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1.
Chem Commun (Camb) ; 55(66): 9829-9832, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31363730

RESUMO

Polyethylene glycol grafted pyrrole-based conjugated polymers are synthesized through a one-pot multicomponent methodology, the self-assemblies of which enable nanoparticle size-selective encapsulation of drug molecules and their sustained release. Efficient loading of curcumin through drug-nanoparticle core interactions is probed using FRET, and the inherently fluorescent nature of polypyrrole could be used to detect these nanocarriers intracellularly.


Assuntos
Portadores de Fármacos , Nanopartículas/química , Polietilenoglicóis/química , Polímeros/química , Pirróis/química , Linhagem Celular Tumoral , Curcumina/administração & dosagem , Transferência Ressonante de Energia de Fluorescência , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Microscopia Eletrônica de Transmissão , Espectrofotometria Ultravioleta
2.
Braz Oral Res ; 33: e075, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31432926

RESUMO

Resinous infiltrants are indicated in the treatment of incipient carious lesions, and further development of these materials may contribute to greater control of these lesions. The aim of this study was to analyze the physical and antibacterial properties of experimental infiltrants containing iodonium salt and chitosan. Nine experimental infiltrants were formulated by varying the concentration of the diphenyliodonium salt (DPI) at 0, 0.5 and 1 mol%; and chitosan at 0, 0.12 and 0.25 g%. The infiltrants contained the monomeric base of triethylene glycol dimethacrylate and bisphenol-A dimethacrylate ethoxylate in a 75 and 25% proportion by weight, respectively; 0.5 mol% camphorquinone and 1 mol% ethyl 4-dimethylaminobenzoate. The degree of conversion was evaluated using Fourier transformer infrared spectroscopy, and the flexural strength and elastic modulus using the three-point bending test. Sorption and solubility in water, and antibacterial analysis (minimum inhibitory concentration and minimum bactericidal concentration) were also analyzed. Data was analyzed statistically by two-way ANOVA and Tukey's test (p<0.05), with the exception of the antibacterial test, which was evaluated by visual inspection. In general, the infiltrant group containing 0.5% DPI and 0.12% chitosan showed high values of degree of conversion, higher values of elastic modulus and flexural strength, and lower sorption values in relation to the other groups. Antibacterial activity was observed in all the groups with DPI, regardless of the concentration of chitosan. The addition of DPI and chitosan to experimental infiltrants represents a valid option for producing infiltrants with desirable physical and antibacterial characteristics.


Assuntos
Antibacterianos/química , Quitosana/química , Resinas Compostas/química , Metacrilatos/química , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Sais/química , Análise de Variância , Antibacterianos/farmacologia , Quitosana/farmacologia , Resinas Compostas/farmacologia , Módulo de Elasticidade , Resistência à Flexão , Lactobacillus acidophilus/efeitos dos fármacos , Cura Luminosa de Adesivos Dentários , Teste de Materiais , Metacrilatos/farmacologia , Testes de Sensibilidade Microbiana , Polietilenoglicóis/farmacologia , Ácidos Polimetacrílicos/farmacologia , Valores de Referência , Reprodutibilidade dos Testes , Sais/farmacologia , Solubilidade , Estatísticas não Paramétricas , Streptococcus mutans/efeitos dos fármacos
3.
Braz Oral Res ; 33: e083, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31460609

RESUMO

This study evaluated the influence of activation modes, on Diametral Tensile Strength (DTS) of dual cured resin cements subjected to a Mechanical Fatigue test (MF). Four dual-cured resin cements (RelyX UNICEM [U], RelyX ARC [A], ENFORCE [E] and Nexus 2 [N]) were activated by three different curing modes as follows: Self-Curing (SC), Dual Cure activation with photoactivation executed directly (DC) and Dual Cure activation with Photoactivation Through Porcelain (DCTP). After 24 hours, half of the sample was subjected to 30.000 fatigue cycles at 1 Hz frequency and 12 N load. Then, all specimens were subjected to DTS test in Instron Universal Testing Machine and data were analyzed by three-way ANOVA and Tukey's Test (5%). The results of DTS test means (MPa) and standard deviation, for each cement factor activated by SC, DC and DCTP was respectively: U (28.12 ± 5.29; 37.44 ± 6.49 and 40.10 ± 4.39), A (49.68 ± 8.42; 55.12 ± 5.16 and 63.43 ± 6.92), E (49.12 ± 3.89; 56.42 ± 8.88 and 56.96 ± 6.45) and N (61.89 ± 11.21; 59.26 ± 9.47 and 62.56 ± 10.93). Turkey's test indicated that DC is related to the highest DTS values; Nexus 2 DTS remained the same independently of activation mode and that the Porcelain disk interposition enhanced DTS only for RelyX ARC the ANOVA statistical test indicated that MF didn't alter the DTS values for all experimental groups. MF results clinical implication is that all cements tested exhibited, in an immediate loading, good cross linked bonds quality.


Assuntos
Bis-Fenol A-Glicidil Metacrilato/química , Cerâmica/química , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Cimentos de Resina/química , Análise de Variância , Cura Luminosa de Adesivos Dentários/métodos , Teste de Materiais , Valores de Referência , Reprodutibilidade dos Testes , Autocura de Resinas Dentárias/métodos , Resistência à Tração
4.
Biomater Sci ; 7(9): 3729-3740, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31403142

RESUMO

Targeted delivery of immunosuppressants to allografts can increase the concentrations of drugs in pathological tissues, improve therapeutic effects and reduce unfavorable side effects. Therefore, we synthesized FK506-loaded microbubbles (FK506-MBs) for site-specific release of FK506 into transplanted hearts by the ultrasound-targeted microbubble destruction (UTMD) technique. The average particle size of FK506-MBs was 1.65 ± 0.32 µm and they had high drug loading and encapsulation efficiency. The in vivo drug concentration in transplanted hearts that were treated with FK506-MBs plus UTMD was about 1.64-fold higher than that in grafts that received free FK506 at the same dosage. The degree of graft rejection in the FK506-MB plus UTMD group was lower than those of other groups. Both infiltration of T cells and secretion of inflammatory cytokines were significantly reduced in the FK506-MB plus UTMD group. More importantly, the mean survival time of the grafts was significantly longer (16.00 ± 0.89 day) than those of the PBS group (6.66 ± 1.36 day) and the FK506 group (12.83 ± 1.17 day). In addition, we also found that the concentration of FK506 in whole blood was lower in the FK506-MB plus UTMD group than that in the FK506 group, which would be beneficial for reducing the side effects. Hence, our results showed that combining FK506-MBs with UTMD was an effective strategy to deliver FK506 to transplanted hearts, which can increase the local drug concentration and enhance its efficacy on rejection. Ultrasound-targeted drug release is safe and radiation-free, with great potential for clinical transformation, and could also be extended to the treatment of other graft rejection cases, such as liver transplantation, kidney transplantation and so on.


Assuntos
Portadores de Fármacos/química , Rejeição de Enxerto/tratamento farmacológico , Transplante de Coração , Imunossupressores/farmacocinética , Miocárdio/metabolismo , Tacrolimo/farmacocinética , Animais , Liberação Controlada de Fármacos , Estudos de Viabilidade , Imunossupressores/administração & dosagem , Masculino , Microbolhas , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos , Tacrolimo/administração & dosagem , Ultrassonografia
5.
Int J Nanomedicine ; 14: 5109-5123, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371950

RESUMO

Background: Renal cell carcinoma (RCC) is notorious for its resistance towards chemotherapy and radiation therapy in general. Combination therapy is often helpful in alleviating the resistance mechanisms by targeting multiple signaling pathways but is usually more toxic than monotherapy. Co-encapsulation of multiple therapeutic agents in a tumor-targeted drug delivery platform is a promising strategy to mitigate these limitations. Methods: A tumor-targeted liposomal formulation was prepared using phospholipids, cholesterol, DSPE-(PEG)2000-OMe and a proprietary tumor-targeting-peptide (TTP)-conjugated lipopeptide. An efficient method was optimized to encapsulate everolimus and vinorelbine in this liposomal formulation. Single drug-loaded liposomes were also prepared for comparison. Finally, the drug-loaded liposomes were tested in vitro and in vivo in two different RCC cell lines. Results: The tumor-targeted liposomal formulation demonstrated excellent tumor-specific uptake. The dual drug-loaded liposomes exhibited significantly higher growth inhibition in vitro compared to the single drug-loaded liposomes in two different RCC cell lines. Similarly, the dual drug-loaded liposomes demonstrated significantly higher suppression of tumor growth compared to the single drug-loaded liposomes in two different subcutaneous RCC xenografts. In addition, the dual drug-loaded liposomes instigated significant reduction in lung metastasis in those experiments. Conclusion: Taken together, this study demonstrates that co-delivery of everolimus and vinorelbine with a tumor-targeted liposomal formulation is an effective approach to achieve improved therapeutic outcome in RCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Everolimo/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Vinorelbina/administração & dosagem , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Antígeno Ki-67/metabolismo , Lipossomos , Neoplasias Pulmonares/secundário , Camundongos SCID , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Pharm Res ; 36(10): 145, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396764

RESUMO

PURPOSE: The immediate plasma metabolism and development of chemo-resistance (single agent) severely hampers the clinical effectiveness of Sorafenib (SRF) in liver cancer therapy. MicroRNA27a inhibition is a promising biological strategy for breast cancer therapy. METHODS: In this study, we aimed to prepare SRF and anti-miRNA27a-loaded anti-GPC3 antibody targeted lipid nanoparticles to enhance the therapeutic efficacy against liver cancers. In this study, we have employed a unique cationic switchable lipid (CSL) as a mean to encapsulate miRNA as well as to confer pH-responsiveness to the nanocarrier system. RESULTS: The G-S27LN was nanosized and offered a pH-responsive release of SRF from the carrier system and we have demonstrated the specific affinity of G-S27LN towards the GPC3-overexpressed HepG2 cancer cells. Anti-microRNA27a significantly increased the protein expression of FOXO1 and PPAR-γ which are crucial components involved in proliferation and apoptosis of tumor cells. Combination of SRF and anti-miRNA27a (G-S27LN) resulted in significantly lower cell viability with a marked increase in the apoptosis cell proportion compared to that of free SRF indicating the synergistic anticancer effect. Animal studies in liver cancer xenograft model demonstrated significant suppression of tumor burden, reduced tumor cell and elevated TUNEL positive apoptosis with no toxicity concerns in animals treated with G-S27LN formulation. CONCLUSION: The CSL-based G-S27LN efficiently co-delivered anti-microRNA27a and SRF and therefore represents a promising therapy to treat liver cancer. This study also brings forth a platform strategy for the effective treatment of number of other advanced cancers.


Assuntos
Antagomirs/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Glipicanas/imunologia , Lipídeos/química , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/imunologia , Nanopartículas/química , Sorafenibe/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/química , Sinergismo Farmacológico , Proteína Forkhead Box O1/metabolismo , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Camundongos Nus , PPAR gama/metabolismo , Fosforilcolina/química , Polietilenoglicóis/química
7.
Anal Bioanal Chem ; 411(21): 5351-5361, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31267193

RESUMO

Exosomes are membrane-bound vesicles secreted by cells, and contain various important biological molecules, such as lipids, proteins, messenger RNAs, microRNAs, and noncoding RNAs. Emerging evidence demonstrates that proteomic analysis of exosomes is of great significance in studying metabolic diseases, tumor metastasis, immune regulation, and so forth. However, exosome proteomic analysis has high requirements with regard to the purity of collected exosomes. Here recent advances in the methods for isolating exosomes and their applications in proteomic analysis are summarized. Graphical abstract.


Assuntos
Exossomos , Proteômica/métodos , Cromatografia de Afinidade/métodos , Humanos , MicroRNAs/metabolismo , Polietilenoglicóis/química , Proteínas/metabolismo , RNA Mensageiro/metabolismo , RNA não Traduzido/metabolismo
8.
J Phys Chem Lett ; 10(16): 4505-4510, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31310141

RESUMO

Owing to their excellent surface plasmonic properties, Au nanobranches have drawn increasing attention in various bioapplications, such as contrast agents for photoacoustic imaging, nanomedicines for photothermal therapy, and carriers for drug delivery. The monodispersity and plasmonic bandwidth of Au nanobranches are of great importance for the efficacy of those bioapplications. However, it is still a challenge to accurately synthesize size- and shape-controlled Au nanobranches. Here we report a facile seed-mediated growth method to synthesize monodisperse Au nanotetrapods (NTPs) with tunable and ultranarrow plasmonic bands. The NTPs have a novel D2d symmetry with four arms elongated in four ⟨110⟩ directions. The growth mechanism of NTPs relies on the delicate kinetic control of deposition and diffusion rates of adatoms. Upon laser irradiation, the PEGylated NTPs possess remarkable photothermal conversion efficiencies and photoacoustic imaging properties. The NTPs can be applied as a multifunctional theranostic agent for both photoacoustic imaging and image-guided photothermal therapy.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Nanomedicina Teranóstica , Polietilenoglicóis/química , Temperatura Ambiente
9.
Pharm Res ; 36(9): 134, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31297653

RESUMO

PURPOSE: Despite extensive preclinical investigations, in-vivo properties and formulation characteristics that improve CNS drug delivery following systemic dosing of nanoemulsions remain incompletely understood. METHODS: The CNS targeting potential of systemically administered nanoemulsions was evaluated by formulating rapamycin containing fish oil nanoemulsions, and testing the combined effect of formulation characteristics such as the circulation half-life and particle size distribution, on CNS delivery of rapamycin containing fish oil nanoemulsions in mice. RESULTS: Results generated with rapamycin nanoemulsions suggested that circulation half-life and particle size distribution did not impact the brain targeting efficiency of rapamycin containing fish oil nanoemulsions. Further, in the absence of any improvement in the systemic exposures of rapamycin, nanoemulsions did not outperform their aqueous counterpart with respect to the extent of CNS drug delivery. CONCLUSIONS: Our findings confirm that BBB penetration, which primarily depends on intrinsic drug-related properties, may not be significantly improved following encapsulation of drugs in nanoemulsions. Graphical Abstract The CNS targeting potential of systemically administered nanoemulsions was investigated by formulating various rapamycin containing fish oil nanoemulsions associated with different formulation characteristics such as the circulation half-life and particle size distribution. The targeting efficiency (TE) defined as the ratio of the brain exposures to the accompanying systemic exposures of rapamycin was estimated for each formulation following IV dosing in mice.


Assuntos
Encéfalo/metabolismo , Óleos de Peixe/química , Nanopartículas/química , Sirolimo/administração & dosagem , Animais , Barreira Hematoencefálica/metabolismo , Permeabilidade da Membrana Celular , Emulsões , Camundongos , Tamanho da Partícula , Polietilenoglicóis/química , Sirolimo/farmacocinética , Distribuição Tecidual
10.
Chem Commun (Camb) ; 55(61): 9039-9042, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292589
11.
J Nanobiotechnology ; 17(1): 83, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291948

RESUMO

BACKGROUND: Macrophages with tumor-tropic migratory properties can serve as a cellular carrier to enhance the efficacy of anti neoplastic agents. However, limited drug loading (DL) and insufficient drug release at the tumor site remain the main obstacles in developing macrophage-based delivery systems. In this study, we constructed a biomimetic delivery system (BDS) by loading doxorubicin (DOX)-loaded reduced graphene oxide (rGO) into a mouse macrophage-like cell line (RAW264.7), hoping that the newly constructed BDS could perfectly combine the tumor-tropic ability of macrophages and the photothermal property of rGO. RESULTS: At the same DOX concentration, the macrophages could absorb more DOX/PEG-BPEI-rGO than free DOX. The tumor-tropic capacity of RAW264.7 cells towards RM-1 mouse prostate cancer cells did not undergo significant change after drug loading in vitro and in vivo. PEG-BPEI-rGO encapsulated in the macrophages could effectively convert the absorbed near-infrared light into heat energy, causing rapid release of DOX. The BDS showed excellent anti-tumor efficacy in vivo. CONCLUSIONS: The BDS that we developed in this study had the following characteristic features: active targeting of tumor cells, stimuli-release triggered by near-infrared laser (NIR), and effective combination of chemotherapy and photothermotherapy. Using the photothermal effect produced by PEG-BPEI-rGO and DOX released from the macrophages upon NIR irradiation, MAs-DOX/PEG-BPEI-rGO exhibited a significant inhibitory effect on tumor growth.


Assuntos
Antineoplásicos/química , Materiais Biomiméticos/química , Portadores de Fármacos/química , Macrófagos/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Liberação Controlada de Fármacos , Grafite/química , Humanos , Hipertermia Induzida , Raios Infravermelhos , Lasers , Masculino , Camundongos Endogâmicos BALB C , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Polietilenoimina/química , Distribuição Tecidual
12.
Chem Commun (Camb) ; 55(63): 9363-9366, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31317136

RESUMO

We developed a biodegradable, oncosensitive, megamer-based delivery system for miRNA therapy. The miRNA nanotherapeutics, activatable by stepwise stimulation of acidity and reduction mimicking tumor microenvironment, efficiently improve liver-specific miR-122 expression, increasing the possibility of translational application of miR-122 therapy against liver cancer.


Assuntos
Portadores de Fármacos/química , MicroRNAs/química , Nanopartículas/química , Polietilenoglicóis/química , Animais , Linhagem Celular Tumoral , Dendrímeros/química , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Transplante Heterólogo
13.
Int J Nanomedicine ; 14: 4461-4474, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31296986

RESUMO

Background: Vincristine is a potent therapeutic agent with well-defined activity against hematologic malignancies and solid tumors. It is a cell-cycle specific drug with concentration and exposure duration dependent activity. When used by liposomal delivery, it exhibits enhanced anti-tumor activity. However, vincristine liposome formulation in the clinic is supplied as a 3-vial-kit due to lacking sufficient stability. So it has to be prepared in situ prior to use through a multi-step process. Purpose: The purpose here is to develop a more stable and ready-to-use liposomal formulation for vincritstine in one vial. Patients and methods: A series of preparations were investigated based on sphingomyelin/cholesterol/PEG2000-DSPE lipid composition, with different drug/lipid (D/L) ratios (1/10, 1/5, 1/2), using an active sucrose octasulfate triethylamine salt gradient loading method. In this work, compared to generic vincristine sulfate liposome injection (GVM), the stability both in vivo and in vitro and efficacy in vivo of novel vincristine liposomes were investigated. Results: It was shown that the degradation of vincristine during 2-8°C storage was significantly decreased from 8.2% in 1 month (GVM) to 2.9% in 12 months (D/L ratio 1/5). The half-time for sphingomyelin/cholesterol/PEG2000-DSPE liposomes in vivo could be adjusted from 17.4 h (D/L ratio 1/10) to 22.7 h (D/L ratio 1/2) in rats, while the half-time for GVM was only 11.1 h. The increase in drug retention contributed to the lower in vivo toxicity. The antitumor efficacy was evaluated using a human melanoma tumor model and showed remarkable improvement compared to GVM. Conclusion: The study demonstrates that the new formulation with the drug/lipid ratio of 1/5 owns a higher encapsulation efficiency, better stability, lower toxicity and superior antitumor efficacy, which is screened out for further development.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/química , Vincristina/química , Vincristina/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Colesterol/química , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos Wistar , Esfingomielinas/química , Vincristina/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Anal Chim Acta ; 1078: 182-188, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31358218

RESUMO

Early detection of toxic proteases in food matrices plays a major role in preventing the occurrence of diseases as well as outbreaks. However, on-site detection of proteases, for instance, botulinum, anthrax and cholera in food matrices remains challenging due to their extremely low lethal dose levels. Here, we report a lateral flow assay (LFA) in a dipstick format for on-site visual detection of proteases in food matrices. The light chain of BoNT serotype A (BoNT/A LC) is used as a model system for validation of the proposed assay using magnetic beads conjugated to a synthetic peptide that provide a specific cleavage site for BoNT/A LC. Magnetic beads serve as both reporters for visual detection and as facilitators for sample clean-up, owing to the efficient magnetic separation protocol adopted. Digestion of the peptide substrate by BoNT/A LC for 5 h followed by the dipstick assay yields a reduction in color intensity of the test line on the dipstick compared to the control line obtained using an un-cleaved peptide substrate. Concentration dependent responses for the assay in carrot juice were obtained with a limit of detection (LOD) of 1 nM/2.5 nM (with/without amplification), also supported by RGB (ΔE) analysis, indicating the potential of the proposed methodology for on-site assaying of proteases in food matrices. Unlike typical affinity-based assays that yield a collective response for the active and inactive forms of the proteases, the proposed functional LFA targets only the active form, thereby enabling a more precise analysis for preventing potential false-positives. The proposed approach could be extended for detection of BoNT serotypes and other proteases in food matrices, upon utilizing appropriate substrates with specific cleavage sites.


Assuntos
Bioensaio/métodos , Toxinas Botulínicas Tipo A/análise , Sucos de Frutas e Vegetais/análise , Sequência de Aminoácidos , Anticorpos/imunologia , Toxinas Botulínicas Tipo A/química , Daucus carota/química , Limite de Detecção , Fenômenos Magnéticos , Peptídeos/química , Polietilenoglicóis/química , Estudo de Prova de Conceito , Estreptavidina/química
15.
Int J Nanomedicine ; 14: 4683-4695, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308653

RESUMO

Purpose: Clinical applications of curcumin (Cur) have been greatly restricted due to its low solubility and poor systemic bioavailability. Three-arm amphiphilic copolymer tricarballylic acid-poly (ε-caprolactone)-methoxypolyethylene glycol (Tri-CL-mPEG) nanoparticles (NPs) were designed to improve the solubility and bioavailability of Cur. The present study adopted a microchannel system to precisely control the preparation of self-assembly polymeric NPs via liquid flow-focusing and gas displacing method. Methods: The amphiphilic three-arm copolymer Tri-CL-mPEG was synthesized and self-assembled into nearly spherical NPs, yielding Cur encapsulated into NP cores (Cur-NPs). The obtained NPs were evaluated for physicochemical properties, morphology, toxicity, cellular uptake by A549 cells, release in vitro, biodistribution, and pharmacokinetics in vivo. Results: Rapidly fabricated and isodispersed Cur-NPs prepared by this method had an average diameter of 116±3 nm and a polydispersity index of 0.197±0.008. The drug loading capacity and entrapment efficiency of Cur-NPs were 5.58±0.23% and 91.42±0.39%, respectively. In vitro release experiments showed sustained release of Cur, with cumulative release values of 40.1% and 66.1% at pH 7.4 and pH 5.0, respectively, after 10 days post-incubation. The results of cellular uptake, biodistribution, and in vivo pharmacokinetics experiments demonstrated that Cur-NPs exhibited better biocompatibility and bioavailability, while additionally enabling greater cellular uptake and prolonged circulation with possible spleen, lung, and kidney targeting effects when compared to the properties of free Cur. Conclusion: These results indicate that Tri-CL-mPEG NPs are promising in clinical applications as a controllable delivery system for hydrophobic drugs.


Assuntos
Curcumina/farmacologia , Microfluídica/métodos , Nanopartículas/química , Polietilenoglicóis/química , Polímeros/química , Ácidos Tricarboxílicos/química , Células A549 , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Curcumina/farmacocinética , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Camundongos , Peso Molecular , Nanopartículas/ultraestrutura , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacos
16.
Adv Mater ; 31(33): e1902462, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31265196

RESUMO

The controlled presentation of proteins from and within materials remains of significant interest for many bioengineering applications. Though "smart" platforms offer control over protein release in response to a single external cue, no strategy has been developed to trigger delivery in response to user-specified combinations of environmental inputs, nor to independently control the release of multiple species from a homogenous material. Here, a modular semisynthetic scheme is introduced to govern the release of site-specifically modified proteins from hydrogels following Boolean logic. A sortase-mediated transpeptidation reaction is used to generate recombinant proteins C-terminally tethered to gels through environmentally sensitive degradable linkers. By varying the connectivity of multiple stimuli-labile moieties within these customizable linkers, YES/OR/AND control of protein release is exhaustively demonstrated in response to one and two-input combinations involving enzyme, reductant, and light. Tethering of multiple proteins each through a different stimuli-sensitive linker permits their independent and sequential release from a common material. It is expected that these methodologies will enable new opportunities in tissue engineering and therapeutic delivery.


Assuntos
Aminoaciltransferases/química , Proteínas de Bactérias/química , Materiais Biocompatíveis/química , Cisteína Endopeptidases/química , Sistemas de Liberação de Medicamentos/métodos , Hidrogéis/química , Proteínas Recombinantes/química , Aminoaciltransferases/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Cisteína Endopeptidases/administração & dosagem , Dissulfetos/química , Liberação Controlada de Fármacos , Humanos , Luz , Oxirredução , Peptídeos/química , Fotólise , Polietilenoglicóis/química , Proteínas Recombinantes/administração & dosagem , Staphylococcus aureus/enzimologia
17.
Int J Nanomedicine ; 14: 4309-4317, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354262

RESUMO

Background: The intraoperative visualization of tumor cells is a powerful modality for surgical treatment of solid tumors. Since the completeness of tumor excision is closely correlated with the survival of patients, probes that can assist in distinguishing tumor cells are highly demanded. Purpose: In the present study, a fluorescent probe JF1 was synthesized for imaging of tumor cells by conjugating a substrate of cathepsin B (quenching moiety) to Oregon Green derivative JF2 using a self-immolative linker. Methods: JF1 was then loaded into the folate-PEG modified CaCO3 nanoparticles. The folate receptor-targeted, pH-dependent, and cathepsin B activable CaCO3 nanoprobe was test in vitro and in vivo for tumor imaging. Results: CaCO3 nanoprobe demonstrated good stability and fast lighting ability in tumors under low pH conditions. It also showed lower fluorescence background than the single cathepsin B dependent fluorescent probe. The pH-dependent and cathepsin B controlled "turn-on" property enables precise and fast indication of tumor in vitro and in vivo. Conclusion: This strategy of controlled drug delivery enables in vivo imaging of tumor nodules with a high signal-to-noise ratio, which has great potential in surgical tumor treatment.


Assuntos
Carbonato de Cálcio/química , Catepsina B/metabolismo , Diagnóstico por Imagem , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Animais , Corantes Fluorescentes/química , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Camundongos , Nanopartículas/ultraestrutura , Neoplasias/patologia , Especificidade de Órgãos , Polietilenoglicóis/química
18.
Int J Nanomedicine ; 14: 4353-4366, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354265

RESUMO

Purpose: Gene therapy has become a promising remedy to treat disease by modifying the person's genes. The therapeutic potential of related tools such as CRISPR-Cas9 depends on the efficiency of delivery to the targeted cells. Numerous transfection reagents have been designed and lots of efforts have been devoted to develop carriers for this purpose. Therefore, the aim of the present study was to develop novel cholesterol-rich lipid-based nanoparticles to enhance transfection efficiency and serum stability. Materials and methods: We constructed two-, three- and four-component cationic liposomes (CLs) to evaluate the combined effect of cholesterol domain and DOPE (dioleoyl phosphatidylethanolamine), a fusogenic lipid, and the PEG (polyethylene glycol) moiety location inside or outside of the cholesterol domain on transfection efficiency and other properties of the particle. Lipoplex formation and pDNA (plasmid DNA) entrapment were assessed by gel retardation assay at different N/P ratios (3, 5, 7). Physicochemical characteristics, cytotoxicity, serum stability and endosomal escape capability of the lipoplexes were studied and transfection potential was measured by firefly luciferase assay. Next, HEK293 cell line stably expressing GFP was utilized to demonstrate the editing of a reporter through Cas9 and sgRNA plasmids delivery by the selected CL formula, which showed the highest transfection efficiency. Results: Among the designed CLs, the four-component formula [DOTAP (1,2-dioleoyl-3-trimethylammoniumpropane)/DOPE/cholesterol/Chol-PEG (cholesterol-polyethylene glycol)] showed the highest rate of transfection at N/P 3. Finally, transfection of Cas9/sgRNA by this formulation at N/P 3 resulted in 39% gene-editing efficiency to knockout GFP reporter. The results also show that this CL with no cytotoxicity effect can totally protect the plasmids from enzymatic degradation in serum. Conclusion: The novel PEGylated cholesterol domain lipoplex providing serum stability, higher transfection efficiency and endosomal release can be used for in vivo Cas9/sgRNA delivery and other future gene-therapy applications.


Assuntos
Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Colesterol/química , Edição de Genes , Nanopartículas/química , Transfecção/métodos , Cátions/química , Morte Celular , Colesterol/análogos & derivados , Ensaio de Desvio de Mobilidade Eletroforética , Endossomos/metabolismo , Ácidos Graxos Monoinsaturados/química , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Lipossomos/química , Tamanho da Partícula , Fosfatidiletanolaminas/química , Plasmídeos/metabolismo , Polietilenoglicóis/química , Compostos de Amônio Quaternário/química , RNA Guia/metabolismo , Eletricidade Estática
19.
Int J Nanomedicine ; 14: 4517-4528, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354271

RESUMO

Purpose: We developed a contrast agent for targeting E-selectin expression. We detected the agent using magnetic resonance imaging (MRI) in vivo in nude mice that had undergone nasopharyngeal carcinoma (NPC) metastasis. Methods: Sialyl Lewis X (sLeX) was conjugated with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. Hydrodynamic size, polydispersity index, and ζ-potential of USPIO-polyethylene glycol (PEG) nanoparticles and USPIO-PEG-sLeX nanoparticles were measured. Component changes in nanoparticles of USPIO, USPIO-PEG, and USPIO-PEG-sLeX were analyzed by thermogravimetric analysis and Fourier-transform infrared spectroscopy. A model of NPC metastasis to inguinal lymph nodes in nude mice was used to investigate characteristics of the USPIO-PEG-sLeX nanoparticles in vivo. We investigated the ability of the T2* value, change in T2* value (ΔT2* value), and enhancement rate (ER) to assess accumulation of USPIO-PEG-sLeX nanoparticles quantitatively in mice of a metastasis group and control group. Four MRI scans were undertaken for each mouse. The first scan (t0) was done before administration of USPIO-PEG-sLeX nanoparticles (0.1 mL) via the tail vein. The other scans were carried out at 0 (t1), 1 (t2), and 2 hours (t3) postinjection. The mean optical density was used to reflect E-selectin expression. Results: sLeX was labeled onto USPIO successfully. In vivo, there were significant interactions between the groups and time for T2* values after administration of USPIO-PEG-sLeX nanoparticles. Six parameters (T2* at t2, ΔT2* at t1, ΔT2* at t2, ER at t1, ER at t2, and ER at t3) were correlated with the mean optical density. Conclusion: USPIO-PEG-sLeX nanoparticles can be used to assess E-selectin expression quantitatively. Use of such molecular probes could enable detection of early metastasis of NPC, more accurate staging, and treatment monitoring.


Assuntos
Dextranos/química , Selectina E/metabolismo , Nanopartículas de Magnetita/química , Animais , Linhagem Celular Tumoral , Dextranos/ultraestrutura , Difusão Dinâmica da Luz , Feminino , Metástase Linfática , Imagem por Ressonância Magnética , Nanopartículas de Magnetita/ultraestrutura , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Nasofaríngeas/patologia , Metástase Neoplásica , Oligossacarídeos/metabolismo , Polietilenoglicóis/química , Eletricidade Estática , Termodinâmica
20.
Int J Nanomedicine ; 14: 4767-4780, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308657

RESUMO

Background: Magnetic nanoparticles (MNPs) can be localized against hemodynamic forces in blood vessels with the application of an external magnetic field. In addition, PEGylation of nanoparticles may increase the half-life of nanocomposites in circulation. In this work, we examined the effect of PEGylation on the magnetic capture of MNPs in vivo. Methods: Laser speckle contrast imaging and capillaroscopy were used to assess the magnetic capture of dextran-coated MNPs and red blood cell (RBC) flow in cremaster microvessels of anesthetized rats. Magnetic capture of MNPs in serum flow was visualized with an in vitro circulating system. The effect of PEGylation on MNP-endothelial cell interaction was studied in cultured cells using an iron assay. Results: In microcirculation through cremaster muscle, magnet-induced retention of 250 nm MNPs was associated with a variable reduction in RBC flow, suggesting a dynamic coupling of hemodynamic and magnetic forces. After magnet removal, faster restoration of flow was observed in PEG(+) than PEG(-) group, which may be attributed to a reduced interaction with vascular endothelium. However, PEGylation appears to be required for magnetic capture of 50 nm MNPs in microvessels, which was associated with increased hydrodynamic diameter to 130±6 nm in serum, but independent of the ς-potential. Conclusion: These results suggest that PEGylation may enhance magnetic capture of smaller MNPs and dispersion of larger MNPs after magnet removal, which may potentially affect the targeting, pharmacokinetics and therapeutic efficacy.


Assuntos
Dextranos/química , Nanopartículas de Magnetita/química , Microcirculação/fisiologia , Polietilenoglicóis/química , Animais , Hemodinâmica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Campos Magnéticos , Microvasos/fisiologia , Ratos Sprague-Dawley , Eletricidade Estática
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