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1.
J Colloid Interface Sci ; 566: 163-170, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32004956

RESUMO

Clay mineral properties, together with solution chemistry, control the assembly of clay platelets into hierarchical structures, including tactoids and aggregates. We studied the effect of salinity on the assembly of kaolinite, illite, and montmorillonite at three critical scales: platelet, tactoid, and aggregate, using cryogenic scanning electron microscopy (cryo-SEM), atomic force microscopy (AFM) and cryo-transmission EM (cryo-TEM), respectively. Cyro-SEM images coupled with original alignment analysis indicate that the degree of aggregate alignment in an ionized solution was significantly higher than in deionized water. Furthermore, upon increasing platelet-platelet bonding energy (montmorillonite > illite > kaolinite), tactoid size increased, packing was less ordered, and aggregate alignment decreased. AFM measurements showed that an increase in ionic-strength caused a decrease in the Young's modulus of the clays, indicating higher tactoid alignment, since, disordered structures, comprising various platelet orientations, are stiffer than highly-aligned structures. We successfully measured distances <1 nm, for both kaolinite and montmorillonite by cryo-TEM, directly demonstrating that increasing ionic-strength reduces platelet-platelet distances. The outcome of this study offers a new approach and methodology to study fundamental colloid-assembly which will trigger future studies investigating additional parameters affecting assembly such as, temperature, solution pH, natural organic matter, and anthropogenic activity.

2.
Soft Matter ; 16(11): 2803-2814, 2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32104873

RESUMO

Viruses are remarkable self-assembled nanobiomaterial-based machines, exposed to a wide range of pH values. Extreme pH values can induce dramatic structural changes, critical for the function of the virus nanoparticles, including assembly and genome uncoating. Tuning cargo-capsid interactions is essential for designing virus-based delivery systems. Here we show how pH controls the structure and activity of wild-type simian virus 40 (wtSV40) and the interplay between its cargo and capsid. Using cryo-TEM and solution X-ray scattering, we found that wtSV40 was stable between pH 5.5 and 9, and only slightly swelled with increasing pH. At pH 3, the particles aggregated, while capsid protein pentamers continued to coat the virus cargo but lost their positional correlations. Infectivity was only partly lost after the particles were returned to pH 7. At pH 10 or higher, the particles were unstable, lost their infectivity, and disassembled. Using time-resolved experiments we discovered that disassembly began by swelling of the particles, poking a hole in the capsid through which the genetic cargo escaped, followed by a slight shrinking of the capsids and complete disassembly. These findings provide insight into the fundamental intermolecular forces, essential for SV40 function, and for designing virus-based nanobiomaterials, including delivery systems and antiviral drugs.

3.
Nano Lett ; 19(9): 5844-5852, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31424944

RESUMO

The majority of developed and approved anticancer nanomedicines have been designed to exploit the dogma of the enhanced permeability and retention (EPR) effect, which is based on the leakiness of the tumor's blood vessels accompanied by impeded lymphatic drainage. However, the EPR effect has been under scrutiny recently because of its variable manifestation across tumor types and animal species and its poor translation to human cancer therapy. To facilitate the EPR effect, systemically injected NPs should overcome the obstacle of rapid recognition and elimination by the mononuclear phagocyte system (MPS). We hypothesized that circulating monocytes, major cells of the MPS that infiltrate the tumor, may serve as an alternative method for achieving increased tumor accumulation of NPs, independent of the EPR effect. We describe here the accumulation of liposomal quantum dots (LipQDs) designed for active delivery via monocytes, in comparison to LipQDs designed for passive delivery (via the EPR effect), following IV administration in a mammary carcinoma model. Hydrophilic QDs were synthesized and entrapped in functionalized liposomes, conferring passive ("stealth" NPs; PEGylated, neutral charge) and active (monocyte-mediated delivery; positively charged) properties by differing in their lipid composition, membrane PEGylation, and charge (positively, negatively, and neutrally charged). The various physicochemical parameters affecting the entrapment yield and optical stability were examined in vitro and in vivo. Biodistribution in the blood, various organs, and in the tumor was determined by the fluorescence intensity and Cd analyses. Following the treatment of animals (intact and mammary-carcinoma-bearing mice) with disparate formulations of LipQDs (differing by their lipid composition, neutrally and positively charged surfaces, and hydrophilic membrane), we demonstrate comparable tumor uptake of QDs delivered by the passive and the active routes (mainly by Ly-6Chi monocytes). Our findings suggest that entrapping QDs in nanosized liposomal formulations, prepared by a new facile method, imparts superior structural and optical stability and a suitable biodistribution profile leading to increased tumor uptake of fluorescently stable QDs.


Assuntos
Lipossomos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Sistema Fagocitário Mononuclear/química , Pontos Quânticos/química , Animais , Vasos Sanguíneos/efeitos dos fármacos , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Lipídeos/química , Lipídeos/farmacologia , Lipossomos/química , Neoplasias Mamárias Animais/patologia , Camundongos , Nanomedicina , Células Neoplásicas Circulantes , Permeabilidade/efeitos dos fármacos
4.
J Phys Chem B ; 123(16): 3535-3542, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-30939005

RESUMO

Incorporation of carbon nanotubes (CNTs) into liquid crystalline phases of cellulose nanocrystals (CNCs) may be used for preparation of hybrids with novel optical, electrical, and mechanical properties. Here, we investigated the effect of nanoparticle diameter, geometry, aspect ratio, and flexibility on the exclusion of dispersed carbon nanostructures (CNs) from the chiral nematic phase (N*) of the CNCs. Although the CNs are nicely dispersed in isotropic suspensions of CNCs, we observe that fullerenes, carbon black, and CNTs are depleted from the N* phase. This observation is surprising as theoretical predictions and previous observations of nanoparticles indicate that nanometric inclusions would be incorporated within the N* phase. Cryogenic transmission electron microscopy imaging reveals that the dispersed CNs induce misorientation of the CNCs, irrespective of their geometry and size. Rheological measurements suggest that about 10% of the CNCs are affected by the CNs. The multiparticle nature of the interaction may be the origin of the nonsize selective exclusion of the CNs. Re-entrant behavior is observed at high CNC concentrations (about 13 wt %), where a (nematic) gel-like phase kinetically traps the CNs. These phases exhibit non-Newtonian flow behavior and birefringence, offering a pathway for preparation of nonisotropic CNCs-CNT composites and thin films via liquid processing.

5.
Nanoscale ; 11(21): 10160-10166, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30994643

RESUMO

Here we show the encapsulation of 35 nm diameter, nearly-spherical, DNA origami by self-assembly of SV40-like (simian virus 40) particles. The self-assembly of this new type of nanoparticles is highly reproducible and efficient. The structure of these particles was determined by cryo-EM. The capsid forms a regular SV40 lattice of T = 7d icosahedral symmetry and the structural features of encapsulated DNA origami are fully visible. These particles are a promising biomaterial for use in various medical applications.


Assuntos
Capsídeo/química , DNA/química , Nanopartículas/química , Vírus 40 dos Símios/química , Capsídeo/ultraestrutura , DNA/ultraestrutura , Nanopartículas/ultraestrutura , Vírus 40 dos Símios/ultraestrutura
6.
Chembiochem ; 20(3): 355-359, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30371005

RESUMO

Biofilms are aggregates of microbial cells that form on surfaces and at interfaces, and are encased in an extracellular matrix. In biofilms made by the soil bacterium Bacillus subtilis, the protein TapA mediates the assembly of the functional amyloid protein TasA into extracellular fibers, and it anchors these fibers to the cell surface. We used circular dichroism and NMR spectroscopy to show that, unlike the structured TasA, TapA is disordered. In addition, TapA is composed of two weakly interacting domains: a disordered C-terminal domain and a more structured N-terminal domain. These two domains also exhibited different structural changes in response to changes in external conditions, such as increased temperatures and the presence of lipid vesicles. Although the two TapA domains weakly interacted in solution, their cooperative interaction with lipid vesicles prevented disruption of the vesicles. These findings therefore suggest that the two-domain composition of TapA is important in its interaction with single or multiple partners in the extracellular matrix in biofilms.


Assuntos
Bacillus subtilis/química , Proteínas de Bactérias/química , Proteínas da Matriz Extracelular/química , Proteínas Intrinsicamente Desordenadas/química , Ressonância Magnética Nuclear Biomolecular
7.
ACS Appl Mater Interfaces ; 10(43): 36711-36720, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30285412

RESUMO

Self-adjusting omniphilic nanocarriers (OPNs) with a multisolvent aptitude were prepared via a Schiff base reaction between chitosan, a natural polysaccharide, and bioactive aldehydes. Experimental studies supported by atomistic molecular dynamics simulations revealed these OPNs can encapsulate insoluble molecular cargo, transport them in aqueous or lipid environments, and deliver them through cross-phase barriers. N-imine dynamic covalent bonds have been incorporated to endow the OPNs with pH responsiveness, also allowing the amplification of their bioactivity, as demonstrated in vitro with the ability to delay fungal proliferation in wheat grains. The reported OPNs hold remarkable potential as biocompatible nanocarriers for the effective delivery of active agents in agriculture, medicine, and cosmetics.


Assuntos
Antifúngicos/química , Portadores de Fármacos/química , Nanopartículas/química , Polissacarídeos/química , Aldeídos/química , Carbono/química , Quitosana/química , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Iminas/química , Lipídeos/química , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Transmissão , Simulação de Dinâmica Molecular , Espectroscopia de Infravermelho com Transformada de Fourier
8.
Biochemistry ; 57(43): 6153-6165, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30247898

RESUMO

Single and double tubulin rings were studied under a range of conditions and during microtubule (MT) assembly and disassembly. Here, tubulin was purified from porcine brain and used without any further modifications or additives that promote ring assembly. The structure of single GDP-rich tubulin rings was determined by cryo-transmission electron microscopy and synchrotron solution X-ray scattering. The scattering curves were fitted to atomic models, using our state-of-the-art analysis software, D+ . We found that there is a critical concentration for ring formation, which increased with GTP concentration with temperature. MT assembly or disassembly, induced by changes in temperature, was analyzed by time-resolved small-angle X-ray scattering. During MT assembly, the fraction of rings and unassembled dimers simultaneously decreased. During MT disassembly, the mass fraction of dimers increased. The increase in the concentration of rings was delayed until the fraction of dimers was sufficiently high. We verified that pure dimers, eluted via size-exclusion chromatography, could also form rings. Interestingly, X-ray radiation triggered tubulin ring disassembly. The concentration of disassembled rings versus exposure time followed a first-order kinetics. The disassembly rate constant and initial concentration were determined. X-ray radiation-triggered disassembly was used to determine the concentration of rings. We confirmed that following a temperature jump, the mass fraction of rings decreased and then stabilized at a constant value during the first stage of the MT assembly kinetics. This study sheds light on the most basic assembly and disassembly conditions for in vitro single GDP-rich tubulin rings and their relation to MT kinetics.


Assuntos
Encéfalo/metabolismo , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Microtúbulos/química , Microtúbulos/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Animais , Cinética , Modelos Teóricos , Conformação Proteica , Multimerização Proteica , Suínos , Raios X
9.
J Am Chem Soc ; 140(44): 14627-14637, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30160101

RESUMO

Semiconductor nanocrystals serve as outstanding model systems for studying quantum confined size and shape effects. Shape control is an important knob for controlling their properties but so far it has been well developed mainly for heavy-metal containing semiconductor nanocrystals, limiting their further widespread utilization. Herein, we report a synthesis of heavy-metal free ZnSe nanocrystals with shape and size control through utilization of well-defined molecular clusters. In this approach, ZnSe nanowires are synthesized and their length and shape control is achieved by introduction of controlled amounts of molecular clusters. As a result of [Zn4(SPh)10](Me4N)2 clusters (Zn4 clusters) addition, short ZnSe nanorods or ZnSe nanodots can be obtained through tuning the ratio of Zn4 clusters to ZnSe. A study using transmission electron microscopy revealed the formation of a hybrid inorganic-organic nanowire, whereby the ligands form a template for self-assembly of ZnSe magic size clusters. The hybrid nanowire template becomes shorter and eventually disappears upon increasing amount of Zn4 clusters in the reaction. The generality of the method is demonstrated by using isostructural [Cu4(SPh)6](Me4N)2 clusters, which presented a new approach to Cu doped ZnSe nanocrystals and provided also a unique opportunity to employ X-ray absorption fine structure spectroscopy for deciphering the changes in the local atomic-scale environment of the clusters and explaining their role in the process of the nanorods formation. Overall, the introduction of molecular clusters presented here opens a path for growth of colloidal semiconductor nanorods, expanding the palette of materials selection with obvious implications for optoelectronic and biomedical applications.

10.
Eur J Pharm Biopharm ; 130: 296-305, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29959035

RESUMO

Since their discovery, liposomes have been widely employed in biomedical research. These nano-size spherical vesicles consisting one or few phospholipid bilayers surrounding an aqueous core are capable of carrying a wide variety of bioactive compounds, including drugs, peptides, nucleic acids, proteins and others. Despite considerable success achieved in synthesis of liposome constructs containing bioactive compounds, preparation of ligand-targeted liposomes comprising large quantities of encapsulated proteins that are capable of affecting pathological cells still remains a big challenge. Here we described a novel method for preparation of small (80-90 nm in diameter) unilamellar liposomes containing very large quantities (thousands of protein molecules per liposome) of heme-containing cytochrome c, highly fluorescent mCherry and highly toxic PE40 (Pseudomonas aeruginosa Exotoxin A domain). Efficient encapsulation of the proteins was achieved through electrostatic interaction between positively charged proteins (at pH lower than pI) and negatively charged liposome membrane. The proteoliposomes containing large quantities of mCherry or PE40 and functionalized with designed ankyrin repeat protein (DARPin)_9-29, which targets human epidermal growth factor receptor 2 (HER2) were shown to specifically stain and kill in sub-nanomolar concentrations HER2-positive cells, overexpressing HER2, respectively. Specific staining and eradication of the receptor-positive cells demonstrated here makes the DARPin-functionalized liposomes carrying large quantities of fluorescent and/or toxic proteins a promising candidate for tumor detection and therapy.


Assuntos
ADP Ribose Transferases/administração & dosagem , Repetição de Anquirina/genética , Toxinas Bacterianas/administração & dosagem , Citocromos c/administração & dosagem , Exotoxinas/administração & dosagem , Proteínas Luminescentes/administração & dosagem , Fatores de Virulência/administração & dosagem , ADP Ribose Transferases/química , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Toxinas Bacterianas/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Citocromos c/química , Exotoxinas/química , Feminino , Heme/química , Humanos , Lipossomos , Proteínas Luminescentes/química , Neoplasias Ovarianas , Tamanho da Partícula , Receptor ErbB-2/metabolismo , Fatores de Virulência/química
11.
Langmuir ; 34(13): 3925-3933, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29513998

RESUMO

A series of four cellulose nanocrystal (CNC) suspensions were prepared from bleached softwood kraft pulp using different conditions of sulfuric acid hydrolysis. The CNCs were identical in size (95 nm in length × 5 nm in width) but had different surface charges corresponding to the harshness of the hydrolysis conditions. Consequently, it was possible to isolate the effects of surface charge on the self-assembly and viscosity of the CNC suspensions across surface charges ranging from 0.27%S to 0.89%S. The four suspensions (never-dried, free of added electrolyte) all underwent liquid crystalline phase separation, but the concentration onset for the emergence of the chiral nematic phase shifted to higher values with increasing surface charge. Similarly, suspension viscosity was also influenced by surface charge, with suspensions of lower surface charge CNCs more viscous and tending to gel at lower concentrations. The properties of the suspensions were interpreted in terms of the increase in effective diameter of the nanocrystals due to the surface electrostatic repulsion of the negative sulfate half-esters, as modified by the screening effects of the H+ counterions in the suspensions. The results suggest that there is a threshold surface charge density (∼0.3%S) above which effective volume considerations are dominant across the concentration range relevant to liquid crystalline phase formation. Above this threshold value, phase separation occurs at the same effective volume fraction of CNCs (∼10 vol %), with a corresponding increase in critical concentration due to the decrease in effective diameter that occurs with increasing surface charge. Below or near this threshold value, the formation of end-to-end aggregates may favor gelation and interfere with ordered phase formation.

12.
J Phys Chem B ; 121(36): 8427-8436, 2017 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-28820593

RESUMO

Microtubule (MT) is made of αß-tubulin heterodimers that dynamically assemble into a hollow nanotube composed of straight protofilaments. MT dynamics is facilitated by hydrolysis of guanosine-5'-triphosphate (GTP) and can be inhibited by either anticancer agents like taxol or the nonhydrolyzable GTP analogues like GMPPCP. Using high-resolution synchrotron X-ray scattering, we have measured and analyzed the scattering curves from solutions of dynamic MT (in other words, in the presence of excess GTP and free of dynamic-inhibiting agents) and examined the effect of two MT stabilizers: taxol and GMPPCP. Previously, we have analyzed the structure of dynamic MT by docking the atomic model of tubulin dimer onto a 3-start left handed helical lattice, derived from the PDB ID 3J6F . 3J6F corresponds to a MT with 14 protofilaments. In this paper, we took into account the possibility of having MT structures containing between 12 and 15 protofilaments. MTs with 12 protofilaments were never observed. We determined the radii, the pitch, and the distribution of protofilament number that best fit the scattering data from dynamic MT or stabilized MT by taxol or GMPPCP. We found that the protofilament number distribution shifted when the MT was stabilized. Taxol increased the mass fraction of MT with 13 protofilaments and decreased the mass fraction of MT with 14 protofilaments. GMPPCP reduced the mass fraction of MT with 15 protofilaments and increased the mass fraction of MT with 14 protofilaments. The pitch, however, remained unchanged regardless of whether the MT was dynamic or stabilized. Higher tubulin concentrations increased the fraction of dynamic MT with 14 protofilaments.


Assuntos
Guanosina Trifosfato/análogos & derivados , Microtúbulos/química , Paclitaxel/química , Tubulina (Proteína)/química , Guanosina Trifosfato/química , Microscopia Eletrônica de Transmissão , Simulação de Acoplamento Molecular , Estabilidade Proteica , Estrutura Quaternária de Proteína , Espalhamento de Radiação , Raios X
13.
J Control Release ; 261: 138-146, 2017 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-28666727

RESUMO

Even though some progress in diagnosis and treatment has been made over the years, there is still no definitive treatment available for Glioblastoma multiforme (GBM). Convection-enhanced delivery (CED), a continuous infusion-mediated pressure gradient via intracranial catheters, studied in clinical trials, enables in situ drug concentrations several orders of magnitude greater than those achieved by systemic administration. We hypothesized that the currently limited efficacy of CED could be enhanced by a liposomal formulation, thus achieving enhanced drug localization to the tumor site with minimal toxicity. We hereby describe a novel approach for treating GBM by CED of liposomes containing the known chemotherapeutic agent, temozolomide (TMZ). A new technique for encapsulating TMZ in hydrophilic (PEGylated) liposomes, characterized by nano-size (121nm), low polydispersity index (<0.13) and with near-neutral charge (-ʒ,0.2mV), has been developed. Co-infusion of PEGylated Gd-DTPA liposomes and TMZ-liposomes by CED in GBM bearing rats, resulted in enhanced tumor detection with longer residence time than free Gd-DTPA. Treatment of GBM-bearing rats with either TMZ solution or TMZ-liposomes resulted in greater tumor inhibition and significantly higher survival. However, the longer survival and smaller tumor volumes exhibited by TMZ liposomal treatment in comparison to TMZ in solution were insignificant (p<0.053); and only significantly lower edema volumes were observed. Thus, there are no clear-cut advantages to use a liposomal delivery system of TMZ via CED over a drug solution.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/farmacologia , Convecção , Dacarbazina/administração & dosagem , Dacarbazina/farmacocinética , Dacarbazina/farmacologia , Gadolínio DTPA/administração & dosagem , Lipossomos , Masculino , Nanopartículas , Tamanho da Partícula , Polietilenoglicóis/química , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Taxa de Sobrevida , Temozolomida , Carga Tumoral
14.
Photosynth Res ; 134(1): 39-49, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28577216

RESUMO

Cyanobacteria light-harvesting complexes can change their structure to cope with fluctuating environmental conditions. Studying in vivo structural changes is difficult owing to complexities imposed by the cellular environment. Mimicking this system in vitro is challenging, as well. The in vivo system is highly concentrated, and handling similar in vitro concentrated samples optically is difficult because of high absorption. In this research, we mapped the cyanobacteria antennas self-assembly pathways using highly concentrated solutions of phycocyanin (PC) that mimic the in vivo condition. PC was isolated from the thermophilic cyanobacterium Thermosynechococcus vulcanus and measured by several methods. PC has three oligomeric states: hexamer, trimer, and monomer. We showed that the oligomeric state was changed upon increase of PC solution concentration. This oligomerization mechanism may enable photosynthetic organisms to adapt their light-harvesting system to a wide range of environmental conditions.


Assuntos
Ficocianina/química , Cianobactérias/metabolismo , Espectrometria de Massas
15.
Oncotarget ; 8(15): 24046-24062, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28445962

RESUMO

The treatment of metastatic androgen-resistant prostate cancer remains a challenge. We describe a protein vector that selectively delivers synthetic dsRNA, polyinosinic/polycytidylic acid (polyIC), to prostate tumors by targeting prostate specific membrane antigen (PSMA), which is overexpressed on the surface of prostate cancer cells.The chimeric protein is built from the double stranded RNA (dsRNA) binding domain of PKR tethered to a single chain anti-PSMA antibody. When complexed with polyIC, the chimera demonstrates selective and efficient killing of prostate cancer cells. The treatment causes the targeted cancer cells to undergo apoptosis and to secrete toxic cytokines. In a "bystander effect", these cytokines kill neighboring cancer cells that do not necessarily overexpress PSMA, and activate immune cells that enhance the killing effect. The strong effects of the targeted polyIC are demonstrated on both 2D cell cultures and 3D tumor spheroids.


Assuntos
Antígenos de Superfície/genética , Efeito Espectador/efeitos dos fármacos , Efeito Espectador/genética , Vetores Genéticos/genética , Glutamato Carboxipeptidase II/genética , RNA de Cadeia Dupla/genética , Proteínas Recombinantes de Fusão/genética , Animais , Antígenos de Superfície/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Quimiotaxia de Leucócito/efeitos dos fármacos , Citocinas/biossíntese , Modelos Animais de Doenças , Expressão Gênica , Genes Reporter , Terapia Genética , Vetores Genéticos/administração & dosagem , Glutamato Carboxipeptidase II/antagonistas & inibidores , Glutamato Carboxipeptidase II/metabolismo , Humanos , Camundongos , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Neoplasias/terapia , Poli I-C/química , Proteínas Recombinantes de Fusão/metabolismo , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/farmacologia , Esferoides Celulares , Ensaios Antitumorais Modelo de Xenoenxerto
16.
ACS Nano ; 11(3): 3038-3051, 2017 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-28196324

RESUMO

Quantum dots (QDs), semiconductor nanocrystals, are fluorescent nanoparticles of growing interest as an imaging tool of a diseased tissue. However, a major concern is their biocompatibility, cytotoxicity, and fluorescence instability in biological milieu, impeding their use in biomedical applications, in general, and for inflammation imaging, in particular. In addition, for an efficient fluorescent signal at the desired tissue, and avoiding systemic biodistribution and possible toxicity, targeting is desired. We hypothesized that phagocytic cells of the innate immunity system (mainly circulating monocytes) can be exploited as transporters of specially designed liposomes containing QDs to the inflamed tissue. We developed a liposomal delivery system of QDs (LipQDs) characterized with high encapsulation yield, enhanced optical properties including far-red emission wavelength and fluorescent stability, high quantum yield, and protracted fluorescent decay lifetime. Treatment with LipQDs, rather than free QDs, exhibited high accumulation and retention following intravenous administration in carotid-injured rats (an inflammatory model). QD-monocyte colocalization was detected in the inflamed arterial segment only following treatment with LipQDs. No cytotoxicity was observed following LipQD treatment in cell cultures, and changes in liver enzymes and gross histopathological changes were not detected in mice and rats, respectively. Our results suggest that the LipQD formulation could be a promising strategy for imaging inflammation.


Assuntos
Sistemas de Liberação de Medicamentos , Inflamação/diagnóstico por imagem , Monócitos/química , Monócitos/metabolismo , Imagem Óptica , Pontos Quânticos/química , Animais , Compostos de Cádmio/química , Células Cultivadas , Lipossomos/química , Lipossomos/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Ratos , Ratos Endogâmicos , Compostos de Selênio/química , Sulfetos/química , Distribuição Tecidual , Compostos de Zinco/química
17.
Langmuir ; 32(36): 9286-92, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27556595

RESUMO

Copolymers with well-defined architectures, controlled molecular weights, and narrow molar mass dispersities (D) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. The resultant polymers contain different combinations of the pH-responsive monomer 2-(diethylaminoethyl) methacrylate (DEAEMA), the hydrophobic comonomer butyl methacrylate (BMA), and a neutral hydrophilic stabilizing monomer polyethylene glycol monomethyl ether methacrylate (designated O950). Surface tension and cryo-TEM measurements of native and heavy-atom stained samples were used to characterize the pH and salt responsiveness of the different polymers as a function of their composition. These studies indicate that while the polymers predominately self-assemble to form spherical micelles, a narrow size distribution is observed in aqueous solutions of poly(O950)-b-(BMA) and poly(O950)-b-(DEAEMA-co-BMA), whereas a broad size distribution characterizes the assemblies of poly(O950)-b-(DEAEMA) and poly(DEAEMA-co-BMA). In the latter case, micelles having diameters around 15-25 nm are found along with smaller aggregates (about 10 nm) mostly arranged in elongated necklace-like structures. The pH and salt-responsiveness of the DEAEMA residue, as indicated by the surface activity of the copolymers, was found to depend on the nature of the additional components: covalently linked hydrophobic groups (BMA) moderated the pH response of the copolymer as compared to nonionic and hydrophilic groups as in poly(O950)-b-(DEAEMA). These results suggest that mutual interactions among the building blocks of self-assembling copolymers should be taken into account when designing responsive copolymers.

18.
Adv Mater ; 28(24): 4944, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27311096

RESUMO

D. Porath, A. Kotlyar, and co-workers transform DNA to a conducting material by metalization through coating or chemical modifications, as described on page 4839. Specific and reversible metalization of poly(dG)-poly(dC) DNA by migration of atoms from silver nanoparticles to the DNA is demonstrated. As the transformation occurs gradually, novel, truly hybrid molecular structures are obtained, paving the way to their usage as nanowires in programmable molecular electronic devices and circuits.


Assuntos
DNA/química , Prata/química , Nanopartículas Metálicas/química , Nanofios/química
19.
Adv Mater ; 28(24): 4839-44, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27116695

RESUMO

Migration of silver atoms from silver nano-particles selectively to a double-stranded poly(dG)-poly(dC) polymer leads to metallization of the DNA. As a result the DNA molecules become shorter and thicker (higher), as evident from the atomic force microscopy imaging analysis. The metalized molecules can be detected by transmission and scanning electron microscopy in contrast to the initial non-metalized ones.


Assuntos
DNA/síntese química , DNA/ultraestrutura , Prata/química , DNA/química , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Polímeros
20.
ACS Chem Neurosci ; 6(11): 1860-9, 2015 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-26317327

RESUMO

Although the precise molecular factors linking amyloid ß-protein (Aß) to Alzheimer's disease (AD) have not been deciphered, interaction of Aß with cellular membranes has an important role in the disease. However, most therapeutic strategies targeting Aß have focused on interfering with Aß self-assembly rather than with its membrane interactions. Here, we studied the impact of three toxicity inhibitors on membrane interactions of Aß42, the longer form of Aß, which is associated most strongly with AD. The inhibitors included the four-residue C-terminal fragment Aß(39-42), the polyphenol (-)-epigallocatechin-3-gallate (EGCG), and the lysine-specific molecular tweezer, CLR01, all of which previously were shown to disrupt different steps in Aß42 self-assembly. Biophysical experiments revealed that incubation of Aß42 with each of the three modulators affected membrane interactions in a distinct manner. Interestingly, EGCG and CLR01 were found to have significant interaction with membranes themselves. However, membrane bilayer disruption was reduced when the compounds were preincubated with Aß42, suggesting that binding of the assembly modulators to the peptide attenuated their membrane interactions. Importantly, our study reveals that even though the three tested compounds affect Aß42 assembly differently, membrane interactions were significantly inhibited upon incubation of each compound with Aß42, suggesting that preventing the interaction of Aß42 with the membrane contributes substantially to inhibition of its toxicity by each compound. The data suggest that interference with membrane interactions is an important factor for Aß42 toxicity inhibitors and should be taken into account in potential therapeutic strategies, in addition to disruption or remodeling of amyloid assembly.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Catequina/análogos & derivados , Bicamadas Lipídicas/química , Fármacos Neuroprotetores/farmacologia , Organofosfatos/farmacologia , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Peptídeos beta-Amiloides/química , Hidrocarbonetos Aromáticos com Pontes/química , Catequina/química , Catequina/farmacologia , Microscopia Crioeletrônica , Dimiristoilfosfatidilcolina/química , Transferência Ressonante de Energia de Fluorescência , Cinética , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Fármacos Neuroprotetores/química , Organofosfatos/química , Fragmentos de Peptídeos/química , Fosfatidilgliceróis/química , Multimerização Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína , Lipossomas Unilamelares/química
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