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2.
Nano Lett ; 19(8): 5515-5523, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31362507

RESUMO

Designing simple-structured nanomedicine without lacking key functionalities, thereby avoiding incomplete damage or relapse of tumor with the administration of a safe dose, is pivotal for successful cancer nanotherapy. We herein presented a nanomedicine of photodynamic therapy (PDT) that simply assembled amphiphilic macromolecules of poly-l-lysine conjugating with photosensitizers onto hydrophobic upconverting nanoparticles. We demonstrated that the nanoformulation, despite its simple structure and synthesis, simultaneously possesses multiple features, including substantial payload of photosensitizers, avid cellular internalization both in vitro and in vivo, efficient diffusion and broad distribution in tumor lesion, and potent fatality for cancer stem cells that are refractory to other therapy modalities. Because of the combination of these functionalities, the tumors in mice were eradicated and no relapse was observed after at least 40 days, just with an extremely low intraperitoneal injection dose of 5.6 mg/kg. Our results suggested a strategy for designing multifunctional nanomedicines with simple construct and efficacious therapeutic response and presented the promising potential of PDT for a radical cure of cancer.


Assuntos
Nanoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Linhagem Celular Tumoral , Células HeLa , Humanos , Camundongos , Nanoconjugados/administração & dosagem , Nanoconjugados/química , Recidiva Local de Neoplasia/prevenção & controle , Células-Tronco Neoplásicas/efeitos dos fármacos , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/química , Polilisina/administração & dosagem , Polilisina/análogos & derivados , Polilisina/uso terapêutico
3.
Adv Ther (Weinh) ; 2(10)2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34095457

RESUMO

Macrophages are key effectors of host defense and metabolism, making them promising targets for transient genetic therapy. Gene editing through delivery of the Cas9-ribonucleoprotein (RNP) provides multiple advantages over gene delivery-based strategies for introducing CRISPR machinery to the cell. There are, however, significant physiological, cellular, and intracellular barriers to the effective delivery of the Cas9 protein and guide RNA (sgRNA) that have to date, restricted in vivo Cas9 protein-based approaches to local/topical delivery applications. Herein we describe a new nanoassembled platform featuring co-engineered nanoparticles and Cas9 protein that has been developed to provide efficient Cas9-sgRNA delivery and concomitant CRISPR editing through systemic tail-vein injection into mice, achieving >8% gene editing efficiency in macrophages of the liver and spleen.

4.
ACS Nano ; 13(1): 229-235, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30516966

RESUMO

Bioorthogonal transformation of prodrugs and profluorophores using transition metal catalysts (TMCs) offers a promising strategy for therapeutic and imaging applications. Here, we report the surface engineering of nanoparticles to specifically localize gold nanoparticles (AuNPs) with encapsulated TMCs (nanozymes) to either the inside or outside of cells. The ability to control nanozyme localization and hence activity was demonstrated by the activation of pro-fluorophores and prodrugs intra- and extracellularly, establishing the potential of engineered nanozyme platforms for both diagnostic and therapeutic purposes.


Assuntos
Membrana Celular/metabolismo , Família 1 do Citocromo P450/metabolismo , Nanopartículas Metálicas/química , Animais , Biocatálise , Permeabilidade da Membrana Celular , Células , Família 1 do Citocromo P450/administração & dosagem , Ouro/química , Células HeLa , Humanos , Camundongos , Células RAW 264.7
5.
Small ; 14(7)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29271047

RESUMO

A modular strategy for the solubilization and protection of hydrophobic transition metal catalysts using the hydrophobic pockets of water soluble gold nanoparticles is reported. Besides preserving original catalyst activity, this encapsulation strategy provides a protective environment for the hydrophobic catalyst and brings reusability. This system provides a versatile platform for the encapsulation of different hydrophobic transition metal catalysts, allowing a wide range of catalysis in water while uniting the advantages of homogeneous and heterogeneous catalysis in the same system.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Catálise , Interações Hidrofóbicas e Hidrofílicas
6.
Chem Commun (Camb) ; 53(62): 8794-8797, 2017 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-28736785

RESUMO

Endocrine disrupting chemicals (EDCs) interact with estrogen receptors (ERs), causing a broad range of adverse health effects. Current assays for EDC activity are slow and often lack sensitivity. We report here an ultra-sensitive nanosensor that can detect estrogenic cellular changes in ER(+) MCF-7 cells rapidly (minutes) at several orders of magnitude lower than the generally used assays. Notably, the sensor responses at these ultra-low EDC levels correlated with an increased synthesis phase (S-phase) cell population of EDC-treated cells. The nanosensor was also able to detect binary EDC mixture effects, with synergism observed for bisphenol A (BPA) - 17ß-estradiol (E2), and antagonism for dicyclohexylphthalate (DCHP) - E2 and benzo(a)pyrene (BaP) - E2.


Assuntos
Disruptores Endócrinos/análise , Estrogênios não Esteroides/análise , Proteínas de Fluorescência Verde/química , Nanopartículas Metálicas/química , Técnicas Biossensoriais/métodos , Antagonismo de Drogas , Sinergismo Farmacológico , Disruptores Endócrinos/farmacologia , Estradiol/análise , Estradiol/farmacologia , Estrogênios não Esteroides/farmacologia , Ouro/química , Humanos , Células MCF-7 , Fase S/efeitos dos fármacos
7.
Anal Chem ; 89(5): 3009-3014, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28193006

RESUMO

Nanomaterials have been extensively used as alternate matrices to minimize the low molecular weight interferences observed in typical MALDI but such nanomaterials typically do not improve the spot-to-spot variability that is commonly seen. In this work, we demonstrate that nanoparticles and low matrix concentrations (<2.5 mg/mL) can be used to homogeneously concentrate analytes into a narrow ring by taking advantage of the "coffee ring" effect. Concentration of the samples in this way leads to enhanced signals when compared to conventional MALDI, with higher m/z analytes being enhanced to the greatest extent. Moreover, the ionization suppression often observed in samples with high salt concentrations can be overcome by preparing samples in this way. The ring that is formed is readily visible, allowing the laser to be focused only on spots that contain analyte. The coffee-ring effect represents a new mode by which nanomaterials can be used to enhance the MALDI-based detection of biomolecules.

8.
Macromolecules ; 50(20): 8202-8211, 2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30700915

RESUMO

Cationic dendrimers are promising vectors for non-viral gene due to their well-defined size and chemistry. We have synthesized a series of succinylated fourth generation (G4) PAMAM dendrimers to control the DNA packaging in dendriplexes, allowing us to probe the role of charge on DNA packaging. The self-assembly of DNA induced by these zwitterionic PAMAM (zPAMAM) was investigated using small-angle x-ray scattering (SAXS). We demonstrate that changing the degree of modification in zPAMAM-DNA significantly alters the packing density of the resulting dendriplexes. Salt sensitivities and pH dependence on the inter-DNA spacing were also examined. The swelling and stability to salt is reduced with increasing degree of PAMAM modification. Lowering the pH leads to significantly tighter hexagonal DNA packaging. In combination, these results show zPAMAM is an effective means to modulate nucleic acid packaging in a deterministic manner.

9.
Nanotechnology ; 27(37): 374001, 2016 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-27505356

RESUMO

We report on nanoparticle-stabilized capsules (NPSCs) as a platform for the co-delivery of survivin-targeted siRNA and tamoxifen. These capsules feature an inner oil core that provides a carrier for tamoxifen, and is coated on the surface with positively charged nanoparticles self-assembled with siRNA. The multifaceted chemical nature of the NPSC system enables the simultaneous delivery of both payloads directly into the cytosol in vitro. The NPSC co-delivery of tamoxifen and survivin-targeted siRNA into breast cancer cells disables the pathways that inhibit apoptosis, resulting in enhanced breast cell death.


Assuntos
Nanopartículas , Citosol , Proteínas Inibidoras de Apoptose , Nanocápsulas , RNA Interferente Pequeno
10.
Small ; 12(28): 3775-9, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27295172

RESUMO

A co-engineered nanoparticle/protein peroxide detector is created. This system features a gold nanoparticle functionalized with a galactose headgroup (AuNP-Gal) that reacts covalently with a boronate-modified green fluorescent protein (PB-GFP). Boronate acid-saccharide complexation between PB-GFP and AuNP-Gal affords a highly stable assembly. This complex is disrupted by peroxide, allowing quantitative and selective monitoring of hydrogen peroxide production in real time.


Assuntos
Técnicas Biossensoriais/métodos , Ouro/química , Peróxido de Hidrogênio/química , Nanopartículas Metálicas/química , Estresse Oxidativo/fisiologia , Galactose/química , Proteínas de Fluorescência Verde/química
11.
Nanomedicine (Lond) ; 11(12): 1535-50, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27246686

RESUMO

AIM: To engineer a photodegradable hydrogel system for actively controlled release of bioactive unmodified RNA at designated time points to induce hMSC osteogenesis. MATERIALS & METHODS: RNA/polyethylenimine complexes were loaded into dual-crosslinked photodegradable hydrogels to examine the capacity of UV light application to trigger their release. The ability of released RNA to drive hMSC osteogenic differentiation was also investigated. RESULTS & CONCLUSION: RNA release from photodegradable hydrogels was accelerated upon UV application, which was not observed in non-photodegradable hydrogels. Regardless of the presence of UV light, released siGFP exhibited high bioactivity by silencing GFP expression in HeLa cells. Importantly, siNoggin or miRNA-20a released from the hydrogels induced hMSC osteogenesis. This system provides a potentially valuable physician/patient-controlled 'on-demand' RNA delivery platform for biomedical applications.


Assuntos
Preparações de Ação Retardada/química , Hidrogéis/química , Células-Tronco Mesenquimais/citologia , MicroRNAs/administração & dosagem , Osteogênese , Fotólise , RNA Interferente Pequeno/administração & dosagem , Diferenciação Celular , Linhagem Celular , Células HeLa , Humanos , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , RNA Interferente Pequeno/genética , Engenharia Tecidual , Raios Ultravioleta
12.
Analyst ; 141(8): 2418-25, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-26979648

RESUMO

Functionalized gold nanoparticles (AuNPs) have unique properties that make them important biomedical materials. Optimal use of these materials, though, requires an understanding of their fate in vivo. Here we describe the use of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to image the biodistributions of AuNPs in tissues from mice intravenously injected with AuNPs. We demonstrate for the first time that the distributions of very small (∼2 nm core) monolayer-protected AuNPs can be imaged in animal tissues at concentrations in the low parts-per-billion range. Moreover, the LA-ICP-MS images reveal that the monolayer coatings on the injected AuNPs influence their distributions, suggesting that the AuNPs remain intact in vivo and their surface chemistry influences how they interact with different organs. We also demonstrate that quantitative images of the AuNPs can be generated when the appropriate tissue homogenates are chosen for matrix matching. Overall, these results demonstrate the utility of LA-ICP-MS for tracking the fate of biomedically-relevant AuNPs in vivo, facilitating the design of improved AuNP-based therapeutics.


Assuntos
Ouro/química , Ouro/metabolismo , Lasers , Nanopartículas Metálicas , Imagem Molecular/métodos , Tamanho da Partícula , Animais , Feminino , Fígado/metabolismo , Espectrometria de Massas , Camundongos , Baço/metabolismo
13.
Adv Healthc Mater ; 5(3): 305-310, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26639103

RESUMO

A photocleavable hydrogel system for on-demand delivery of genetic material is reported. The release of short interfering RNAs can be triggered by the application of UV light without any loss in bioactivity. This approach provides a promising external stimulus-based nucleic acid delivery platform for applications in disease therapeutics and tissue regeneration.


Assuntos
Hidrogéis/química , RNA Interferente Pequeno/química , Técnicas de Transferência de Genes , Humanos , Luz , Ácidos Nucleicos/química , Regeneração/fisiologia , Engenharia Tecidual/métodos
14.
Tetrahedron Lett ; 56(23): 3653-3657, 2015 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-26074630

RESUMO

Host-guest interactions between a synthetic receptor, cucurbit[7]uril (CB[7]), and gold nanoparticles (AuNPs) have been quantified using isothermal titration calorimetry. AuNPs were functionalized with ligands containing tertiary or quaternary benzylamine derivatives, with electron donating or withdrawing groups at the para position of the benzene ring. Analysis of binding interactions reveals that functional groups at the para position have no significant effect on binding constant. However, headgroups bearing a permanent positive charge increased the binding of AuNPs to CB[7] ten-fold compared to monomethyl counterparts.

15.
Nat Chem ; 7(7): 597-603, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26100809

RESUMO

Bioorthogonal catalysis broadens the functional possibilities of intracellular chemistry. Effective delivery and regulation of synthetic catalytic systems in cells are challenging due to the complex intracellular environment and catalyst instability. Here, we report the fabrication of protein-sized bioorthogonal nanozymes through the encapsulation of hydrophobic transition metal catalysts into the monolayer of water-soluble gold nanoparticles. The activity of these catalysts can be reversibly controlled by binding a supramolecular cucurbit[7]uril 'gate-keeper' onto the monolayer surface, providing a biomimetic control mechanism that mimics the allosteric regulation of enzymes. The potential of this gated nanozyme for use in imaging and therapeutic applications was demonstrated through triggered cleavage of allylcarbamates for pro-fluorophore activation and propargyl groups for prodrug activation inside living cells.


Assuntos
Nanopartículas Metálicas/química , Elementos de Transição/química , Catálise , Células HeLa , Humanos
16.
Org Biomol Chem ; 13(8): 2474-2479, 2015 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-25569869

RESUMO

Prolonged retention of internalized nanoparticulate systems inside cells improves their efficacy in imaging, drug delivery, and theranostic applications. Especially, regulating exocytosis of the nanoparticles is a key factor in the fabrication of effective nanocarriers for chemotherapeutic treatments but orthogonal control of exocytosis in the cellular environment is a major challenge. Herein, we present the first example of regulating exocytosis of gold nanoparticles (AuNPs), a model drug carrier, by using a simple host-guest supramolecular system. AuNPs featuring quaternary amine head groups were internalized into the cells through endocytosis. Subsequent in situ treatment of a complementary cucurbit[7]uril (CB[7]) to the amine head groups resulted in the AuNP-CB[7] complexation inside cells, rendering particle assembly. This complexation induced larger particle assemblies that remained sequestered in the endosomes, inhibiting exocytosis of the particles without any observed cytotoxicity.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Exocitose , Nanopartículas Metálicas/química , Aminas/química , Hidrocarbonetos Aromáticos com Pontes/química , Endossomos/metabolismo , Ouro/química , Ouro/metabolismo , Humanos , Imidazóis/química , Células MCF-7
17.
Supramol Chem ; 27(1-2): 123-126, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27122961

RESUMO

A new class of cationic gold nanoparticles has been synthesized bearing benzyl moieties featuring -NO2 and -OMe groups to investigate the regioisomeric control of aromatic nanoparticle-protein recognition. In general, nanoparticles bearing electron withdrawing group demonstrated higher binding affinities towards green fluorescent protein (GFP) compared to electron-donating groups. Significantly, a ~7.5 and ~4.3 fold increase in binding with GFP was observed for -NO2 groups in meta- and para-position respectively, while ortho-substitution showed similar binding compared to the unsubstituted ring. These findings demonstrated that nanoparticle-protein interaction can be controlled by the tuning the spatial orientation and the relative electronic properties of the aromatic substituents. This improved biomolecular recognition provides opportunities for enhanced biosensing and functional protein delivery to the cells.

18.
Nat Nanotechnol ; 10(1): 65-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25502312

RESUMO

Screening methods that use traditional genomic, transcriptional, proteomic and metabonomic signatures to characterize drug mechanisms are known. However, they are time consuming and require specialized equipment. Here, we present a high-throughput multichannel sensor platform that can profile the mechanisms of various chemotherapeutic drugs in minutes. The sensor consists of a gold nanoparticle complexed with three different fluorescent proteins that can sense drug-induced physicochemical changes on cell surfaces. In the presence of cells, fluorescent proteins are rapidly displaced from the gold nanoparticle surface and fluorescence is restored. Fluorescence 'turn on' of the fluorescent proteins depends on the drug-induced cell surface changes, generating patterns that identify specific mechanisms of cell death induced by drugs. The nanosensor is generalizable to different cell types and does not require processing steps before analysis, offering an effective way to expedite research in drug discovery, toxicology and cell-based sensing.


Assuntos
Antineoplásicos/administração & dosagem , Monitoramento de Medicamentos/instrumentação , Nanotecnologia/instrumentação , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Espectrometria de Fluorescência/instrumentação , Animais , Bioensaio/instrumentação , Linhagem Celular Tumoral , Desenho de Equipamento , Análise de Falha de Equipamento , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
19.
Nanoscale ; 6(15): 8873-7, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-24960536

RESUMO

Interfacing synthetic materials with biomacromolecules provides new systems for biological applications. We report the creation of a reversible multivalent supramolecular "zipper" recognition motif between gold nanoparticles and proteins. In this assembly, carboxylate-functionalized nanoparticles interact strongly with oligohistidine tags. This interaction can be tuned through His-tag length, and offers unique binding profiles based on the pH and electrolyte concentration of the medium.


Assuntos
Materiais Biocompatíveis/química , Ácidos Carboxílicos/química , Histidina/química , Nanopartículas/química , Proteínas/química , Clonagem Molecular , Escherichia coli/metabolismo , Engenharia Genética , Ouro/química , Proteínas de Fluorescência Verde/química , Concentração de Íons de Hidrogênio , Íons , Ligantes , Substâncias Macromoleculares/química , Nanopartículas Metálicas/química , Ligação Proteica , Engenharia de Proteínas , Proteínas Recombinantes/química
20.
Curr Opin Colloid Interface Sci ; 19(2): 49-55, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24955019

RESUMO

Inorganic nanomaterials have a wide array of physical and structural properties that make them attractive candidates for imaging and therapeutic delivery. Nanoparticle platforms have been intensely studied for these applications, and examples are starting to enter the clinic. This review looks at why inorganic particles provide promising platforms for biomedicine, and what issues need to be addressed for them to reach their potential.

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