tumor cell motility study demonstrated that EZH2 siRNA loaded in NPs can decrease the migration and invasion capabilities of tumor cells by downregulating the expression of EZH2 mRNA and protein. In particular, an antiproliferation study revealed that the co-delivery of siRNA and ETP in the multifunctional NPs can induce a synergistic therapeutic effect on NSCLC. In vivo targeting evaluation showed that cRGDyC-PEG modification on NPs exhibited a low distribution in normal organs and an obvious accumulation in orthotopic lung tumor. Furthermore, targeted NPs co-delivering siRNA and ETP showed superior inhibition on tumor growth and metastasis and produced minimal systemic toxicity. These findings indicated that multifunctional NPs can be utilized as a co-delivery system, and that the combination of EZH2 siRNA and ETP can effectively treat NSCLC.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Etoposídeo/administração & dosagem , Nanopartículas/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Células A549 , Animais , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Terapia Combinada , Liberação Controlada de Fármacos , Etoposídeo/química , Feminino , Humanos , Camundongos Nus , Nanopartículas/química , Polímeros/administração & dosagem , Polímeros/química , RNA Interferente Pequeno/química
8.
Int J Nanomedicine ; 12: 4241-4256, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28652730

RESUMO

Physicochemical properties, including particle size, zeta potential, and drug release behavior, affect targeting efficiency, cellular uptake, and antitumor effect of nanocarriers in a formulated drug-delivery system. In this study, a novel stepwise pH-responsive nanodrug delivery system was developed to efficiently deliver and significantly promote the therapeutic effect of doxorubicin (DOX). The system comprised dimethylmaleic acid-chitosan-urocanic acid and elicited stepwise responses to extracellular and intracellular pH. The nanoparticles (NPs), which possessed negative surface charge under physiological conditions and an appropriate nanosize, exhibited advantageous stability during blood circulation and enhanced accumulation in tumor sites via enhanced permeability and retention effect. The tumor cellular uptake of DOX-loaded NPs was significantly promoted by the first-step pH response, wherein surface charge reversion of NPs from negative to positive was triggered by the slightly acidic tumor extracellular environment. After internalization into tumor cells, the second-step pH response in endo/lysosome acidic environment elicited the on-demand intracellular release of DOX from NPs, thereby increasing cytotoxicity against tumor cells. Furthermore, stepwise pH-responsive NPs showed enhanced antiproliferation effect and reduced systemic side effect in vivo. Hence, the stepwise pH-responsive NPs provide a promising strategy for efficient delivery of antitumor agents.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Quitosana/química , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Avaliação Pré-Clínica de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Concentração de Íons de Hidrogênio , Malonatos/química , Camundongos Endogâmicos BALB C , Nanopartículas/química , Tamanho da Partícula , Distribuição Tecidual , Ácido Urocânico/química
9.
J Biomed Mater Res B Appl Biomater ; 105(5): 1114-1125, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27008163

RESUMO

The development of effective and stable carriers of small interfering RNA (siRNA) is important for treating cancer with multidrug resistance (MDR). We developed a new gene and drug co-delivery system and checked its characteristics. Low-density lipoprotein (LDL) was coupled with N-succinyl chitosan (NSC) Lipoic acid (LA) micelles and co-delivered MDR1 siRNA and paclitaxel (PTX-siRNA/LDL-NSC-LA) to enhance antitumor effects by silencing the MDR gene of tumors (Li et al., Adv Mater 2014;26:8217-8224). In our study, we developed a new type of containing paclitaxel-loaded micelles and siRNA-loaded LDL nanoparticle. This "binary polymer" is pH and reduction dual-sensitive core-crosslinked micelles. PTX-siRNA/LDL-NSC-LA had an average particle size of (171.6 ± 6.42) nm, entrapment efficiency of (93.92 ± 1.06) %, and drug-loading amount of (12.35% ± 0.87) %. In vitro, MCF-7 cells, high expressed LDL receptor, were more sensitive to this delivery system than to taxol® and cell activity was inhibited significantly. Fluorescence microscopy showed that PTX-siRNA/LDL-NSC-LA was uptaken very conveniently and played a key role in antitumor activity. PTX-siRNA/LDL-NSC-LA protected the siRNA from degradation by macrophage phagocytosis and evidently down-regulated the level of mdr1 mRNA as well as the expression of P-gp. We tested the target ability of PTX-siRNA/LDL-NSC-LA in vivo in tumor-bearing nude mice. Results showed that this system could directly deliver siRNA and PTX to cancer cells. Thus, new co-delivering siRNA and antitumor drugs should be explored for solving MDR in cancer. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1114-1125, 2017.


Assuntos
Quitosana , Técnicas de Transferência de Genes , Lipoproteínas LDL , Micelas , Proteínas de Neoplasias , Neoplasias Experimentais , Paclitaxel/farmacologia , RNA Interferente Pequeno , Ácido Tióctico , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Quitosana/química , Quitosana/farmacologia , Feminino , Humanos , Lipoproteínas LDL/química , Lipoproteínas LDL/farmacologia , Células MCF-7 , Camundongos , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , RNA Interferente Pequeno/biossíntese , RNA Interferente Pequeno/genética , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Biomed Mater Res B Appl Biomater ; 105(7): 2093-2106, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-27405391

RESUMO

P-glycoprotein (P-gp) plays an importantrole in multidrug resistance (MDR), proved to be one of the major obstacles in cancer chemotherapy. Cationic polymers could specifically deliver siRNA to tumor cells and thus reverse MDR by the downregulation of P-gp. In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl-chitosan-poly-l-lysine-palmitic acid (NSC-PLL-PA) to deliver siRNA-P-gp (siRNA-micelle) or doxorubicin (Dox-micelle). The resulting micelle exhibited an efficient binding ability for siRNA and high encapsulation efficiency for Dox, with an average particle size of ∼170 nm. siRNA-micelle and Dox-micellewere instable at low pH, thereby enhancing tumor accumulation and intracellular release of the encapsulated siRNA and Dox. siRNA-micelle micelles could enhance the knockdown efficacy of siRNA by improving the transfection efficiency, downregulating P-gp expression, and passing the drug efflux transporters, thereby improving the therapeutic effects of Dox-micelle. However, P-gp could transfer from HepG2/ADM to HepG2 cells independent of the expression of mdr1, and the acquired resistance could permit tumor cells to survive and develop intrinsic P-gp-mediated resistance, thereby limiting the desired efficiency of chemotherapeutics. This study demonstrated the effectiveness of siRNA-micelle for tumor-targeted delivery, MDR reversal, and provided an effective strategy for the treatment of cancers that develop MDR. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2093-2106, 2017.


Assuntos
Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Micelas , Proteínas de Neoplasias , Neoplasias , RNA Interferente Pequeno , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Células Hep G2 , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia
11.
J Integr Plant Biol ; 59(1): 2-14, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27762067

RESUMO

SIZ1 is a small ubiquitin-related modifier (SUMO) E3 ligase that mediates post-translational SUMO modification of target proteins and thereby regulates developmental processes and hormonal and environmental stress responses in Arabidopsis. However, the role of SUMO E3 ligases in crop plants is largely unknown. Here, we identified and characterized two Glycine max (soybean) SUMO E3 ligases, GmSIZ1a and GmSIZ1b. Expression of GmSIZ1a and GmSIZ1b was induced in response to salicylic acid (SA), heat, and dehydration treatment, but not in response to cold, abscisic acid (ABA), and NaCl treatment. Although GmSIZ1a was expressed at higher levels than GmSIZ1b, both genes encoded proteins with SUMO E3 ligase activity in vivo. Heterologous expression of GmSIZ1a or GmSIZ1b rescued the mutant phenotype of Arabidopsis siz1-2, including dwarfism, constitutively activated expression of pathogen-related genes, and ABA-sensitive seed germination. Simultaneous downregulation of GmSIZ1a and GmSIZ1b (GmSIZ1a/b) using RNA interference (RNAi)-mediated gene silencing decreased heat shock-induced SUMO conjugation in soybean. Moreover, GmSIZ1RNAi plants exhibited reduced plant height and leaf size. However, unlike Arabidopsis siz1-2 mutant plants, flowering time and SA levels were not significantly altered in GmSIZ1RNAi plants. Taken together, our results indicate that GmSIZ1a and GmSIZ1b mediate SUMO modification and positively regulate vegetative growth in soybean.


Assuntos
Proteínas de Plantas/metabolismo , Soja/enzimologia , Soja/crescimento & desenvolvimento , Ubiquitina-Proteína Ligases/metabolismo , Núcleo Celular/metabolismo , Regulação para Baixo/genética , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Folhas de Planta/anatomia & histologia , Proteínas de Plantas/genética , Transporte Proteico , Reação em Cadeia da Polimerase em Tempo Real , Ácido Salicílico/metabolismo , Soja/anatomia & histologia , Soja/genética , Frações Subcelulares/metabolismo
12.
ACS Appl Mater Interfaces ; 8(47): 32146-32158, 2016 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-27933846

RESUMO

The efficient delivery of antitumor agents to tumor sites faces numerous obstacles, such as poor cellular uptake and slow intracellular drug release. In this regard, smart nanoparticles (NPs) that respond to the unique microenvironment of tumor tissues have been widely used for drug delivery. In this study, novel charge-reversal and reduction-responsive histidine-grafted chitosan-lipoic acid NPs (HCSL-NPs) were selected for efficient therapy of breast cancer by enhancing cell internalization and intracellular pH- and reduction-triggered doxorubicin (DOX) release. The surface charge of HCSL-NPs presented as negative at physiological pH and reversed to positive at the extracellular and intracellular pH of the tumor. In vitro release investigation revealed that DOX/HCSL-NPs demonstrated a sustained drug release under the physiological condition, whereas rapid DOX release was triggered by both endolysosome pH and high-concentration reducing glutathione (GSH). These NPs exhibited enhanced internalization at extracellular pH, rapid intracellular drug release, and improved cytotoxicity against 4T1 cells in vitro. Excellent tumor penetrating efficacy was also found in 4T1 tumor spheroids and solid tumor slices. In vivo experiments demonstrated that HCSL-NPs exhibited excellent tumor-targeting ability in tumor tissues as well as excellent antitumor efficacy and low systemic toxicity in breast tumor-bearing BALB/c mice. These results indicated that the novel charge-reversal and reduction-responsive HCSL-NPs have great potential for targeted and efficient delivery of chemotherapeutic drugs in cancer treatments.


Assuntos
Nanopartículas , Animais , Doxorrubicina , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C
13.
Int J Pharm ; 511(2): 728-40, 2016 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-27484835

RESUMO

Internal stimuli, such as intracellular lysosomal pH, enzyme, redox and reduction, can be applied to improve biological specificity of chemotherapeutic drugs for cancer therapy. Thus, functionalized copolymers based on their response to specific microenvironment of tumor regions have been designed as smart drug vesicles for enhanced anti-cancer efficiency and reduced side effects. Herein, we reported dually pH/reduction-responsive novel micelles based on self-assembly of carboxymethyl chitosan-cysteamine-N-acetyl histidine (CMCH-SS-NA) and doxorubicin (DOX). The tailor-made dually responsive micelles demonstrated favorable stability in normal physiological environment and triggered rapid drug release in acidic and/or reduction environment. Additionally, the nanocarriers responded to the intracellular environment in an ultra-fast manner within several minutes, which led to the pinpointed release of DOX in tumor cells effectively and ensured higher DOX concentrations within tumor areas with the aid of targeted delivery, thereby leading to enhanced tumor ablation. Thus, this approach with sharp drug release behavior represented a versatile strategy to provide a promising paradigm for cancer therapy.


Assuntos
Doxorrubicina/farmacologia , Doxorrubicina/farmacocinética , Micelas , Microambiente Tumoral/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quitosana/análogos & derivados , Quitosana/química , Cisteamina/química , Doxorrubicina/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Feminino , Histidina/química , Concentração de Íons de Hidrogênio , Fígado/metabolismo , Camundongos , Oxirredução , Ratos , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Sci Rep ; 6: 23859, 2016 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-27030638

RESUMO

Co-delivery of chemotherapeutics and siRNA with different mechanisms in a single system is a promising strategy for effective cancer therapy with synergistic effects. In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl chitosan-poly-L-lysine-palmitic acid (NSC-PLL-PA) to co-deliver doxorubicin (Dox) and siRNA-P-glycoprotein (P-gp) (Dox-siRNA-micelle). Dox-siRNA-micelle was unstable in pH 5.3 medium than in pH 7.4 medium, which corresponded with the in vitro rapid release of Dox and siRNA in acidic environments. The antitumor efficacy of Dox-siRNA-micelle in vitro significantly increased, especially in HepG2/ADM cells, which was due to the downregulation of P-gp. Moreover, almost all the Dox-siRNA-micelles accumulated in the tumor region beyond 24 h post-injection, and the co-delivery system significantly inhibited tumor growth with synergistic effects in vivo. This study demonstrated the effectiveness of Dox-siRNA-micelles in tumor-targeting and MDR reversal, and provided a promising strategy to develop a co-delivery system with synergistic effects for combined cancer therapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antibióticos Antineoplásicos/farmacologia , Terapia Combinada/métodos , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Hepáticas/terapia , RNA Interferente Pequeno/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Expressão Gênica , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Micelas , RNA Interferente Pequeno/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Int J Nanomedicine ; 11: 325-36, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26855571

RESUMO

In this study, harmine liposomes (HM-lip) were prepared through the thin-film hydration-pH-gradient method and then coated with N-trimethyl chitosan (TMC). Particle size, zeta potential, entrapment efficiency, and in vitro release of HM-lip and TMC-coated harmine liposomes (TMC-HM-lip) were also determined. Sprague Dawley rats were further used to investigate the pharmacokinetics in vivo. Retention behavior in mouse gastrointestinal tract (GIT) was studied through high-performance liquid chromatography and near-infrared imaging. Degradation was further evaluated through incubation with Caco-2 cell homogenates, and a Caco-2 monolayer cell model was used to investigate the uptake and transport of drugs. HM-lip and TMC-HM-lip with particle size of 150-170 nm, an entrapment efficiency of about 81%, and a zeta potential of negative and positive, respectively, were prepared. The release of HM from HM-lip and TMC-HM-lip was slower than that from HM solution and was sensitive to pH. TMC-HM-lip exhibited higher oral bioavailability and had prolonged retention time in GIT. HM-lip and TMC-HM-lip could also protect HM against degradation in Caco-2 cell homogenates. The uptake amount of TMC-HM-lip was higher than that of HM and HM-lip. TMC-HM-lip further demonstrated higher apparent permeability coefficient (P(app)) from the apical to the basolateral side than HM and HM-lip because of its higher uptake and capability to open tight junctions in the cell monolayers. TMC-HM-lip can prolong the retention time in the GIT, protect HM against enzyme degradation, and improve transport across Caco-2 cell monolayers, thus enhancing the oral bioavailability of HM.


Assuntos
Quitosana/química , Trato Gastrointestinal/efeitos dos fármacos , Harmina/metabolismo , Lipossomos/química , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Portadores de Fármacos/química , Trato Gastrointestinal/citologia , Trato Gastrointestinal/metabolismo , Humanos , Técnicas In Vitro , Lipossomos/administração & dosagem , Camundongos , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley
16.
Sci Rep ; 5: 17904, 2015 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-26639052

RESUMO

An antibody that specifically interacts with an antigen could be applied to an active targeting delivery system. In this study, CD147 antibody was coupled with α-hed chitosan nanoparticles (α-Hed-CS-NPs). α-Hed-CS-CD147-NPs were round and spherical in shape, with an average particle size of 148.23 ± 1.75 nm. The half-maximum inhibiting concentration (IC50) of α-Hed-CS-CD147-NPs in human liver cancer cell lines HepG2 and SMMC-7721 was lower than that of free α-Hed and α-Hed-CS-NPs. α-Hed-induced cell death was mainly triggered by apoptosis. The increase in intracellular accumulation of α-Hed-CS-CD147-NPs was also related to CD147-mediated internalization through the Caveolae-dependent pathway and lysosomal escape. The higher targeting antitumor efficacy of α-Hed-CS-CD147-NPs than that α-Hed-CS-NPs was attributed to its stronger fluorescence intensity in the tumor site in nude mice.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Basigina/imunologia , Quitosana/química , Endocitose/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Nanopartículas/química , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Animais , Anexina A5/metabolismo , Apoptose/efeitos dos fármacos , Citometria de Fluxo , Fluorescência , Células Hep G2 , Humanos , Imagem Tridimensional , Espaço Intracelular/metabolismo , Camundongos Nus , Microscopia Confocal , Nanopartículas/ultraestrutura , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Tamanho da Partícula , Propídio/metabolismo , Saponinas/síntese química , Saponinas/química , Espectroscopia de Infravermelho com Transformada de Fourier , Espectroscopia de Luz Próxima ao Infravermelho , Frações Subcelulares/metabolismo
18.
Int J Pharm ; 492(1-2): 141-51, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26188316

RESUMO

This study aimed to prepare efficient cRGDyK peptide-decorated micelles for the targeted therapy of non-small-cell lung cancer (NSCLC). An amphiphilic copolymer N-succinyl-palmitoyl-chitosan (SPCS) was synthesized and characterized. cRGDyK peptide is a ligand that can target tumors via specific binding integrin receptor overexpressed on tumor neovascularization and cells. cRGDyK-functionalized SPCS micelles loaded with paclitaxel (PTX/cRGDyK-SPCS) were prepared by film dispersion method and then characterized according to morphology, size, and zeta potential. PTX/cRGDyK-SPCS micelles presented pH-triggered drug release behavior under acidic conditions. The accumulation of micelles detected by laser confocal fluorescence microscopy and flow cytometry showed that cRGDyK-SPCS micelles were easily taken up by A549 cells marked with the luciferase gene (luc-A549). Meanwhile, co-localization of the micelles and lysosomes was recorded dynamically using a live cell station. MTT assays and cell apoptosis studies revealed that cell viability was significantly inhibited by PTX/cRGDyK-SPCS micelles. More importantly, in vivo animal studies showed that cRGDyK-SPCS micelles mainly accumulated in the orthotopic tumor site. PTX/cRGDyK-SPCS micelles exhibited better anti-tumor activity in subcutaneous and orthotopic lung tumors compared with PTX/SPCS micelles and Taxol(®). These results suggested that PTX/cRGDyK-SPCS micelles had better cancer targeting capacity and superior anti-tumor efficacy. Thus, these micelles have great potential as novel carriers in delivering anti-tumor drugs.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Quitosana/análogos & derivados , Quitosana/administração & dosagem , Paclitaxel/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Quitosana/uso terapêutico , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos Nus , Micelas , Microtúbulos/efeitos dos fármacos , Paclitaxel/química , Paclitaxel/uso terapêutico , Peptídeos Cíclicos/química , Peptídeos Cíclicos/uso terapêutico , Carga Tumoral/efeitos dos fármacos
19.
Int J Nanomedicine ; 9: 2919-32, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24966673

RESUMO

N-Succinyl-chitosan (NSC) was synthesized and NSC nanoparticles (NPs) with loaded osthole (Ost) (Ost/NSC-NPs) were prepared by emulsion solvent diffusion. Subsequently, low-density lipoprotein (LDL)-mediated NSC-NPs with loaded Ost (Ost/LDL-NSC-NPs) were obtained by coupling LDL with Ost/NSC-NPs through amide linkage. The average particle size of Ost/NSC-NPs was approximately 145 nm, the entrapment efficiency was 78.28%±2.06%, and the drug-loading amount was 18.09%±0.17%. The release of Ost from Ost/NSC-NPs in vitro showed a more evident sustained effect than the native material. The half maximal inhibitory concentration of Ost/LDL-NSC-NPs was only 16.23% that of the free Ost at 24 hours in HepG2 cells. Ost inhibited HepG2 cell proliferation by arresting cells in the synthesis phase of the cell cycle and by triggering apoptosis. Cellular uptake and subcellular localization in vitro and near-infrared fluorescence real-time imaging in vivo showed that Ost/LDL-NSC-NPs had high targeting efficacy. Therefore, LDL-NSC-NPs are a promising system for targeted Ost delivery to liver tumor.


Assuntos
Quitosana/química , Cumarínicos/administração & dosagem , Lipoproteínas/farmacocinética , Nanoconjugados/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Receptores de LDL/metabolismo , Animais , Cumarínicos/química , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Lipoproteínas/química , Camundongos , Camundongos Nus , Nanocápsulas/administração & dosagem , Nanocápsulas/química , Nanoconjugados/administração & dosagem , Nanoconjugados/ultraestrutura , Neoplasias Experimentais/patologia , Resultado do Tratamento
20.
Biomaterials ; 35(22): 5965-76, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24768047

RESUMO

Developing safe and effective carriers of small interference RNA (siRNA) is a significant demand for the systemic delivery of siRNA. In this study, low-density lipoprotein (LDL) was isolated from human plasma and loaded with cholesterol-conjugated siRNA to silence the multidrug resistant gene of tumors. Chol-siRNA/LDL-coupled N-succinyl chitosan nanoparticles loaded with doxorubicin (Dox-siRNA/LDL-SCS-NPs) were then prepared and characterised. The Dox-siRNA/LDL-SCS-NPs had average particle size of 206.4 ± 9.2 nm, entrapment efficiency of 71.06% ± 1.42%, and drug-loading amount of 12.35% ± 0.87%. In vitro antitumor activity revealed that cell growth was significantly inhibited. The accumulation of Dox by fluorescence microscopy and flow cytometry showed that LDL-coupled nanoparticles were more easily taken up than Dox-SCS-NPs. Results of confocal microscopy and reverse transcription-PCR revealed the highly efficient uptake of siRNA and the decrease in mdr1 mRNA expression. LDL-coupled nanoparticles protected siRNA from macrophage phagocytosis by dynamic observation using live cell station. In vivo tumor-targeting suggested that Cy7-labelled Dox-LDL-SCS-NPs were markedly accumulated in an analyzed in situ liver tumor model. Results indicated that LDL-SCS-NPs were effective tumor-targeting vectors and that the preparation form may provide a new strategy for co-delivering siRNA and antitumor drugs.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Quitosana/química , Doxorrubicina/administração & dosagem , Lipoproteínas LDL/química , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos , Feminino , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , RNA Interferente Pequeno/genética
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