Dual Responsive, Stabilized Nanoparticles for Efficient In Vivo Plasmid Delivery

Wei, Hua; Volpatti, Lisa R.; Sellers, Drew L.; Maris, Don O.; Andrews, Ian W.; Hemphill, Ashton S.; Chan, Leslie W.; Chu, David S.H.; Horner, Philip J.; Pun, Suzie H.

doi:10.1002/anie.201301896

Cited by 115 publications

(89 citation statements)

References 47 publications

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“…siRNA-PA completely loaded into the NPs at a 4:1 N:P ratio, while unmodified siRNA necessitated a 6:1 ratio for the polymer utilized in these studies (Figure 2). These data suggest that hydrophobization of siRNA is an efficient means to improve siRNA cargo loading and stability of NPs 18 . Other reports that nanoparticle carriers loaded with lipid-modified siRNA form particles at lower N:P ratios and with increased stability also support this conclusion 32, 34, 35 .…”

Section: Discussionmentioning

confidence: 85%

“…Hydrophobization of nucleic acid delivery systems has been demonstrated to enhance carrier stability and transfection efficiency in a broadly applicable manner 7, 12, 17, 18 . The conjugation of hydrophobic moieties to siRNA can increase siRNA nuclease resistance and enhance cellular internalization without detrimentally impacting gene silencing activity 19, 20 .…”

Section: Introductionmentioning

confidence: 99%

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Conjugation of palmitic acid improves potency and longevity of siRNA delivered via endosomolytic polymer nanoparticles

Sarett

Kilchrist

Miteva

et al. 2015

J Biomedical Materials Res

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Clinical translation of siRNA therapeutics has been limited by the inability to effectively overcome the rigorous delivery barriers associated with intracellular-acting biologics. Here, in order to address both potency and longevity of siRNA gene silencing, pH-responsive micellar nanoparticle (NP) carriers loaded with siRNA conjugated to palmitic acid (siRNA-PA) were investigated as a combined approach to improve siRNA endosomal escape and stability. Conjugation to hydrophobic PA improved NP loading efficiency relative to unmodified siRNA, enabling complete packaging of siRNA-PA at a lower polymer:siRNA ratio. PA conjugation also increased intracellular uptake of the nucleic acid cargo by 35-fold and produced a 3.1-fold increase in intracellular half-life. The higher uptake and improved retention of siRNA-PA NPs correlated to a 2- and 11-fold decrease in gene silencing IC50 in comparison to siRNA NPs in fibroblasts and mesenchymal stem cells, respectively, for both the model gene luciferase and the therapeutically relevant gene PHD2. PA conjugation also significantly increased longevity of silencing activity following a single treatment, as observed in fibroblasts. Thus, conjugation of PA to siRNA paired with endosomolytic NPs is a promising approach to enhance the functional efficacy of siRNA in tissue regenerative and other applications.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Conjugation of palmitic acid improves potency and longevity of siRNA delivered via endosomolytic polymer nanoparticles

Sarett

Kilchrist

Miteva

et al. 2015

J Biomedical Materials Res

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“…The reducible 2-hydroxyethyl-2′-(bromoisobutyryl)ethyl disulfide double-head initiator (HO-SS-iBuBr) and PCL-SS-p[(GMA-TEPA)- s -OEGMA] were synthesized as previously reported [11]. Briefly, ring-opening polymerization (ROP) of caprolactone was performed using HO-SS-iBuBr as the initiator and Sn(Oct) 2 as the catalyst.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, our group designed and synthesized a polymeric carrier that demonstrated successful gene transfer to the subventricular zone [11]. This copolymer, PCL-SS-p[(GMA-TEPA)- s -OEGMA], consists of a block of poly(ε-caprolactone) (PCL) connected by a reducible disulfide to a statistical copolymer of tetraethylenepentamine (TEPA)-decorated poly(glycidyl methacrylate) (GMA) and oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA).…”

Section: Introductionmentioning

confidence: 99%

“…After polyplex internalization, the TEPA groups contribute to endosomal escape by the proton sponge effect and the internal disulfide bond can be reduced by cytosolic glutathione facilitating polyplex destabilization and nucleic acid release. These PCL-SS-p[(GMA-TEPA)- s -OEGMA] polyplexes were shown to have diameters less than 200 nm and delivered nucleic acids to mouse brains in vivo after intraventricular injection [11]. However, gene transfer was limited to a few cell layers adjacent to the ventricular surface [12].…”

Section: Introductionmentioning

confidence: 99%

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Microbubbles and ultrasound increase intraventricular polyplex gene transfer to the brain

Tan

Pham

Zong

et al. 2016

Journal of Controlled Release

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Neurons in the brain can be damaged or lost from neurodegenerative disease, stroke, or traumatic injury. Although neurogenesis occurs in mammalian adult brains, the levels of natural neurogenesis are insufficient to restore function in these cases. Gene therapy has been pursued as a promising strategy to induce differentiation of neural progenitor cells into functional neurons. Non-viral vectors are a preferred method of gene transfer due to potential safety and manufacturing benefits but suffer from lower delivery efficiencies compared to viral vectors. Since the neural stem and progenitor cells reside in the subventricular zone of the brain, intraventricular injection has been used as an administration route for gene transfer to these cells. However, the choroid plexus epithelium remains an obstacle to delivery. Recently, transient disruption of the blood-brain barrier by microbubble-enhanced ultrasound has been used to successfully improve drug delivery to the brain after intravenous injection. In this work, we demonstrate that microbubble-enhanced ultrasound can similarly improve gene transfer to the subventricular zone after intraventricular injection. Microbubbles of different surface charges (neutral, slightly cationic, and cationic) were prepared, characterized by acoustic flow cytometry, and evaluated for their ability to increase the permeability of immortalized choroid plexus epithelium monolayers in vitro. Based on these results, slightly cationic microbubbles were evaluated for microbubble and ultrasound-mediated enhancement of non-viral gene transfer in vivo. When coupled with our previously reported gene delivery vehicles, the slightly cationic microbubbles significantly increased ultrasound-mediated transfection of the murine brain when compared to commercially available Definity® microbubbles. Temporary disruption of the choroid plexus by microbubble-enhanced ultrasound is therefore a viable way of enhancing gene delivery to the brain and merits further research.

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Control of DNA Packaging by Block Catiomers for Systemic Gene Delivery System

Osada

2019

Molecular Technology

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Dual Responsive, Stabilized Nanoparticles for Efficient In Vivo Plasmid Delivery

Abstract: A small case of love and hate: A block‐statistical copolymer combining reversible hydrophobization and statistical hydrophilization allows the preparation of pH value‐ and reduction‐responsive nanoparticles (polyplexes) for efficient in vivo plasmid delivery.

Cited by 115 publications

References 47 publications

Conjugation of palmitic acid improves potency and longevity of siRNA delivered via endosomolytic polymer nanoparticles

Conjugation of palmitic acid improves potency and longevity of siRNA delivered via endosomolytic polymer nanoparticles

Microbubbles and ultrasound increase intraventricular polyplex gene transfer to the brain

Control of DNA Packaging by Block Catiomers for Systemic Gene Delivery System

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