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  1. Article ; Online: Tuning Composition of Polymer and Porous Silicon Composite Nanoparticles for Early Endosome Escape of Anti-microRNA Peptide Nucleic Acids.

    Kelly, Isom B / Fletcher, R Brock / McBride, James R / Weiss, Sharon M / Duvall, Craig L

    ACS applied materials & interfaces

    2020  Volume 12, Issue 35, Page(s) 39602–39611

    Abstract: Porous silicon nanoparticles (PSNPs) offer tunable pore structure and easily modified surface chemistry, enabling high loading capacity for drugs with diverse chemicophysical properties. While PSNPs are also cytocompatible and degradable, PSNP ... ...

    Abstract Porous silicon nanoparticles (PSNPs) offer tunable pore structure and easily modified surface chemistry, enabling high loading capacity for drugs with diverse chemicophysical properties. While PSNPs are also cytocompatible and degradable, PSNP integration into composite structures can be a useful approach to enhance carrier colloidal stability, drug-cargo loading stability, and endosome escape. Here, we explored PSNP polymer composites formed by coating of oxidized PSNPs with a series of poly[ethylene glycol-
    MeSH term(s) Cell Line, Tumor ; Cell Survival/drug effects ; Endosomes/metabolism ; Humans ; Hydrogen-Ion Concentration ; Hydrophobic and Hydrophilic Interactions ; MicroRNAs/antagonists & inhibitors ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Nanoparticles/chemistry ; Nanoparticles/toxicity ; Peptide Nucleic Acids/chemistry ; Peptide Nucleic Acids/metabolism ; Polymers/chemical synthesis ; Polymers/chemistry ; Porosity ; RNA Interference ; Silicon/chemistry
    Chemical Substances MIRN122 microRNA, human ; MicroRNAs ; Peptide Nucleic Acids ; Polymers ; Silicon (Z4152N8IUI)
    Language English
    Publishing date 2020-08-21
    Publishing country United States
    Document type Journal Article
    ISSN 1944-8252
    ISSN (online) 1944-8252
    DOI 10.1021/acsami.0c05827
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Tuning Composition of Polymer and Porous Silicon Composite Nanoparticles for Early Endosome Escape of Anti-microRNA Peptide Nucleic Acids

    Kelly, Isom B / Fletcher, R. Brock / McBride, James R / Weiss, Sharon M / Duvall, Craig L

    ACS applied materials & interfaces. 2020 July 31, v. 12, no. 35

    2020  

    Abstract: Porous silicon nanoparticles (PSNPs) offer tunable pore structure and easily modified surface chemistry, enabling high loading capacity for drugs with diverse chemicophysical properties. While PSNPs are also cytocompatible and degradable, PSNP ... ...

    Abstract Porous silicon nanoparticles (PSNPs) offer tunable pore structure and easily modified surface chemistry, enabling high loading capacity for drugs with diverse chemicophysical properties. While PSNPs are also cytocompatible and degradable, PSNP integration into composite structures can be a useful approach to enhance carrier colloidal stability, drug-cargo loading stability, and endosome escape. Here, we explored PSNP polymer composites formed by coating of oxidized PSNPs with a series of poly[ethylene glycol-block-(dimethylaminoethyl methacrylate-co-butyl methacrylate)] (PEG-DB) diblock copolymers with varied molar ratios of dimethylaminoethyl methacrylate (D) and butyl methacrylate (B) in the random copolymer block. We screened and developed PSNP composites specifically toward intracellular delivery of microRNA inhibitory peptide nucleic acids (PNA). While a copolymer with 50 mol % B (50B) is optimal for early endosome escape in free polymer form, its pH switch was suppressed when it was formed into 50B polymer-coated PSNP composites (50BCs). We demonstrate that a lower mol % B (30BC) is the ideal PEG-DB composition for PSNP/PEG-DB nanocomposites based on having both the highest endosome disruption potential and miR-122 inhibitory activity. At a 1 mM PNA dose, 30BCs facilitated more potent inhibition of miR-122 in comparison to 40BC (p = 0.0095), 50BC (p < 0.0001), or an anti-miR-122 oligonucleotide delivered with the commercial transfection reagent Fugene 6. Using a live cell galectin 8-based endosome disruption reporter, 30BCs had greater endosomal escape than 40BCs and 50BCs within 2 h after treatment, suggesting that rapid endosome escape correlates with higher intracellular bioactivity. This study provides new insight on the polymer structure-dependent effects on stability, endosome escape, and cargo intracellular bioavailability for endosomolytic polymer-coated PSNPs.
    Keywords bioactive properties ; bioavailability ; coatings ; composite polymers ; drugs ; ethylene ; galectins ; microRNA ; nanocomposites ; nanoparticles ; oligonucleotides ; oxidation ; pH ; peptides ; silicon ; transfection
    Language English
    Dates of publication 2020-0731
    Size p. 39602-39611.
    Publishing place American Chemical Society
    Document type Article
    ISSN 1944-8252
    DOI 10.1021/acsami.0c05827
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Nonviral

    Fletcher, R Brock / Stokes, Larry D / Kelly, Isom B / Henderson, Katelyn M / Vallecillo-Viejo, Isabel C / Colazo, Juan M / Wong, Benjamin V / Yu, Fang / d'Arcy, Richard / Struthers, Morgan N / Evans, Brian C / Ayers, Jacob / Castanon, Matthew / Weirich, Michael J / Reilly, Sarah K / Patel, Shrusti S / Ivanova, Yoanna I / Silvera Batista, Carlos A / Weiss, Sharon M /
    Gersbach, Charles A / Brunger, Jonathan M / Duvall, Craig L

    ACS nano

    2023  Volume 17, Issue 17, Page(s) 16412–16431

    Abstract: The complexity of CRISPR machinery is a challenge to its application for ... ...

    Abstract The complexity of CRISPR machinery is a challenge to its application for nonviral
    MeSH term(s) Mice ; Animals ; CRISPR-Cas Systems/genetics ; Silicon ; Porosity ; Polymers ; Nanoparticles
    Chemical Substances Silicon (Z4152N8IUI) ; Polymers
    Language English
    Publishing date 2023-08-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1936-086X
    ISSN (online) 1936-086X
    DOI 10.1021/acsnano.2c12261
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Gal8 Visualization of Endosome Disruption Predicts Carrier-Mediated Biologic Drug Intracellular Bioavailability.

    Kilchrist, Kameron V / Dimobi, Somtochukwu C / Jackson, Meredith A / Evans, Brian C / Werfel, Thomas A / Dailing, Eric A / Bedingfield, Sean K / Kelly, Isom B / Duvall, Craig L

    ACS nano

    2019  Volume 13, Issue 2, Page(s) 1136–1152

    Abstract: Endolysosome entrapment is one of the key barriers to the therapeutic use of biologic drugs that act intracellularly. The screening of prospective nanoscale endosome-disrupting delivery technologies is currently limited by methods that are indirect and ... ...

    Abstract Endolysosome entrapment is one of the key barriers to the therapeutic use of biologic drugs that act intracellularly. The screening of prospective nanoscale endosome-disrupting delivery technologies is currently limited by methods that are indirect and cumbersome. Here, we statistically validate Galectin 8 (Gal8) intracellular tracking as a superior approach that is direct, quantitative, and predictive of therapeutic cargo intracellular bioactivity through in vitro high-throughput screening and in vivo validation. Gal8 is a cytosolically dispersed protein that, when endosomes are disrupted, redistributes by binding to glycosylation moieties selectively located on the inner face of endosomal membranes. The quantitative redistribution of a Gal8 fluorescent fusion protein from the cytosol into endosomes is demonstrated as a real-time, live-cell assessment of endosomal integrity that does not require labeling or modification of either the carrier or the biologic drug and that allows quantitative distinction between closely related, endosome-disruptive drug carriers. Through screening two families of siRNA polymeric carrier compositions at varying dosages, we show that Gal8 endosomal recruitment correlates strongly ( r = 0.95 and p < 10
    MeSH term(s) Biological Availability ; Biological Products/chemistry ; Biological Products/metabolism ; Drug Carriers/chemistry ; Drug Carriers/metabolism ; Drug Delivery Systems ; Endosomes/chemistry ; Endosomes/metabolism ; Galectins/chemistry ; Galectins/metabolism ; High-Throughput Screening Assays ; Humans
    Chemical Substances Biological Products ; Drug Carriers ; Galectins ; LGALS8 protein, human
    Language English
    Publishing date 2019-01-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1936-086X
    ISSN (online) 1936-086X
    DOI 10.1021/acsnano.8b05482
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Kupffer cell release of platelet activating factor drives dose limiting toxicities of nucleic acid nanocarriers.

    Jackson, Meredith A / Patel, Shrusti S / Yu, Fang / Cottam, Matthew A / Glass, Evan B / Hoogenboezem, Ella N / Fletcher, R Brock / Dollinger, Bryan R / Patil, Prarthana / Liu, Danielle D / Kelly, Isom B / Bedingfield, Sean K / King, Allyson R / Miles, Rachel E / Hasty, Alyssa M / Giorgio, Todd D / Duvall, Craig L

    Biomaterials

    2020  Volume 268, Page(s) 120528

    Abstract: This work establishes that Kupffer cell release of platelet activating factor (PAF), a lipidic molecule with pro-inflammatory and vasoactive signaling properties, dictates dose-limiting siRNA nanocarrier-associated toxicities. High-dose intravenous ... ...

    Abstract This work establishes that Kupffer cell release of platelet activating factor (PAF), a lipidic molecule with pro-inflammatory and vasoactive signaling properties, dictates dose-limiting siRNA nanocarrier-associated toxicities. High-dose intravenous injection of siRNA-polymer nano-polyplexes (si-NPs) elicited acute, shock-like symptoms in mice, associated with increased plasma PAF and consequently reduced PAF acetylhydrolase (PAF-AH) activity. These symptoms were completely prevented by prophylactic PAF receptor inhibition or Kupffer cell depletion. Assessment of varied si-NP chemistries confirmed that toxicity level correlated to relative uptake of the carrier by liver Kupffer cells and that this toxicity mechanism is dependent on carrier endosome disruptive function. 4T1 tumor-bearing mice, which exhibit increased circulating leukocytes, displayed greater sensitivity to these toxicities. PAF-mediated toxicities were generalizable to commercial delivery reagent in vivo-jetPEI® and an MC3 lipid formulation matched to an FDA-approved nanomedicine. These collective results establish Kupffer cell release of PAF as a key mediator of siRNA nanocarrier toxicity and identify PAFR inhibition as an effective strategy to increase siRNA nanocarrier tolerated dose.
    MeSH term(s) Animals ; Biological Transport ; Kupffer Cells/metabolism ; Mice ; Platelet Activating Factor/metabolism ; RNA, Messenger/metabolism ; Signal Transduction
    Chemical Substances Platelet Activating Factor ; RNA, Messenger
    Language English
    Publishing date 2020-11-23
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 603079-8
    ISSN 1878-5905 ; 0142-9612
    ISSN (online) 1878-5905
    ISSN 0142-9612
    DOI 10.1016/j.biomaterials.2020.120528
    Database MEDical Literature Analysis and Retrieval System OnLINE

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