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1.
ACS Nano ; 18(1): 592-599, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38147573

RESUMO

Antisense oligonucleotides hold therapeutic promise for various lung disorders, but their efficacy is limited by suboptimal delivery. To address this challenge, we explored the use of inhaled bottlebrush polymer-DNA conjugates, named pacDNA, as a delivery strategy. Inhaled pacDNA exhibits superior mucus penetration, achieving a uniform and sustained lung distribution in mice. Targeting the 5' splice site of an aberrant enhanced green fluorescence protein (EGFP) pre-mRNA in EGFP-654 mice, inhaled pacDNA more efficiently corrects splicing than a B-peptide conjugate and restores EGFP expression in the lung. Additionally, in an orthotopic NCI-H358 non-small-cell lung tumor mouse model, inhaled pacDNA targeting wild-type KRAS mRNA effectively suppresses KRAS expression and inhibits lung tumor growth, requiring a substantially lower dosage compared to intravenously injected pacDNA. These findings demonstrate the potential of bottlebrush polymer-DNA conjugates as a promising agent for enhanced oligonucleotide therapy in the lung and advancing the treatment landscape for lung disorders.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Camundongos , Animais , Oligonucleotídeos , Polímeros , Proteínas Proto-Oncogênicas p21(ras) , Pulmão , DNA
2.
RSC Chem Biol ; 4(2): 138-145, 2023 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-36794022

RESUMO

We have developed a non-cationic transfection vector in the form of bottlebrush polymer-antisense oligonucleotide (ASO) conjugates. Termed pacDNA (polymer-assisted compaction of DNA), these agents show improved biopharmaceutical characteristics and antisense potency in vivo while suppressing non-antisense side effects. Nonetheless, there still is a lack of the mechanistic understanding of the cellular uptake, subcellular trafficking, and gene knockdown with pacDNA. Here, we show that the pacDNA enters human non-small cell lung cancer cells (NCI-H358) predominantly by scavenger receptor-mediated endocytosis and macropinocytosis and trafficks via the endolysosomal pathway within the cell. The pacDNA significantly reduces a target gene expression (KRAS) in the protein level but not in the mRNA level, despite that the transfection of certain free ASOs causes ribonuclease H1 (RNase H)-dependent degradation of KRAS mRNA. In addition, the antisense activity of pacDNA is independent of ASO chemical modification, suggesting that the pacDNA always functions as a steric blocker.

3.
Macromolecules ; 55(6): 2235-2242, 2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-36187461

RESUMO

Herein, we demonstrate that macromonomers consisting of organics-soluble, chemically protected oligonucleotides (protDNA) and poly(ethylene glycol) (PEG) chains can be converted into bottlebrush polymers of distinct architectures via ring-opening metathesis polymerization (ROMP). Using a custom norbornene-containing phosphoramidite, two types of macromonomers were obtained: a linear norbornene-protDNA-PEG structure and a Y-shaped structure where the polymerizable norbornene group is situated at the junction where protDNA and PEG meet. With this strategy, the PEG chains can be placed either near the backbone of the bottlebrush or on its periphery, and in principle anywhere between these two extremes by adjusting the norbornene location, which makes this strategy attractive for constructing architecturally sophisticated oligonucleotide-containing copolymers.

4.
ACS Appl Mater Interfaces ; 13(36): 42533-42542, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34472829

RESUMO

Despite potency against a variety of cancers in preclinical systems, melittin (MEL), a major peptide in bee venom, exhibits non-specific toxicity, severe hemolytic activity, and poor pharmacological properties. Therefore, its advancement in the clinical translation system has been limited to early-stage trials. Herein, we report a biohybrid involving a bottlebrush-architectured poly(ethylene glycol) (PEG) and MEL. Termed pacMEL, the conjugate consists of a high-density PEG arrangement, which provides MEL with steric inhibition against protein access, while the high molecular weight of pacMEL substantially enhances plasma pharmacokinetics with a ∼10-fold increase in the area under the curve (AUC∞) compared to free MEL. pacMEL also significantly reduces hepatic damage and unwanted innate immune response and all but eliminated hemolytic activities of MEL. Importantly, pacMEL passively accumulates at subcutaneously inoculated tumor sites and exhibits stronger tumor-suppressive activity than molecular MEL. Collectively, pacMEL makes MEL a safer and more appealing drug candidate.


Assuntos
Antineoplásicos/uso terapêutico , Meliteno/análogos & derivados , Meliteno/uso terapêutico , Neoplasias/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Feminino , Humanos , Meliteno/farmacocinética , Meliteno/toxicidade , Camundongos Endogâmicos C57BL , Polietilenoglicóis/síntese química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Polym Chem ; 12(15): 2193-2204, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-34394751

RESUMO

A deep integration of nucleic acids with other classes of materials have become the basis of many useful technologies. Among these biohybrids, nucleic acid-containing copolymers has seen rapid development in both chemistry and application. This review focuses on the various synthetic approaches to access nucleic acid-polymer biohybrids spanning post-polymerization conjugation, nucleic acids in polymerization, solid-phase synthesis, and nucleoside/nucleobase-functionalized polymers. We highlight the challenges associated with working with nucleic acids with each approach and the ingenuity of the solutions, with the hope of lowering the entry barrier and inpsiring further investigations in this exciting area.

6.
J Am Chem Soc ; 143(3): 1296-1300, 2021 01 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.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Hiperpigmentação/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Resorcinóis/uso terapêutico , Preparações Clareadoras de Pele/uso terapêutico , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Hiperpigmentação/patologia , Melaninas/metabolismo , Camundongos Endogâmicos C57BL , Monofenol Mono-Oxigenase/antagonistas & inibidores , Oligonucleotídeos Antissenso/genética , Pró-Fármacos/uso terapêutico , Receptor Tipo 1 de Melanocortina/genética , Receptor Tipo 1 de Melanocortina/metabolismo , Pele/patologia , Raios Ultravioleta
7.
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.


Assuntos
DNA/química , Oligonucleotídeos Antissenso/farmacocinética , Polietilenoglicóis/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/sangue , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oligonucleotídeos Antissenso/sangue , Oligonucleotídeos Antissenso/química , Distribuição Tecidual
8.
ACS Nano ; 12(8): 8323-8329, 2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30027730

RESUMO

Sodium-ion batteries offer an attractive option for grid-level energy storage due to the high natural abundance of sodium and low material cost of sodium compounds. Phosphorus (P) is a promising anode material for sodium-ion batteries, with a theoretical capacity of 2596 mAh/g. The red phosphorus (RP) form has worse electronic conductivity and lower initial Coulombic efficiency than black phosphorus (BP), but high material cost and limited production capacity have slowed the development of BP anodes. To address these challenges, we have developed a simple and scalable method to synthesize layered BP/graphene composite (BP/rGO) by pressurization at room temperature. A carbon-black-free and binder-free BP/rGO anode prepared with this method achieved specific charge capacities of 1460.1, 1401.2, 1377.6, 1339.7, 1277.8, 1123.78, and 720.8 mAh/g in a rate capability test at charge and discharge current densities of 0.1, 0.5, 1, 5, 10, 20, and 40 A/g, respectively. In a cycling performance test, after 500 deep cycles, the capacity of BP/rGO anodes stabilized at 1250 and 640 mAh/g at 1 and 40 A/g, respectively, which marks a significant performance improvement for sodium-ion battery anodes.

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