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1.
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.

2.
ACS Appl Mater Interfaces ; 12(41): 45830-45837, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-32936615

RESUMO

Herein, we report a novel strategy to enhance the antisense activity and the pharmacokinetics of therapeutic oligonucleotides. Through the DNA hybridization chain reaction, DNA hairpins modified with poly(ethylene glycol) (PEG) form a bottlebrush architecture consisting of a double-stranded DNA backbone, PEG side chains, and antisense overhangs. The assembled structure exhibits high PEG density on the surface, which suppresses unwanted interactions between the DNA and proteins (e.g., enzymatic degradation) while allowing the antisense overhangs to hybridize with the mRNA target and thereby deplete target protein expression. We show that these PEGylated bottlebrushes targeting oncogenic KRAS can achieve much higher antisense efficacy compared with unassembled hairpins with or without PEGylation and can inhibit the proliferation of lung cancer cells bearing the G12C mutant KRAS gene. Meanwhile, these structures exhibit elevated blood retention times in vivo due to the biological stealth properties of PEG and the high molecular weight of the overall assembly. Collectively, this self-assembly approach bears the characteristics of a simple, safe, yet highly translatable strategy to improve the biopharmaceutical properties of therapeutic oligonucleotides.

3.
J Mater Chem B ; 8(31): 6697-6709, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32597455

RESUMO

Self-immolative polymers (SIPs) have been under development for over a decade, and efforts for their application followed shortly after their inception. One main area of application of SIPs is biomedicine, where they are used to construct devices and biosensors, develop new biotechnology abilities, or directly interface with the living system. Where traditional polymers are stable at room temperature, SIPs undergo rapid degradation when a labile capping group is removed, allowing SIPs to offer a highly unusual degradation profile compared with traditional polymers. This review summarizes the recent efforts to leverage the unique properties of SIPs for biomedical purposes, which are categorized into sensors, drug delivery, and biotechnology. By doing so, this review aims to stimulate future studies in this rapidly growing and promising area.

4.
J Control Release ; 323: 240-252, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32272123

RESUMO

Nucleic acids have not been widely considered as an optimal material for drug delivery. Indeed, unmodified nucleic acids are enzymatically unstable, too hydrophilic for cell uptake and payload encapsulation, and may cause unintended biological responses such as immune system activation and prolongation of the blood coagulation pathway. Recently, however, three major areas of development surrounding nucleic acids have made it worthwhile to reconsider their role for drug delivery. These areas include DNA/RNA nanotechnology, multivalent nucleic acid nanostructures, and nucleic acid aptamers, which, respectively, provide the ability to engineer nanostructures with unparalleled levels of structural control, completely reverse certain biological properties of linear/cyclic nucleic acids, and enable antibody-level targeting using an all-nucleic acid construct. These advances, together with nucleic acids' ability to respond to various stimuli (engineered or natural), have led to a rapidly increasing number of drug delivery systems with potential for spatiotemporally controlled drug release. In this review, we discuss recent progress in nucleic acid-based drug delivery strategies, their potential, unique use cases, and risks that must be overcome or avoided.

5.
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
6.
Chem ; 5(6): 1584-1596, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31903440

RESUMO

Herein, we develop a facile route to bring DNA to the organic phase, which greatly expands the types of structures accessible using DNA macromonomers. Phosphotriester- and exocyclic amine-protected DNA was synthesized and further modified with a norbornene moiety, which enables homopolymerization via ring-opening metathesis to produce brush-type DNA graft polymers in high yields. Subsequent deprotection cleanly reveals the natural phosphodiester DNA. The method not only achieves high molecular weight DNA graft polymers but when carried out at low monomer:catalyst ratios, yields oligomers that can be further fractionated to molecularly pure, monodisperse entities with one through ten DNA strands per molecule. In addition, we demonstrate substantial simplification in the preparation of traditionally difficult DNA-containing structures, such as DNA/poly(ethylene glycol) diblock graft copolymers and DNA amphiphiles. We envision that the marriage of oligonucleotides with the vast range of organic-phase polymerizations will result in many new classes of materials with yet unknown properties.

7.
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
8.
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
9.
Macromolecules ; 51(8): 2899-2905, 2018 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30713355

RESUMO

We have synthesized a series of stimuli-responsive brush polymers by grafting azide-terminated side chains onto a self-immolative, alkyne-bearing poly(benzyl ether) backbone, which is prepared by anionic polymerization of quinone methide-based monomers. Upon exposure to a decapping reagent (Pd(0) or F-), these brush polymers undergo an irreversible degradation cascade from head to tail to yield individual side chains. It is observed that several factors affect the depolymerization kinetics, including solvent polarity, type of counterion, the rate of the decapping chemistry, and interestingly, the rigidity of the side chains.

10.
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
11.
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
12.
Methods Mol Biol ; 1570: 209-221, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28238139

RESUMO

It is often desirable to simultaneously target different cellular pathways to improve the overall efficacy of a drug or to circumvent drug resistance in therapeutic treatments. Nucleic acid therapy has been considered attractive for such combination therapies due to its possible synergistic effects with traditional chemotherapy, especially for targets that do not yet have small molecule inhibitors. However, the co-delivery of nucleic acids and chemotherapeutics typically involves the use of inherently cytotoxic/immunogenic, polycationic carrier systems, for which the benefit is often overshadowed by adverse side effects. Herein, we detail the construction and characterization of a DNA-drug nanostructure that consists almost entirely of payload molecules. Upon triggering with light, the nanostructure collapses via an irreversible, self-immolative process and releases free oligonucleotides, drug molecules, and small molecule fragments. We demonstrate that the nanostructures can be used as a dual-delivery agent in vitro without a carrier system and that the released model drug (camptothecin, CPT) exhibits similar levels of cytotoxicity as unmodified drugs toward cancer cells.


Assuntos
Antineoplásicos Fitogênicos , Camptotecina , DNA , Luz , Nanoestruturas , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Camptotecina/administração & dosagem , Camptotecina/síntese química , Camptotecina/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Click , DNA/química , Liberação Controlada de Fármacos , Humanos , Cinética , Nanopartículas/química , Nanopartículas/ultraestrutura , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Raios Ultravioleta
14.
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
15.
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
16.
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
17.
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
18.
Chem Commun (Camb) ; 51(37): 7843-6, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25855414

RESUMO

A solid-phase synthesis for nucleic acid-polymer amphiphiles is developed. Using this strategy, several DNA-b-polymer amphiphiles are synthesized, and their self-assembly in aqueous solution is investigated. This general method can in principle be extended to nearly all polymers synthesized by atom transfer radical polymerization to produce a variety of nucleic acid-polymer conjugates.


Assuntos
Ácidos Nucleicos/química , Polímeros/química , Tensoativos/síntese química , Cinética , Estrutura Molecular , Ácidos Nucleicos/síntese química , Tamanho da Partícula , Polímeros/síntese química , Propriedades de Superfície , Tensoativos/química , Termodinâmica
19.
J Am Chem Soc ; 137(19): 6112-5, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25924099

RESUMO

The simultaneous intracellular delivery of multiple types of payloads, such as hydrophobic drugs and nucleic acids, typically requires complex carrier systems. Herein, we demonstrate a self-deliverable form of nucleic acid-drug nanostructure that is composed almost entirely of payload molecules. Upon light activation, the nanostructure sheds the nucleic acid shell, while the core, which consists of prodrug molecules, disintegrates via an irreversible self-immolative process, releasing free drug molecules and small molecule fragments. We demonstrate that the nanostructures exhibit enhanced stability against DNase I compared with free DNA, and that the model drug (camptothecin) released exhibits similar efficacy as free, unmodified drugs toward cancer cells.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , DNA/administração & dosagem , Preparações de Ação Retardada/química , Nanoestruturas/química , Pró-Fármacos/administração & dosagem , Humanos , Luz , Modelos Moleculares
20.
J Am Chem Soc ; 136(29): 10214-7, 2014 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-25000330

RESUMO

Triblock copolymer brushes were functionalized with nucleic acid sequences, which allowed the polymers to connect head-to-tail and form supramolecular nanostructures. Two approaches were designed and implemented, using either a palindromic DNA attached to both ends of the polymer or two different DNA sequences attached regiospecifically. Given appropriate conditions, the DNA-brush conjugates self-assembled to form either nanoworms with length up to several microns or cross-linked networks. This process is analogous to the step-growth polymerization of small molecule monomers.


Assuntos
DNA/química , Nanoestruturas/química , Polímeros/química , Polímeros/síntese química , Sequências Repetidas Invertidas , Maleimidas/química , Microscopia Eletrônica de Transmissão , Norbornanos/química , Hibridização de Ácido Nucleico , Polietilenoglicóis/química , Polimerização , Succinimidas/química , Propriedades de Superfície
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