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1.
Nat Commun ; 11(1): 3384, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636379

RESUMO

Targeting single mediators has failed to reduce the mortality of sepsis. We developed a telodendrimer (TD) nanotrap (NT) to capture various biomolecules via multivalent, hybrid and synergistic interactions. Here, we report that the immobilization of TD-NTs in size-exclusive hydrogel resins simultaneously adsorbs septic molecules, e.g. lipopolysaccharides (LPS), cytokines and damage- or pathogen-associated molecular patterns (DAMPs/PAMPs) from blood with high efficiency (92-99%). Distinct surface charges displayed on the majority of pro-inflammatory cytokines (negative) and anti-inflammatory cytokines (positive) allow for the selective capture via TD NTs with different charge moieties. The efficacy of NT therapies in murine sepsis is both time-dependent and charge-dependent. The combination of the optimized NT therapy with a moderate antibiotic treatment results in a 100% survival in severe septic mice by controlling both infection and hyperinflammation, whereas survival are only 50-60% with the individual therapies. Cytokine analysis, inflammatory gene activation and tissue histopathology strongly support the survival benefits of treatments.


Assuntos
Dendrímeros/química , Inflamação/terapia , Nanopartículas/química , Sepse/terapia , Adsorção , Animais , Antibacterianos/uso terapêutico , Citocinas/metabolismo , Feminino , Humanos , Hidrogéis , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanomedicina , Padrões Moleculares Associados a Patógenos , Células RAW 264.7
2.
Nat Commun ; 11(1): 2139, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358489

RESUMO

A longstanding goal in science and engineering is to mimic the size, structure, and functionality present in biology with synthetic analogs. Today, synthetic globular polymers of several million molecular weight are unknown, and, yet, these structures are expected to exhibit unanticipated properties due to their size, compactness, and low inter-chain interactions. Here we report the gram-scale synthesis of dendritic polymers, mega hyperbranched polyglycerols (mega HPGs), in million daltons. The mega HPGs are highly water soluble, soft, nanometer-scale single polymer particles that exhibit low intrinsic viscosities. Further, the mega HPGs are lubricants acting as interposed single molecule ball bearings to reduce the coefficient of friction between both hard and soft natural surfaces in a size dependent manner. We attribute this result to their globular and single particle nature together with its exceptional hydration. Collectively, these results set the stage for new opportunities in the design, synthesis, and evaluation of mega polymers.


Assuntos
Dendrímeros/química , Glicerol/química , Lubrificantes/química , Nanotecnologia/métodos , Polímeros/química , Substâncias Macromoleculares/química , Propriedades de Superfície
3.
Int J Nanomedicine ; 15: 2633-2646, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368045

RESUMO

Objective: The aim of this study is to fabricate functional scaffolds to gene delivery bone morphogenetic protein-2 (BMP-2) plasmid for bone formation in bone tissue engineering. Methods: Dendriplexes (DPs) of generation 4 polyamidoamin (G4-PAMAM)/BMP-2 plasmid were prepared through microfluidic (MF) platform. The physiochemical properties and toxicity of DPs were evaluated by DLS, AFM, FESEM and MTT assay. In order to create a suitable environment for stem cell growth and differentiation, poly-l-lactic acid (PLLA) and poly-l-lactic acid/poly (ethylene oxide) (PLLA/PEO) scaffolds containing hydroxyapatite nanoparticles (HA) and DPs were fabricated by the electrospinning method. The osteogenic potency of the scaffolds on human adipose tissue-derived mesenchymal stem cells (hASCs) was investigated. Results: The results revealed that tuning the physical properties of DPs by adjusting flow parameters in microfluidic platform can easily improve the cell viability compared to conventional bulk mixing method. Also, the result showed that the presence of HA and DPs in PLLA/PEO scaffold enhanced alkaline phosphatase (ALP) activity and increased the amount of deposited Ca, as well as, related to osteogenesis gen markers. Conclusion: This study indicated that on using the MF platform in preparation of DPs and loading them along with HA in PLLA/PEO scaffold, the osteogenic differentiation of hASCs could be tuned.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Osso e Ossos/fisiologia , Durapatita/química , Microfluídica , Nanofibras/química , Poliaminas/química , Engenharia Tecidual/métodos , Tecidos Suporte/química , Fosfatase Alcalina/metabolismo , Cálcio/metabolismo , Adesão Celular , Morte Celular , Diferenciação Celular , Proliferação de Células , Forma Celular , DNA/metabolismo , Dendrímeros/química , Humanos , Células-Tronco Mesenquimais/metabolismo , Nanopartículas/química , Tamanho da Partícula , Plasmídeos/metabolismo , Poliésteres/química , Resistência à Tração
4.
Int J Nanomedicine ; 15: 2789-2808, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368055

RESUMO

Glioblastoma (GB) is a grade IV astrocytoma that maintains a poor prognosis with respect to current treatment options. Despite major advancements in the fields of surgery and chemoradiotherapy over the last few decades, the life expectancy for someone with glioblastoma remains virtually unchanged and warrants a new approach for treatment. Poly(amidoamine) (PAMAM) dendrimers are a type of nanomolecule that ranges in size (between 1 and 100 nm) and shape and can offer a new viable solution for the treatment of intracranial tumors, including glioblastoma. Their ability to deliver a variety of therapeutic cargo and penetrate the blood-brain barrier (BBB), while preserving low cytotoxicity, make them a favorable candidate for further investigation into the treatment of glioblastoma. Here, we present a systematic review of the current advancements in PAMAM dendrimer technology, including the wide spectrum of dendrimer generations formulated, surface modifications, core modifications, and conjugations developed thus far to enhance tumor specificity and tumor penetration for treatment of glioblastoma. Furthermore, we highlight the extensive variety of therapeutics capable of delivery by PAMAM dendrimers for the treatment of glioblastoma, including cytokines, peptides, drugs, siRNAs, miRNAs, and organic polyphenols. While there have been prolific results stemming from aggressive research into the field of dendrimer technology, there remains a nearly inexhaustible amount of questions that remain unanswered. Nevertheless, this technology is rapidly developing and is nearing the cusp of use for aggressive tumor treatment. To that end, we further highlight future prospects in focus as researchers continue developing more optimal vehicles for the delivery of therapeutic cargo.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Dendrímeros/química , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Dendrímeros/uso terapêutico , Humanos
5.
Int J Nanomedicine ; 15: 2751-2764, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368053

RESUMO

Introduction: A multifunctional redox- and pH-responsive polymeric drug delivery system is designed and investigated for targeted anticancer drug delivery to liver cancer. Methods: The nanocarrier (His-PAMAM-ss-PEG-Tf, HP-ss-PEG-Tf) is constructed based on generation 4 polyamidoamine dendrimer (G4 PAMAM). Optimized amount of histidine (His) residues is grafted on the surface of PAMAM to obtain enhanced pH-sensitivity and proton-buffering capacity. Disulfide bonds (ss) are introduced between PAMAM and PEG to reach accelerated intracellular drug release. Transferrin (Tf) was applied to achieve active tumor targeting. Doxorubicin (DOX) is loaded in the hydrophobic cavity of the nanocarrier to exert its anti-tumor effect. Results: The results obtained from in vitro and in vivo evaluation indicate that HP-ss-PEG-Tf/DOX complex has pH and redox dual-sensitive properties, and exhibit higher cellular uptake and cytotoxicity than the other control groups. Flow cytometry and confocal microscopy display internalization of HP-ss-PEG-Tf/DOX via clathrin mediated endocytosis and effective endosomal escape in HepG2 cancer cells. Additionally, cyanine 7 labeled HP-ss-PEG-Tf conjugate could quickly accumulate in the HepG2 tumor. Remarkably, HP-ss-PEG-Tf/DOX present superior anticancer activity, enhanced apoptotic activity and lower heart and kidney toxicity in vivo. Discussion: Thus, HP-ss-PEG-Tf is proved to be a promising candidate for effective targeting delivery of DOX into the tumor.


Assuntos
Antineoplásicos/administração & dosagem , Dendrímeros/química , Portadores de Fármacos/administração & dosagem , Nylons/química , Transferrina/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Dendrímeros/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Células Hep G2 , Histidina/química , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Oxirredução , Polietilenoglicóis/química , Succinimidas/química , Transferrina/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Int J Nanomedicine ; 15: 483-495, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32158206

RESUMO

Background: The complex preparation procedures and severe toxicities are two major obstacles facing the wide use of chimeric antigen receptor-modified T (CAR-T) cells in clinical cancer immunotherapy. The nanotechnology-based T cell temporary CAR modification may be a potential approach to solve these problems and make the CAR-T cell-based tumor therapy feasible and broadly applicable. Methods: A series of plasmid DNA-loaded self-assembled nanoparticles (pDNA@SNPsx/y) prepared from adamantane-grafted polyamidoamine (Ad-PAMAM) dendrimers of different generations (G1 or G5) and cyclodextrin-grafted branched polyethylenimine (CD-PEI) of different molecular weights (800, 2000, or 25,000 Da) were characterized and evaluated. The detailed physicochemical properties, cellular interaction, and cytotoxicity of selected pDNA@SNPG1/800 were systematically investigated. Thereafter, the epidermal growth factor receptor variant III (EGFRvIII) CAR-expression plasmid vector (pEGFRvIII-CAR) was constructed and encapsulated into SNPG1/800. The resulting pEGFRvIII-CAR@SNPG1/800 was used for Jurkat cell transient transfection, and the EGFRvIII-CAR expressed in transfected cells was measured by flow cytometry and Western blot. Finally, the response of EGFRvIII CAR-positive Jurkat T cell to target tumor cell was evaluated. Results: The pDNA@SNPG1/800 showed the highest efficacy in Jurkat cell gene transfection and exhibited low cytotoxicity. pEGFRvIII-CAR@SNPG1/800 can efficiently deliver pEGFRvIII-CAR into Jurkat T cells, thereby resulting in transient EGFRvIII-CAR expression in transfected cells. EGFRvIII-CAR that is present on the cell membrane enabled Jurkat T cells to recognize and bind specifically with EGFRvIII-positive tumor cells. Conclusion: These results indicated that pEGFRvIII-CAR@SNPG1/800 can effectively achieve T-cell transient CAR modification, thereby demonstrating considerable potential in CAR-T cancer therapy.


Assuntos
Receptores ErbB/genética , Técnicas de Transferência de Genes , Imunoterapia Adotiva/métodos , Nanopartículas/química , Linfócitos T/fisiologia , Linhagem Celular Tumoral , Dendrímeros/química , Vetores Genéticos , Humanos , Iminas/química , Imunoterapia , Células Jurkat , Peso Molecular , Polietilenos/química , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/genética , Transfecção/métodos
7.
Int J Nanomedicine ; 15: 1469-1480, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184599

RESUMO

Purpose: In spite of its enhanced efficacy and reduced side effects in clinical hepatocellular carcinoma (HCC) therapy, the therapeutic efficacy of antitumor angiogenesis inhibitor sorafenib (SFB) is still restricted due to short in vivo half-life and drug resistance. Here, a novel SFB-loaded dendritic polymeric nanoparticle (NP-TPGS-SFB) was developed for enhanced therapy of HCC. Methods: NP-TPGS-SFB was fabricated by encapsulating SFB with biodegradable dendritic polymers poly(amidoamine)-poly(γ-benzyl-L-Glutamate)-b-D-α-tocopheryl polyethylene glycol 1000 succinate (PAM-PBLG-b-TPGS). Results: NP-TPGS-SFB exhibited excellent stability and achieved acid-responsive release of SFB. It also exhibited much higher cellular uptake efficiency in HepG2 human liver cells than PEG-conjugated NP (NP-PEG-SFB). Furthermore, MTT assay confirmed that NP-TPGS-SFB induced higher cytotoxicity than NP-PEG-SFB and free SFB, respectively. Lastly, NP-TPGS-SFB significantly inhibited tumor growth in mice bearing HepG2 xenografts, with negligible side effects. Conclusion: Our result suggests that NP-TPGS-SFB may be a novel approach for enhanced therapy of HCC with promising potential.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Dendrímeros/química , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/administração & dosagem , Sorafenibe/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/patologia , Dendrímeros/farmacocinética , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Nanopartículas/química , Polímeros/química , Polímeros/farmacocinética , Vitamina E/química , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Chemistry ; 26(26): 5903-5910, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32142179

RESUMO

First-in-class CuII and AuIII metaled phosphorus dendrons were synthesized and showed significant antiproliferative activity against several aggressive breast cancer cell lines. The data suggest that the cytotoxicity increases with reducing length of the alkyl chains, whereas the replacement of CuII with AuIII considerably increases the antiproliferative activity of metaled phosphorus dendrons. Very interestingly, we found that the cell death pathway is related to the nature of the metal complexed by the plain dendrons. CuII metaled dendrons showed a potent caspase-independent cell death pathway, whereas AuIII metaled dendrons displayed a caspase-dependent apoptotic pathway. The complexation of plain dendrons with AuIII increased the cellular lethality versus dendrons with CuII and promoted the translocation of Bax into the mitochondria and the release of Cytochrome C (Cyto C).


Assuntos
Citocromos c/metabolismo , Dendrímeros/metabolismo , Metais/química , Mitocôndrias/química , Fósforo/química , Apoptose , Morte Celular , Citocromos c/química , Dendrímeros/química , Humanos , Células MCF-7 , Metais/metabolismo , Mitocôndrias/metabolismo , Estrutura Molecular , Fósforo/metabolismo
9.
Sci Adv ; 6(4): eaay8514, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010790

RESUMO

Poor transport of neuropharmaceutics through central nervous system (CNS) barriers limits the development of effective treatments for CNS disorders. We present the facile synthesis of a novel neuroinflammation-targeting polyethylene glycol-based dendrimer (PEGOL-60) using an efficient click chemistry approach. PEGOL-60 reduces synthetic burden by achieving high hydroxyl surface density at low generation, which plays a key role in brain penetration and glia targeting of dendrimers in CNS disorders. Systemically administered PEGOL-60 crosses impaired CNS barriers and specifically targets activated microglia/macrophages at the injured site in diverse animal models for cerebral palsy, glioblastoma, and age-related macular degeneration, demonstrating its potential to overcome impaired blood-brain, blood-tumor-brain, and blood-retinal barriers and target key cells in the CNS. PEGOL-60 also exhibits powerful intrinsic anti-oxidant and anti-inflammatory effects in inflamed microglia in vitro. Therefore, PEGOL-60 is an effective vehicle to specifically deliver therapies to sites of CNS injury for enhanced therapeutic outcomes in a range of neuroinflammatory diseases.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Dendrímeros/administração & dosagem , Microglia/efeitos dos fármacos , Microglia/metabolismo , Polietilenoglicóis , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Doenças do Sistema Nervoso Central/etiologia , Doenças do Sistema Nervoso Central/metabolismo , Fenômenos Químicos , Técnicas de Química Sintética , Dendrímeros/síntese química , Dendrímeros/química , Modelos Animais de Doenças , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Microglia/imunologia , Terapia de Alvo Molecular , Polietilenoglicóis/química , Coelhos
10.
Biomater Sci ; 8(3): 758-762, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31965126

RESUMO

Six cationic lipidoid fluorodendrimers are synthesized to construct hybrid lipid-polymer nanoparticles for siRNA delivery. By screening the nanoplatforms including fluorodendrimers with different chemical structures, the optimized nanoparticle NPF13-5 mediates the most efficient silencing of prohibitin 1, inhibition of cell proliferation, and induction of cell apoptosis towards A549 lung adenocarcinoma cells.


Assuntos
Dendrímeros/química , Sistemas de Liberação de Medicamentos/métodos , Lipídeos/química , Nanopartículas/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/instrumentação , Humanos , Polímeros/síntese química , Polímeros/química , Proteínas Repressoras/genética
11.
J Photochem Photobiol B ; 204: 111803, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32000112

RESUMO

Infectious diseases constitute a serious problem for human health and life. Although many bacterial and fungal infections can be successfully cured by commonly used antibiotics, a new threat emerges in the form of microbial resistance. For this reason, researchers try to find not only new active pharmaceutical ingredients for conventional antibiotherapy but also try to develop new strategies of microbial inactivation. Photodynamic antimicrobial chemotherapy, which relies on reactive oxygen species generated in situ in the presence of a photosensitizer and with the light of an appropriate wavelength, is one of them. Porphyrazines have been considered as potential photosensitizers for anticancer and antimicrobial photodynamic therapy. In this study, three tribenzoporphyrazines with dendrimeric peripheral substituents were subjected to in vitro antimicrobial photocytotoxicity study. One magnesium(II) tribenzoporphyrazine with peripheral 3,5-bis(3,5-dimethoxybenzyloxy)benzylsulfanyl substituents was synthesized and subjected to physicochemical characterization using NMR, UV-Vis, and mass spectrometry techniques. In photochemical studies this molecule revealed moderate singlet oxygen generation ability (ΦΔDMF = 0.12, ΦΔDMSO = 0.13). The other two magnesium(II) tribenzoporphyrazines applied in the biological study were 4-[3,5-di(hydroxymethyl)phenoxy]butylsulfanyl-substituted tribenzoporphyrazine and 4-[3,5-bis(benzyloxy)benzyloxy]phenyl-substituted tribenzopyrazinoporphyrazine. For the assessment, three microbial strains were chosen: Gram-positive bacteria Staphylococcus aureus ATCC 25923, Gram-negative bacteria Escherichia coli ATCC 25922, and fungal strain Candida albicans ATCC 10231. Very high activity against Staphylococcus aureus at low 10-6 M concentration was recorded for magnesium(II) tribenzoporphyrazines with peripheral 3,5-bis(3,5-dimethoxybenzyloxy)benzylsulfanyl and 4-[3,5-di(hydroxymethyl)phenoxy]butylsulfanyl substituents with calculated log reductions of 4.4 and 4.8, respectively. It is worth noting that magnesium(II) tribenzoporphyrazine with 4-[3,5-di(hydroxymethyl)phenoxy]butylsulfanyl substituents revealed also 3.2 log reduction in bacterial growth at the concentration 10-7 M.


Assuntos
Anti-Infecciosos/farmacologia , Dendrímeros/química , Pirazinas/química , Staphylococcus aureus/efeitos dos fármacos , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Candida albicans/efeitos dos fármacos , Candida albicans/efeitos da radiação , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos da radiação , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos da radiação , Luz , Testes de Sensibilidade Microbiana , Pirazinas/síntese química , Pirazinas/farmacologia , Oxigênio Singlete/metabolismo , Staphylococcus aureus/efeitos da radiação
12.
Colloids Surf B Biointerfaces ; 188: 110762, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31911391

RESUMO

Co-delivery of therapeutic agents and small interfering RNA (siRNA) can be achieved by a suitable nanovehicle. In this work, the solubility and bioavailability of curcumin (Cur) were enhanced by entrapment in a polyamidoamine (PAMAM) dendrimer, and a polyplex was formed by grafting Bcl-2 siRNA onto the surface amine groups to produce PAMAM-Cur/Bcl-2 siRNA nanoparticles (NPs). The synthesized polyplex NPs had a particle size of ∼180 nm, and high Cur loading content of ∼82 wt%. Moreover, the PAMAM-Cur/Bcl-2 siRNA NPs showed more effective cellular uptake, and higher inhibition of tumor cell proliferation compared to PAMAM-Cur nanoformulation and free Cur, due to the combined effect of co-delivery of Cur and Bcl-2 siRNA. The newly described PAMAM-Cur/Bcl-2 siRNA polyplex NPs could be a promising co-delivery nanovehicle.


Assuntos
Antineoplásicos/farmacologia , Curcumina/farmacologia , Dendrímeros/farmacologia , Sistemas de Liberação de Medicamentos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Curcumina/química , Dendrímeros/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Tamanho da Partícula , RNA Interferente Pequeno/química , Propriedades de Superfície
13.
Chemistry ; 26(5): 1037-1041, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31749263

RESUMO

High aspect ratio, sugar-decorated 2D nanosheets are ideal candidates for the capture and agglutination of bacteria. Herein, the design and synthesis of two carbohydrate-based Janus amphiphiles that spontaneously self-assemble into high aspect ratio 2D sheets are reported. The unique structural features of the sheets include the extremely high aspect ratio and dense display of galactose on the surface. These structural characteristics allow the sheet to act as a supramolecular 2D platform for the capture and agglutination of E. coli through specific multivalent noncovalent interactions, which significantly reduces the mobility of the bacteria and leads to the inhibition of their proliferation. Our results suggest that the design strategy demonstrated here can be applied as a general approach for the crafting of biomolecule-decorated 2D nanosheets, which can perform as 2D platforms for their interaction with specific targets.


Assuntos
Dendrímeros/metabolismo , Escherichia coli/metabolismo , Galactose/química , Nanoestruturas/química , Aglutinação/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dendrímeros/química , Humanos , Nanopartículas Metálicas/química , Microscopia de Força Atômica , Nanoestruturas/toxicidade , Prata/química
14.
Talanta ; 206: 120213, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514887

RESUMO

Phthalate esters (PAEs) are an important kind of environmental endocrine disrupting chemicals, and have attracted great attention in environmental field. Present study described a new method for rapid and sensitive determination of PAEs including dibenzyl phthalate (DPhP), dibutyl phthalate (DnPP), and dicyclohexyl phthalate (DCHP) from aqueous matrices based on magnetic solid-phase extraction. Polyamidoamine (PAMAM) dendrimers-grafted magnetic-nanoparticles were synthesized and characterized, and the expected integration of more multifunctional sites of PAMAM dendrimers and rapid separation property was utilized for method development. To achieve the best extraction efficiency, several important parameters were optimized including the dosage of the adsorbent, sample pH, kind and volume of eluent, extraction time, desorption time, ionic strength. Under the optimal conditions, three phthalate esters were well enriched and simultaneously determined by high performance liquid chromatography with variable wavelength detector (VWD). Excellent linearities were observed in the range of 0.1-600 µg L-1 for DPhP and DnPP and 0.5-600 µg L-1 for DCHP, and all correlation coefficients (R2) were larger than 0.997. The limits of detection (LODs, S/N = 3) were ranged from 0.025 to 0.16 µg L-1. The spiked recoveries of PAEs in real water samples were in the range of 93.5-101.8% with satisfied relative standard deviations (RSDs) ranging from 0.9 to 4.1%. The prepared magnetic materials have shown good adsorption capability for PAEs and the developed method earned merits such as high sensitivity, simplicity, rapidness and environmental friendliness, which can be used as a robust alternative tool for monitoring PAEs in water samples.


Assuntos
Dendrímeros/química , Ésteres/análise , Nanopartículas de Magnetita/química , Ácidos Ftálicos/análise , Poluentes Químicos da Água/análise , Cromatografia Líquida de Alta Pressão/métodos , Dibutilftalato/análise , Lagos/análise , Limite de Detecção , Oceanos e Mares , Extração em Fase Sólida/métodos
15.
Mater Sci Eng C Mater Biol Appl ; 106: 110245, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753357

RESUMO

The recent discovery of small interfering RNAs (siRNAs) has opened new avenues for designing personalized treatment options for various diseases. However, the therapeutic application of siRNAs has been confronted with many challenges because of short half-life in circulation, poor membrane penetration, difficulty in escaping from endosomes, and insufficient release into the cytosol. To overcome these challenges, we designed a diethylenetriamine (DETA)- and tetraethylenepentamine (TEPA)-modified polyamidoamine dendrimer generation 4.5 (PDG4.5), and characterized it using 1H nuclear magnetic resonance (NMR), 13C NMR, correlation spectroscopy (COSY), heteronuclear single-quantum correlation spectroscopy (HSQC), and Fourier transform infrared (FTIR) spectroscopy followed by conjugation with siRNA. The PDG4.5-DETA and PDG4.5-TEPA polyplexes exhibited spherical nanosize, ideal zeta potential, and effective siRNA binding ability, protected the siRNA from nuclease attack, and revealed less cytotoxicity of PDG4.5-DETA and PDG4.5-TEPA in HeLa cells. More importantly, the polyplexes also revealed good cellular internalization and facilitated translocation of the siRNA into the cytosol. Thus, PDG4.5-DETA and PDG4.5-TEPA can act as potential siRNA carriers in future medical and pharmaceutical applications.


Assuntos
Dendrímeros/química , Etilenodiaminas/química , Nylons/química , Poliaminas/química , RNA Interferente Pequeno/química , Portadores de Fármacos/química , Células HeLa , Humanos , Espectroscopia de Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier
16.
Anal Chim Acta ; 1096: 61-68, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31883592

RESUMO

Sensitive and reliable detection of biomarkers is of vital importance in tumor early detection and clinical therapy. A novel fluorescent/electrochemical dual-responsive immunosensing platform for reliable and sensitive quantification of biomarkers was designed based on cation-exchange reaction. To construct such a versatile platform, the model analyte, carcinoembryonic antigen (CEA), was captured by magnetic Fe3O4 nanoparticles bound with primary antibodies (Fe3O4-Ab1) and then recognized by the detection antibodies conjugated complex containing poly(amidoamine) (PAMAM), carbon nanotube (CNT) and carboxyl functionalized CdSe nanocrystals (NCs) (CNT-PAMAM-CdSe NCs-Ab2). Via ligand exchange, the stable CdSe nanocrystals were easily functionalized with carboxylate ion (CdSe-COO-) and showed high hydrophilicity. The CdSe-COO- was effectively and densely conjugated to CNT coated dendrimer PAMAM that possesses large specific surface area. Finally, the target CEA was detected based on cation-exchange reaction (CER) by adding Ag+ to release thousands of cations Cd2+, which were detected by fluorescence and electrochemistry simultaneously. The electrochemical measurement was performed by directly detecting Cd2+ through square wave voltammetry (SWV), which displayed an excellent correlation with CEA from 5 pg/mL to 50 ng/mL, with a limit of detection (LOD) of 1.7 pg/mL. The fluorescence detection was implemented since free Cd2+ could trigger the weak fluorescence metal-sensitive dyes (Rhod-5N) to generate extremely high fluorescence signal. The fluorescence results showed the LOD for CEA detection was 0.25 pg/mL with a calibration curve range from 1 pg/mL to 20 ng/mL. The dual signal outputs showed an attractively self-correcting ability, which provides the capability of avoiding false positive signal and making the detection result more reliable. The proposed dual-responsive platform holds great promises for biomarkers detection in clinical diagnostics and therapy.


Assuntos
Anticorpos Imobilizados/química , Técnicas Biossensoriais/métodos , Compostos de Cádmio/química , Antígeno Carcinoembrionário/sangue , Nanopartículas/química , Compostos de Selênio/química , Antígeno Carcinoembrionário/análise , Cátions/química , Dendrímeros/química , Técnicas Eletroquímicas/métodos , Corantes Fluorescentes/química , Humanos , Imunoensaio/métodos , Limite de Detecção , Nanopartículas de Magnetita/química , Nanotubos de Carbono/química , Espectrometria de Fluorescência/métodos
17.
Cancer Lett ; 469: 340-354, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31629930

RESUMO

Therapeutic biomacromolecules are confronted with in vivo challenges of low bio-stability and poor tumor tissue-penetration. Herein, we report for the first time, our development and characterization of a hybrid nanocomposite for delivering a Bcl-2-converting peptide (NuBCP9, N9 hereafter) and testing its efficacy alone or together with doxorubicin (DOX). The hybrid nanocomposite is composed of the internal large pore sized-mesoporous silica nanoparticles (MSNs) and the external highly-branched polyamidoamine (PAMAM) dendrimers, into which N9 peptide and DOX were encapsulated for the different sub-cellular delivery to treat drug-resistant cancer. The nanocomposite possessed the particle and pore sizes of ~37 nm and ~8 nm, which displayed the superior tumor penetration capacity over naked MSNs both in cultured-3D tumor sphere and in live animal models. Moreover, the dual drug nanocomposite exhibited a great synergistic anticancer effect on Bcl-2-positive cancer cells in vitro and animals with the negligible toxic side effects. The tumor inhibition rate of the nanocomposite (89%) was five times as much as the two drugs combination. This design provides a new effective, safe and versatile strategy to fabricate large pore-sized MSNs with the organic-inorganic hybrid framework to concurrently transport therapeutic peptides and chemotherapeutics to the specific sub-cellular locations for the synergistic cancer therapy and drug resistance reversal, which has significant impact on the development of improved cancer therapeutics.


Assuntos
Antineoplásicos/farmacologia , Nanocompostos/química , Neoplasias/tratamento farmacológico , Oligopeptídeos/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Dendrímeros/química , Dendrímeros/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Xenoenxertos , Humanos , Camundongos , Neoplasias/genética , Neoplasias/patologia , Oligopeptídeos/química , Proteínas Proto-Oncogênicas c-bcl-2/genética
18.
Colloids Surf B Biointerfaces ; 185: 110623, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31735420

RESUMO

Bio-nanogate involves synthesized or natural molecules as a 'gate' towards bioreceptors and responds upon the presence of targeted analytes in nanoscale dimension. Development of bio-nanogate improves analyte selectivity and signal response across various types of biosensors. The versatility of PAMAM dendrimers to form conjugates with guest molecules, such as proteins can be utilized in forming a bio-nanogate. PAMAM interaction with peptide bioreceptor for antibody detection is of interest in this study. This study investigated the interaction of synthesized immunogenic 'a' determinant (aD) region of hepatitis B virus surface antigen (HBsAg) with PAMAM G4 and anti-HBsAg antibody, as a potential bio-nanogate for anti-HBsAg detection. The aD peptide fused with maltose binding protein (MBP), was confirmed with Western blotting. Nano-Differential Scanning Fluorimetry (nano-DSF) study revealed that the interaction of MBP-aD with anti-HBsAg indicated a higher thermal stability as compared to its interaction with PAMAM G4. Electrochemical impedance spectroscopy showed that a higher binding constant of MBP-aD interaction with anti-HBsAg (0.92 µM-1) was observed at maximum saturation, as compared with PAMAM G4 (0.07 µM-1). Thermodynamic parameters demonstrated that MBP-aD interacted with anti-HBsAg and PAMAM G4, through van der Waals and hydrogen bonding. These analyses suggest that the weak interaction of MBP-aD and PAMAM G4 may form a potential bio-nanogate. It is hypothesized that the presence of anti-HBsAg has a higher affinity towards MBP-aD which may displace PAMAM G4 in the anti-HBsAg detection system. This interaction study is crucial as an initial platform of using peptide-PAMAM as a bio-nanogate in an antibody detection system.


Assuntos
Antígenos de Superfície/análise , Dendrímeros/química , Hepatite B/imunologia , Nanopartículas/química , Peptídeos/química , Sequência de Aminoácidos , Proteínas Ligantes de Maltose/metabolismo , Ligação Proteica , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura
19.
Pharm Dev Technol ; 25(1): 9-19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30633621

RESUMO

Delivery of negatively charged, high molecular weight and unstable siRNA is difficult. The present study describes the development and comparison of cationic liposomes (CLs) and polyamidoamine (PAMAM) dendrimer generation 4 (PG4) nanocarriers of gene for cancer therapy. CLs and PG4 were complexed with anticancer siRNA (siPlk1) to form siPlk1-CLs lipoplex and siPlk1-PG4 dendriplex. siPlk1-CLs/PG4 complexes were characterized for average particle size, zeta potential, fluorescence and integrity of siPlk1 by agarose gel electrophoresis, ethidium bromide intercalation assay, circular dichroism, protection against RNase and stability in serum. The complexation of CLs/siPlk1 and PG4/siPlk1 were at a 100/1 and 2/1 charge ratio respectively. The CLs and PG4 were effective in protecting siPlk1 from RNase activity, also they enhanced the siPlk1 serum stability. Additionally, siPlk1-CLs and siPlk1-PG4 were evaluated by cell culture studies. In vitro anticancer activity study using MCF-7 cells showed that siPlk1-CLs and siPlk1-PG4 causes nearly similar cell death. Both siPlk1-CLs and siPlk1-PG4 resulted in enhanced cellular uptake of siPlk1 in MDA-MB-231 cells compared to naked siPlk1 solution. Cell cycle analysis suggested that increased cell population arrest in subG1 phase by siPlk1-CLs and siPlk1-PG4 compared to naked siPlk1 solution. These observations suggested that CLs and PG4 can be a potential carrier for siPlk1 delivery in breast cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cátions/química , Proteínas de Ciclo Celular/genética , Dendrímeros/química , Lipossomos/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Neoplasias da Mama/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Feminino , Humanos , Células MCF-7 , Tamanho da Partícula , Transfecção/métodos
20.
Mater Sci Eng C Mater Biol Appl ; 107: 110341, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761235

RESUMO

Cancer theranostics represents a strategy that aims at combining diagnosis with therapy through the simultaneous imaging and targeted delivery of therapeutics to cancer cells. Recently, the folate receptor alpha has emerged as an attractive theranostic target due to its overexpression in multiple solid tumors and its great functional versatility. In fact, it can be incorporated into folate-conjugated nano-systems for imaging and drug delivery. Hence, it can be used along the line of personalized clinical strategies as both an imaging tool and a delivery method ensuring the selective transport of treatments to tumor cells, thus highlighting its theranostic qualities. In this review, we will explore these theranostic characteristics in detail and assess their clinical potential. We will also discuss the technological advances that have allowed the design of sophisticated folate-based nanocarriers harboring various chemical properties and suited for the transport of various therapeutic agents.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Ácido Fólico/química , Nanoestruturas/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Dendrímeros/química , Dendrímeros/farmacologia , Receptor 1 de Folato/metabolismo , Ácido Fólico/metabolismo , Ácido Fólico/farmacocinética , Humanos , Lipossomos/administração & dosagem , Terapia de Alvo Molecular/métodos , Nanoestruturas/química , Neoplasias/metabolismo , Microambiente Tumoral
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