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1.
Artigo em Inglês | MEDLINE | ID: mdl-33605142

RESUMO

The modulation of the terahertz (THz) wave is fundamental for its applications in next-generation communications, biological imaging, sensing, and so forth. Searching for higher efficient modulation is still in progress, although plenty of materials have been explored for tuning THz wave. In this work, optical-transparent self-assembled MXene films are used to modulate the THz reflection at the SiO2/MXene/air interface based on the impedance matching mechanism. By adjusting the number of stacked MXene layers/concentrations of MXene dispersions, the sheet conductivity of the MXene films will be changed so that the impedance at the SiO2/MXene/air interface can be tuned and lead to a giant modulation of THz reflection. Particularly, we demonstrate that the MXene films have highly efficient THz modulation from antireflection to reflection-enhancing with a relative reflection of 27% and 406%, respectively. This work provides a new pathway for developing the MXene films with the combination of optical-transparency and high smart THz reflection characteristics, and the films can be applied for THz antireflection or reflection-enhancing.

2.
J Am Chem Soc ; 143(3): 1296-1300, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33433203

RESUMO

Oligonucleotide-based materials such as spherical nucleic acid (SNA) have been reported to exhibit improved penetration through the epidermis and the dermis of the skin upon topical application. Herein, we report a self-assembled, skin-depigmenting SNA structure, which is based upon a bifunctional oligonucleotide amphiphile containing an antisense oligonucleotide and a tyrosinase inhibitor prodrug. The two components work synergistically to increase oligonucleotide cellular uptake, enhance drug solubility, and promote skin penetration. The particles were shown to reduce melanin content in B16F10 melanoma cells and exhibited a potent antimelanogenic effect in an ultraviolet B-induced hyperpigmentation mouse model.

3.
Sci Adv ; 6(28): eabb6594, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32923598

RESUMO

Inefficient injection of microparticles through conventional hypodermic needles can impose serious challenges on clinical translation of biopharmaceutical drugs and microparticle-based drug formulations. This study aims to determine the important factors affecting microparticle injectability and establish a predictive framework using computational fluid dynamics, design of experiments, and machine learning. A numerical multiphysics model was developed to examine microparticle flow and needle blockage in a syringe-needle system. Using experimental data, a simple empirical mathematical model was introduced. Results from injection experiments were subsequently incorporated into an artificial neural network to establish a predictive framework for injectability. Last, simulations and experimental results contributed to the design of a syringe that maximizes injectability in vitro and in vivo. The custom injection system enabled a sixfold increase in injectability of large microparticles compared to a commercial syringe. This study highlights the importance of the proposed framework for optimal injection of microparticle-based drugs by parenteral routes.

4.
Sci Transl Med ; 12(556)2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32801144

RESUMO

Activation of the stimulator of interferon gene (STING) pathway within the tumor microenvironment has been shown to generate a strong antitumor response. Although local administration of STING agonists has promise for cancer immunotherapy, the dosing regimen needed to achieve efficacy requires frequent intratumoral injections over months. Frequent dosing for cancer treatment is associated with poor patient adherence, with as high as 48% of patients failing to comply. Multiple intratumoral injections also disrupt the tumor microenvironment and vascular networks and therefore increase the risk of metastasis. Here, we developed microfabricated polylactic-co-glycolic acid (PLGA) particles that remain at the site of injection and release encapsulated STING agonist as a programmable sequence of pulses at predetermined time points that mimic multiple injections over days to weeks. A single intratumoral injection of STING agonist-loaded microparticles triggered potent local and systemic antitumor immune responses, inhibited tumor growth, and prolonged survival as effectively as multiple soluble doses, but with reduced metastasis in several mouse tumor models. STING agonist-loaded microparticles improved the response to immune checkpoint blockade therapy and substantially decreased the tumor recurrence rate from 100 to 25% in mouse models of melanoma when administered during surgical resection. In addition, we demonstrated the therapeutic efficacy of STING microparticles on an orthotopic pancreatic cancer model in mice that does not allow multiple intratumoral injections. These findings could directly benefit current STING agonist therapy by decreasing the number of injections, reducing risk of metastasis, and expanding its applicability to hard-to-reach cancers.

5.
J Am Chem Soc ; 142(23): 10297-10301, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32453555

RESUMO

Herein, we report the DNA-mediated self-assembly of bivalent bottlebrush polymers, a process akin to the step-growth polymerization of small molecule monomers. In these "condensation reactions", the polymer serves as a steric guide to limit DNA hybridization in a fixed direction, while the DNA serves as a functional group equivalent, connecting complementary brushes to form well-defined, one-dimensional nanostructures. The polymerization was studied using spectroscopy, microscopy, and scattering techniques and was modeled numerically. The model made predictions of the degree of polymerization and size distribution of the assembled products, and suggested the potential for branching at hybridization junctions, all of which were confirmed experimentally. This study serves as a theoretical basis for the polymer-assembly approach which has the potential to open up new possibilities for suprapolymers with controlled architecture, macromonomer sequence, and end-group functionalities.

6.
Sci Transl Med ; 11(518)2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31723037

RESUMO

Micronutrient deficiencies affect up to 2 billion people and are the leading cause of cognitive and physical disorders in the developing world. Food fortification is effective in treating micronutrient deficiencies; however, its global implementation has been limited by technical challenges in maintaining micronutrient stability during cooking and storage. We hypothesized that polymer-based encapsulation could address this and facilitate micronutrient absorption. We identified poly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methylmethacrylate) (1:2:1) (BMC) as a material with proven safety, offering stability in boiling water, rapid dissolution in gastric acid, and the ability to encapsulate distinct micronutrients. We encapsulated 11 micronutrients (iron; iodine; zinc; and vitamins A, B2, niacin, biotin, folic acid, B12, C, and D) and co-encapsulated up to 4 micronutrients. Encapsulation improved micronutrient stability against heat, light, moisture, and oxidation. Rodent studies confirmed rapid micronutrient release in the stomach and intestinal absorption. Bioavailability of iron from microparticles, compared to free iron, was lower in an initial human study. An organotypic human intestinal model revealed that increased iron loading and decreased polymer content would improve absorption. Using process development approaches capable of kilogram-scale synthesis, we increased iron loading more than 30-fold. Scaled batches tested in a follow-up human study exhibited up to 89% relative iron bioavailability compared to free iron. Collectively, these studies describe a broad approach for clinical translation of a heat-stable ingestible micronutrient delivery platform with the potential to improve micronutrient deficiency in the developing world. These approaches could potentially be applied toward clinical translation of other materials, such as natural polymers, for encapsulation and oral delivery of micronutrients.


Assuntos
Temperatura Alta , Micronutrientes/administração & dosagem , Microesferas , Administração Oral , Animais , Disponibilidade Biológica , Transporte Biológico , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Feminino , Humanos , Ácido Hialurônico/química , Absorção Intestinal , Intestinos/fisiologia , Ferro/metabolismo , Metacrilatos/química , Camundongos , Oxirredução , Raios Ultravioleta , Vitamina A/metabolismo , Água
7.
Sci Adv ; 5(2): eaav9322, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30801019

RESUMO

Nonhepatic delivery of small interfering RNAs (siRNAs) remains a challenge for development of RNA interference-based therapeutics. We report a noncationic vector wherein linear poly(ethylene glycol) (PEG), a polymer generally considered as inert and safe biologically but ineffective as a vector, is transformed into a bottlebrush architecture. This topology provides covalently embedded siRNA with augmented nuclease stability and cellular uptake. Consisting almost entirely of PEG and siRNA, the conjugates exhibit a ~25-fold increase in blood elimination half-life and a ~19-fold increase in the area under the curve compared with unmodified siRNA. The improved pharmacokinetics results in greater tumor uptake and diminished liver capture. Despite the structural simplicity these conjugates efficiently knock down target genes in vivo without apparent toxic and immunogenic reactions. Given the benign biological nature of PEG and its widespread precedence in biopharmaceuticals, we anticipate the brush polymer-based technology to have a significant impact on siRNA therapeutics.


Assuntos
Portadores de Fármacos , Técnicas de Silenciamento de Genes , Polietilenoglicóis , Interferência de RNA , RNA Interferente Pequeno , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Humanos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacologia
8.
Nano Lett ; 18(11): 7378-7382, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30376347

RESUMO

Herein, we design and synthesize site-specifically PEGylated oligonucleotide hairpins and demonstrate that their ability to undergo hybridization chain reaction is nearly unaffected by the PEGylation. The resulting DNA-backboned bottlebrush polymers with PEG side chains exhibit increased resistance against nucleolytic degradation, enhanced thermal stabilities, and elevated blood retention times in vivo, which collectively pave the way for more therapeutically focused DNA nanostructure designs.


Assuntos
Oligonucleotídeos , Polietilenoglicóis , Oligonucleotídeos/química , Oligonucleotídeos/farmacocinética , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética
9.
Adv Mater ; 30(51): e1803925, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30328144

RESUMO

The emergence of antimicrobial resistance poses a major challenge to healthcare. Probiotics offer a potential alternative treatment method but are often incompatible with antibiotics themselves, diminishing their overall therapeutic utility. This work uses biofilm-inspired encapsulation of probiotics to confer temporary antibiotic protection and to enable the coadministration of probiotics and antibiotics. Probiotics are encapsulated within alginate, a crucial component of pseudomonas biofilms, based on a simple two-step alginate cross-linking procedure. Following exposure to the antibiotic tobramycin, the growth and metabolic activity of encapsulated probiotics are unaffected by tobramycin, and they show a four-log survival advantage over free probiotics. This results from tobramycin sequestration on the periphery of alginate beads which prevents its diffusion into the core but yet allows probiotic byproducts to diffuse outward. It is demonstrated that this approach using tobramycin combined with encapsulated probiotic has the ability to completely eradicate methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa in coculture, the two most widely implicated bacteria in chronic wounds.


Assuntos
Biofilmes , Materiais Biomiméticos/química , Portadores de Fármacos/química , Infecções/tratamento farmacológico , Probióticos/química , Probióticos/uso terapêutico , Ácido Algínico/química , Cápsulas
10.
Proc Natl Acad Sci U S A ; 115(17): 4340-4344, 2018 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-29632214

RESUMO

Herein, we report a class of molecular spherical nucleic acid (SNA) nanostructures. These nano-sized single molecules are synthesized from T8 polyoctahedral silsesquioxane and buckminsterfullerene C60 scaffolds, modified with 8 and 12 pendant DNA strands, respectively. These conjugates have different DNA surface densities and thus exhibit different levels of nuclease resistance, cellular uptake, and gene regulation capabilities; the properties displayed by the C60 SNA conjugate are closer to those of conventional and prototypical gold nanoparticle SNAs. Importantly, the C60 SNA can serve as a single entity (no transfection agent required) antisense agent to efficiently regulate gene expression. The realization of molecularly pure forms of SNAs will open the door for studying the interactions of such structures with ligands and living cells with a much greater degree of control than the conventional polydisperse forms of SNAs.


Assuntos
Modelos Moleculares , Conformação de Ácido Nucleico , Poli T/química
11.
Nano Res ; 11(10): 5519-5534, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30740197

RESUMO

PEGylation, the attachment of poly(ethylene glycol) (PEG), has been adopted to improve the pharmacokinetic properties of oligonucleotide therapeutics for nearly 30 years. Prior efforts mainly focused on the investigation of linear or slightly branched PEG having different molecular weights, terminal functional groups, and possible oligonucleotide sites for functionalization. Recent studies on highly branched PEG (including brush, star, and micellar structures) indicate superior properties in several areas including cellular uptake, gene regulation efficacy, reduction of side effects, and biodistribution. This review focuses on comparing the effects of PEG architecture on the physiochemical and biological properties of the PEGylated oligonucleotide.

12.
ACS Nano ; 11(12): 11931-11945, 2017 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-29120602

RESUMO

Nanopore-based sensors for nucleic acid sequencing and single-molecule detection typically employ pore-forming membrane proteins with hydrophobic external surfaces, suitable for insertion into a lipid bilayer. In contrast, hydrophilic pore-containing molecules, such as DNA origami, have been shown to require chemical modification to favor insertion into a lipid environment. In this work, we describe a strategy for inserting polar proteins with an inner pore into lipid membranes, focusing here on a circular 12-subunit assembly of the thermophage G20c portal protein. X-ray crystallography, electron microscopy, molecular dynamics, and thermal/chaotrope denaturation experiments all find the G20c portal protein to have a highly stable structure, favorable for nanopore sensing applications. Porphyrin conjugation to a cysteine mutant in the protein facilitates the protein's insertion into lipid bilayers, allowing us to probe ion transport through the pore. Finally, we probed the portal interior size and shape using a series of cyclodextrins of varying sizes, revealing asymmetric transport that possibly originates from the portal's DNA-ratchet function.


Assuntos
Proteínas do Capsídeo/química , Bicamadas Lipídicas/química , Simulação de Acoplamento Molecular , Nanotecnologia , Porfirinas/química , Temperatura , Cristalografia por Raios X , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Estrutura Molecular , Nanoporos , Tamanho da Partícula , Propriedades de Superfície , Thermus thermophilus/química
13.
Chem Res Toxicol ; 30(11): 2002-2012, 2017 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-28823149

RESUMO

DNA damage is a constant threat and can be bypassed in a process called translesion synthesis, which is typically carried out by Y-family DNA polymerases. Y-family DNA polymerases are conserved in all domains of life and tend to have specificity for certain types of DNA damage. Escherichia coli DinB and its human ortholog pol κ can bypass specific minor groove deoxyguanine adducts efficiently and are inhibited by major groove adducts, as Y-family DNA polymerases make contacts with the minor groove side of the DNA substrate and lack contacts with the major groove at the nascent base pair. DinB is inhibited by major groove adducts more than pol κ, and they each have active site loops of different lengths, with four additional amino acids in the DinB loop. We previously showed that the R35A active site loop mutation in DinB allows for bypass of the major groove adduct N6-furfuryl-dA. These observations led us to investigate the different active site loops by creating loop swap chimeras of DinB with a pol κ loop and vice versa by changing the loop residues in a stepwise fashion. We then determined their activity with undamaged DNA or DNA containing N2-furfuryl-dG or N6-furfuryl-dA. The DinB proteins with the pol kappa loop have low activity on all templates but have decreased misincorporation compared to either wild-type protein. The kappa proteins with the DinB loop retain activity on all templates and have decreased misincorporation compared to either wild-type protein. We assessed the thermal stability of the proteins and observed an increase in stability in the presence of all DNA templates and additional increases generally only in the presence of the undamaged and N2-furfuryl-dG adduct and dCTP, which correlates with activity. Overall we find that pol κ is more tolerant to changes in the active site loop than DinB.


Assuntos
DNA Polimerase Dirigida por DNA/química , Proteínas de Escherichia coli/química , Escherichia coli/química , Sequência de Aminoácidos , Domínio Catalítico , DNA/química , DNA/metabolismo , Adutos de DNA/química , Adutos de DNA/metabolismo , Dano ao DNA , DNA Polimerase Dirigida por DNA/metabolismo , Estabilidade Enzimática , Escherichia coli/enzimologia , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Humanos , Modelos Moleculares , Homologia Estrutural de Proteína
14.
Small ; 13(43)2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28696590

RESUMO

Unwanted stimulation of the innate immune system by foreign nucleic acids has been one of the major barriers preventing bioactive sequences from reaching market. Foreign nucleic acids can be recognized by multiple pattern recognition receptors (PRRs), which trigger a signaling cascade to activate host defense systems, leading to a range of side effects. This study demonstrates that polyethylene glycol (PEG)-modified DNA strands can greatly reduce the activation of the innate immune system, and the extent of reduction is dependent upon polymer architecture. Highly branched brushes with long PEG side chains achieve the best suppression by blocking PRR interactions via a local steric effect. Interestingly, the brush polymer creates little barrier toward DNA-DNA interaction. Quantification of inflammatory cytokines in both mRNA and protein levels as well as the extent of cellular uptake shows a direct correlation between steric congestion and reduction of cellular immune response. These results suggest that the brush architecture offers unique advantages for PEGylating oligonucleotides in the context of minimizing unwanted immune system activation.


Assuntos
Imunidade Celular , Oligonucleotídeos/farmacologia , Polímeros/farmacologia , Animais , Endonucleases/metabolismo , Imunidade Celular/efeitos dos fármacos , Camundongos , Oligonucleotídeos/síntese química , Oligonucleotídeos/química , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Células RAW 264.7
15.
J Am Chem Soc ; 139(31): 10605-10608, 2017 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-28737410

RESUMO

PEGylation of an oligonucleotide using a brush polymer can improve its biopharmaceutical characteristics, including enzymatic stability and biodistribution. Herein, we quantitatively explore the nuclease accessibility of the nucleic acid as a function of "depth" toward the backbone of the brush polymer. It is found that protein accessibility decreases as the nucleotide is located closer to the backbone. Thus, by moving the conjugation point from the terminus of the nucleic acid strand to an internal position, much smaller brushes can be used to achieve the same level of steric shielding. This finding also makes it possible to assess antisense gene regulation efficiency of these brush-DNA conjugates as a function of their nuclease stability.


Assuntos
DNA/química , DNA/farmacologia , Inativação Gênica/efeitos dos fármacos , Nucleotídeos/química , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Bioensaio , Desoxirribonucleases/química , Estabilidade Enzimática , Nucleotídeos/farmacologia , Propriedades de Superfície
17.
Angew Chem Int Ed Engl ; 56(5): 1239-1243, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-28032948

RESUMO

PEGylation is an attractive approach to modifying oligonucleotides intended for therapeutic purposes. PEG conjugation reduces protein interactions with the oligonucleotide, and helps to overcome their intrinsic biopharmaceutical shortcomings, such as poor enzymatic stability, rapid body clearance, and unwanted immunostimulation. However, the effect of PEG architecture and the manner in which the PEG component interferes with the hybridization of the oligonucleotide remain poorly understood. In this study, we systematically compare the hybridization thermodynamics and protein accessibility of several DNA conjugates involving linear, Y-shaped, and brush-type PEG. It is found that PEGylated DNA experiences two opposing effects: local excluded volume effect and chemical interactions, the strengths of which are architecture-dependent. Notably, the brush architecture is able to offer significantly greater protein shielding capacity than its linear or Y-shaped counterparts, while maintaining nearly identical free energy for DNA hybridization compared with free DNA.


Assuntos
Oligonucleotídeos/química , Polietilenoglicóis/química , DNA/química , DNA/metabolismo , Cinética , Hibridização de Ácido Nucleico , Oligonucleotídeos/metabolismo , Termodinâmica , Temperatura de Transição
18.
J Am Chem Soc ; 138(34): 10834-7, 2016 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-27522867

RESUMO

Nucleic acids are generally regarded as the payload in gene therapy, often requiring a carrier for intracellular delivery. With the recent discovery that spherical nucleic acids enter cells rapidly, we demonstrate that nucleic acids also have the potential to act as a delivery vehicle. Herein, we report an amphiphilic DNA-paclitaxel conjugate, which forms stable micellar nanoparticles in solution. The nucleic acid component acts as both a therapeutic payload for intracellular gene regulation and the delivery vehicle for the drug component. A bioreductively activated, self-immolative disulfide linker is used to tether the drug, allowing free drug to be released upon cell uptake. We found that the DNA-paclitaxel nanostructures enter cells ∼100 times faster than free DNA, exhibit increased stability against nuclease, and show nearly identical cytotoxicity as free drug. These nanostructures allow one to access a gene target and a drug target using only the payloads themselves, bypassing the need for a cocarrier system.


Assuntos
DNA/química , Portadores de Fármacos/química , Oligonucleotídeos/química , Dissulfetos/química , Micelas , Modelos Moleculares , Nanopartículas/química , Conformação de Ácido Nucleico , Paclitaxel/química
19.
J Am Chem Soc ; 138(29): 9097-100, 2016 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-27420413

RESUMO

Negatively charged nucleic acids are often complexed with polycationic transfection agents before delivery. Herein, we demonstrate that a noncationic, biocompatible polymer, polyethylene glycol, can be used as a transfection vector by forming a brush polymer-DNA conjugate. The brush architecture provides embedded DNA strands with enhanced nuclease stability and improved cell uptake. Because of the biologically benign nature of the polymer component, no cytotoxicity was observed. This approach has the potential to address several long-lasting challenges in oligonucleotide therapeutics.


Assuntos
DNA Antissenso/química , DNA Antissenso/genética , Polietilenoglicóis/química , Transfecção , Sequência de Bases , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Conformação de Ácido Nucleico
20.
J Am Chem Soc ; 137(39): 12466-9, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26378378

RESUMO

Difficult biopharmaceutical characteristics of oligonucleotides, such as poor enzymatic stability, rapid clearance by reticuloendothelial organs, immunostimulation, and coagulopathies, limit their application as therapeutics. Many of these side effects are initiated via sequence-specific or nonsequence-specific interactions with proteins. Herein, we report a novel form of brush-polymer/DNA conjugate that provides the DNA with nanoscale steric selectivity: Hybridization kinetics with complementary DNA remains nearly unaffected, but interactions with proteins are significantly retarded. The relative lengths of the brush side chain and the DNA strand are found to play a critical role in the degree of selectivity. Being able to evade protein adhesion also improves in vivo biodistribution, thus making these molecular nanostructures promising materials for oligonucleotide-based therapies.


Assuntos
Nanoestruturas/química , Oligonucleotídeos/química , Polímeros/química , Animais , Coagulação Sanguínea , Camundongos , Estrutura Molecular
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