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Dual carrier-cargo hydrophobization and charge ratio optimization improve the systemic circulation and safety of zwitterionic nano-polyplexes.
Jackson MA, Bedingfield SK, Yu F, Stokan ME, Miles RE, Curvino EJ, Hoogenboezem EN, Bonami RH, Patel SS, Kendall PL, Giorgio TD, Duvall CL
(2019) Biomaterials 192: 245-259
MeSH Terms: Animals, Cations, Cell Line, Tumor, Female, Humans, Hydrophobic and Hydrophilic Interactions, Mice, Inbred BALB C, Mice, Nude, Nanostructures, Neoplasms, Polymers, RNA, Small Interfering, RNAi Therapeutics, Tissue Distribution
Show Abstract · Added April 10, 2019
While polymeric nano-formulations for RNAi therapeutics hold great promise for molecularly-targeted, personalized medicine, they possess significant systemic delivery challenges including rapid clearance from circulation and the potential for carrier-associated toxicity due to cationic polymer or lipid components. Herein, we evaluated the in vivo pharmacokinetic and safety impact of often-overlooked formulation parameters, including the ratio of carrier polymer to cargo siRNA and hydrophobic siRNA modification in combination with hydrophobic polymer components (dual hydrophobization). For these studies, we used nano-polyplexes (NPs) with well-shielded, zwitterionic coronas, resulting in various NP formulations of equivalent hydrodynamic size and neutral surface charge regardless of charge ratio. Doubling nano-polyplex charge ratio from 10 to 20 increased circulation half-life five-fold and pharmacokinetic area under the curve four-fold, but was also associated with increased liver enzymes, a marker of hepatic damage. Dual hydrophobization achieved by formulating NPs with palmitic acid-modified siRNA (siPA-NPs) both reduced the amount of carrier polymer required to achieve optimal pharmacokinetic profiles and abrogated liver toxicities. We also show that optimized zwitterionic siPA-NPs are well-tolerated upon long-term, repeated administration in mice and exhibit greater than two-fold increased uptake in orthotopic MDA-MB-231 xenografts compared to commercial transfection reagent, in vivo-jetPEI. These data suggest that charge ratio optimization has important in vivo implications and that dual hydrophobization strategies can be used to maximize both NP circulation time and safety.
Copyright © 2018 Elsevier Ltd. All rights reserved.
0 Communities
2 Members
0 Resources
14 MeSH Terms
Zwitterionic Nanocarrier Surface Chemistry Improves siRNA Tumor Delivery and Silencing Activity Relative to Polyethylene Glycol.
Jackson MA, Werfel TA, Curvino EJ, Yu F, Kavanaugh TE, Sarett SM, Dockery MD, Kilchrist KV, Jackson AN, Giorgio TD, Duvall CL
(2017) ACS Nano 11: 5680-5696
MeSH Terms: Animals, Cell Line, Tumor, Drug Carriers, Female, Humans, Male, Mice, Nude, Nanostructures, Neoplasms, Phosphorylcholine, Polyethylene Glycols, Polymers, RNA, Small Interfering, RNAi Therapeutics, Surface Properties
Show Abstract · Added March 14, 2018
Although siRNA-based nanomedicines hold promise for cancer treatment, conventional siRNA-polymer complex (polyplex) nanocarrier systems have poor pharmacokinetics following intravenous delivery, hindering tumor accumulation. Here, we determined the impact of surface chemistry on the in vivo pharmacokinetics and tumor delivery of siRNA polyplexes. A library of diblock polymers was synthesized, all containing the same pH-responsive, endosomolytic polyplex core-forming block but different corona blocks: 5 kDa (benchmark) and 20 kDa linear polyethylene glycol (PEG), 10 kDa and 20 kDa brush-like poly(oligo ethylene glycol), and 10 kDa and 20 kDa zwitterionic phosphorylcholine-based polymers (PMPC). In vitro, it was found that 20 kDa PEG and 20 kDa PMPC had the highest stability in the presence of salt or heparin and were the most effective at blocking protein adsorption. Following intravenous delivery, 20 kDa PEG and PMPC coronas both extended circulation half-lives 5-fold compared to 5 kDa PEG. However, in mouse orthotopic xenograft tumors, zwitterionic PMPC-based polyplexes showed highest in vivo luciferase silencing (>75% knockdown for 10 days with single IV 1 mg/kg dose) and 3-fold higher average tumor cell uptake than 5 kDa PEG polyplexes (20 kDa PEG polyplexes were only 2-fold higher than 5 kDa PEG). These results show that high molecular weight zwitterionic polyplex coronas significantly enhance siRNA polyplex pharmacokinetics without sacrificing polyplex uptake and bioactivity within tumors when compared to traditional PEG architectures.
0 Communities
1 Members
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15 MeSH Terms
Patterning protein complexes on DNA nanostructures using a GFP nanobody.
Sommese RF, Hariadi RF, Kim K, Liu M, Tyska MJ, Sivaramakrishnan S
(2016) Protein Sci 25: 2089-2094
MeSH Terms: Actin-Related Protein 2-3 Complex, Animals, DNA, Green Fluorescent Proteins, Nanostructures, Recombinant Fusion Proteins, Single-Domain Antibodies, Swine
Show Abstract · Added April 7, 2017
DNA nanostructures have become an important and powerful tool for studying protein function over the last 5 years. One of the challenges, though, has been the development of universal methods for patterning protein complexes on DNA nanostructures. Herein, we present a new approach for labeling DNA nanostructures by functionalizing them with a GFP nanobody. We demonstrate the ability to precisely control protein attachment via our nanobody linker using two enzymatic model systems, namely adenylyl cyclase activity and myosin motility. Finally, we test the power of this attachment method by patterning unpurified, endogenously expressed Arp2/3 protein complex from cell lysate. By bridging DNA nanostructures with a fluorescent protein ubiquitous throughout cell and developmental biology and protein biochemistry, this approach significantly streamlines the application of DNA nanostructures as a programmable scaffold in biological studies.
© 2016 The Protein Society.
1 Communities
1 Members
0 Resources
8 MeSH Terms
Hydrolytic charge-reversal of PEGylated polyplexes enhances intracellular un-packaging and activity of siRNA.
Werfel TA, Swain C, Nelson CE, Kilchrist KV, Evans BC, Miteva M, Duvall CL
(2016) J Biomed Mater Res A 104: 917-27
MeSH Terms: Amines, Carboxylic Acids, Cell Line, Tumor, Cell Survival, Fluorescence Resonance Energy Transfer, Hemolysis, Humans, Hydrolysis, Methacrylates, Microscopy, Confocal, Nanostructures, Polyethylene Glycols, RNA Interference, RNA, Small Interfering
Show Abstract · Added March 14, 2018
Hydrolytically degrading nano-polyplexes (HDG-NPs) that reverse charge through conversion of tertiary amines to carboxylic acids were investigated to improve intracellular un-packaging of siRNA and target gene silencing compared to a non-degradable analog (non-HDG-NPs). Both NP types comprised reversible addition-fragmentation chain-transfer (RAFT) synthesized diblock copolymers of a poly(ethylene glycol) (PEG) corona-forming block and a cationic block for nucleic acid packaging that incorporated butyl methacrylate (BMA) and either dimethylaminoethyl methacrylate (DMAEMA, non-HDG-NPs) or dimethylaminoethyl acrylate (DMAEA, HDG-NPs). HDG-NPs decreased significantly in size and released significantly more siRNA (∼40%) than non-HDG-NPs after 24 h in aqueous solution. While both HDG-NPs and non-HDG-NPs had comparable uptake and cytotoxicity up to 150 nM siRNA doses, HDG-NPs achieved significantly higher target gene silencing of the model gene luciferase in vitro. High resolution FRET confocal microscopy was used to monitor the intracellular un-packaging of siRNA. Non-HDG-NPs had significantly higher FRET efficiency than HDG-NPs, indicating that siRNA delivered from HDG-NPs was more fully un-packaged and therefore had improved intracellular bioavailability.
© 2016 Wiley Periodicals, Inc.
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1 Members
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14 MeSH Terms
Endosomolytic Nano-Polyplex Platform Technology for Cytosolic Peptide Delivery To Inhibit Pathological Vasoconstriction.
Evans BC, Hocking KM, Kilchrist KV, Wise ES, Brophy CM, Duvall CL
(2015) ACS Nano 9: 5893-907
MeSH Terms: Cells, Cultured, Coronary Vasospasm, Cytosol, Drug Delivery Systems, Humans, Muscle, Smooth, Vascular, Nanostructures, Nanotechnology, Oligopeptides, Polymers, Vasoconstriction
Show Abstract · Added March 14, 2018
A platform technology has been developed and tested for delivery of intracellular-acting peptides through electrostatically complexed nanoparticles, or nano-polyplexes, formulated from an anionic endosomolytic polymer and cationic therapeutic peptides. This delivery platform has been initially tested and optimized for delivery of two unique vasoactive peptides, a phosphomimetic of heat shock protein 20 and an inhibitor of MAPKAP kinase II, to prevent pathological vasoconstriction (i.e., vasospasm) in human vascular tissue. These peptides inhibit vasoconstriction and promote vasorelaxation by modulating actin dynamics in vascular smooth muscle cells. Formulating these peptides into nano-polyplexes significantly enhances peptide uptake and retention, facilitates cytosolic delivery through a pH-dependent endosomal escape mechanism, and enhances peptide bioactivity in vitro as measured by inhibition of F-actin stress fiber formation. In comparison to treatment with the free peptides, which were endowed with cell-penetrating sequences, the nano-polyplexes significantly increased vasorelaxation, inhibited vasoconstriction, and decreased F-actin formation in the human saphenous vein ex vivo. These results suggest that these formulations have significant potential for treatment of conditions such as cerebral vasospasm following subarachnoid hemorrhage. Furthermore, because many therapeutic peptides include cationic cell-penetrating segments, this simple and modular platform technology may have broad applicability as a cost-effective approach for enhancing the efficacy of cytosolically active peptides.
0 Communities
1 Members
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11 MeSH Terms
Phage-display-guided nanocarrier targeting to atheroprone vasculature.
Hofmeister LH, Lee SH, Norlander AE, Montaniel KR, Chen W, Harrison DG, Sung HJ
(2015) ACS Nano 9: 4435-46
MeSH Terms: Amino Acid Sequence, Animals, Apolipoproteins E, Atherosclerosis, Biopterin, Carotid Arteries, Disease Susceptibility, Drug Carriers, Male, Mice, Molecular Sequence Data, Nanomedicine, Nanostructures, Oligopeptides, Peptide Library
Show Abstract · Added March 31, 2015
In regions of the circulation where vessels are straight and unbranched, blood flow is laminar and unidirectional. In contrast, at sites of curvature, branch points, and regions distal to stenoses, blood flow becomes disturbed. Atherosclerosis preferentially develops in these regions of disturbed blood flow. Current therapies for atherosclerosis are systemic and may not sufficiently target these atheroprone regions. In this study, we sought to leverage the alterations on the luminal surface of endothelial cells caused by this atheroprone flow for nanocarrier targeting. In vivo phage display was used to discover unique peptides that selectively bind to atheroprone regions in the mouse partial carotid artery ligation model. The peptide GSPREYTSYMPH (PREY) was found to bind 4.5-fold more avidly to the region of disturbed flow and was used to form targeted liposomes. When administered intravenously, PREY-targeted liposomes preferentially accumulated in endothelial cells in the partially occluded carotid artery and other areas of disturbed flow. Proteomic analysis and immunoblotting indicated that fibronectin and Filamin-A were preferentially bound by PREY nanocarriers in vessels with disturbed flow. In additional experiments, PREY nanocarriers were used therapeutically to deliver the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), which we have previously shown to be deficient in regions of disturbed flow. This intervention increased vascular BH4 and reduced vascular superoxide in the partially ligated artery in wild-type mice and reduced plaque burden in the partially ligated left carotid artery of fat fed atheroprone mice (ApoE(-/-)). Targeting atheroprone sites of the circulation with functionalized nanocarriers provides a promising approach for prevention of early atherosclerotic lesion formation.
1 Communities
1 Members
0 Resources
15 MeSH Terms
A new paradigm for treatment of glaucoma.
Galloway RL, Delisi M, Harth EM, Mawn LA
(2014) Conf Proc IEEE Eng Med Biol Soc 2014: 6147-50
MeSH Terms: Animals, Blindness, Delayed-Action Preparations, Endoscopy, Equipment Design, Glaucoma, Humans, Magnetic Resonance Imaging, Nanoparticles, Nanostructures, Nanotechnology, Neuroprotective Agents, Phantoms, Imaging, Polyesters, Skull, Swine
Show Abstract · Added February 15, 2016
Glaucoma is the leading irreversible cause of blindness in the world. We are developing a new image-guidance system to deliver a neuroprotective drug in a controlled release nanosponge. The system consists of a magnetically tracked image-guidance system, the nanosponge material and the drug. We have characterized the performance of each aspect in phantoms, animals and ex-vivo human tissue.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Stretchable gas barrier achieved with partially hydrogen-bonded multilayer nanocoating.
Holder KM, Spears BR, Huff ME, Priolo MA, Harth E, Grunlan JC
(2014) Macromol Rapid Commun 35: 960-4
MeSH Terms: Bentonite, Gases, Hydrogen Bonding, Nanostructures, Oxygen, Polyethyleneimine, Propylene Glycols, Surface Properties
Show Abstract · Added February 15, 2016
Super gas barrier nanocoatings are recently demonstrated by combining polyelectrolytes and clay nanoplatelets with layer-by-layer deposition. These nanobrick wall thin films match or exceed the gas barrier of SiOx and metallized films, but they are relatively stiff and lose barrier with significant stretching (≥ 10% strain). In an effort to impart stretchability, hydrogen-bonding polyglycidol (PGD) layers are added to an electrostatically bonded thin film assembly of polyethylenimine (PEI) and montmorillonite (MMT) clay. The oxygen transmission rate of a 125-nm thick PEI-MMT film increases more than 40x after being stretched 10%, while PGD-PEI-MMT trilayers of the same thickness maintain its gas barrier. This stretchable trilayer system has an OTR three times lower than the PEI-MMT bilayer system after stretching. This report marks the first stretchable high gas barrier thin film, which is potentially useful for applications that require pressurized elastomers.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Perfluorocarbon nanoemulsions with fluorescent, colloidal and magnetic properties.
Janjic JM, Shao P, Zhang S, Yang X, Patel SK, Bai M
(2014) Biomaterials 35: 4958-68
MeSH Terms: Animals, Cell Line, Tumor, Cell Survival, Emulsions, Fluorescent Dyes, Fluorocarbons, Magnetic Resonance Imaging, Mice, Nanostructures, Particle Size, Spectroscopy, Near-Infrared, Surface-Active Agents
Show Abstract · Added April 2, 2019
Bimodal imaging agents that combine magnetic resonance imaging (MRI) and nearinfrared (NIR) imaging formulated as nanoemulsions became increasingly popular for imaging inflammation in vivo. Quality of in vivo imaging using nanoemulsions is directly dependent on their integrity and stability. Here we report the design of nanoemulsions for bimodal imaging, where both photostability and colloidal stability are equally addressed. A highly chemically and photo stable quaterrylenediimide dye was introduced into perfluoro-15-crown-5 ether (PCE) nanoemulsions. The nanoemulsions were prepared with PCE and Miglyol 812N mixed at 1:1 v/v ratio as internal phase stabilized by non-ionic surfactants. Data shows exceptional colloidal stability demonstrated as unchanged droplet size (~130 nm) and polydispersity (<0.15) after 182 days follow up at both 4 and 25 °C. Nanoemulsions also sustained the exposure to mechanical and temperature stress, and prolonged exposure to light without changes in droplet size, (19)F signal or fluorescence signal. No toxicity was observed in vitro in model inflammatory cells upon 24 h exposure while confocal microscopy showed that nanoemulsions droplets accumulated in the cytoplasm. Overall, our data demonstrates that design of bimodal imaging agents requires consideration of stability of each imaging component and that of the nanosystem as a whole to achieve excellent imaging performance.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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1 Members
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MeSH Terms
Injectable foams for regenerative medicine.
Prieto EM, Page JM, Harmata AJ, Guelcher SA
(2014) Wiley Interdiscip Rev Nanomed Nanobiotechnol 6: 136-54
MeSH Terms: Biocompatible Materials, Dosage Forms, Humans, Hydrogels, Injections, Nanostructures, Regenerative Medicine
Show Abstract · Added February 23, 2016
The design of injectable biomaterials has attracted considerable attention in recent years. Many injectable biomaterials, such as hydrogels and calcium phosphate cements (CPCs), have nanoscale pores that limit the rate of cellular migration and proliferation. While introduction of macroporosity has been suggested to increase cellular infiltration and tissue healing, many conventional methods for generating macropores often require harsh processing conditions that preclude their use in injectable foams. In recent years, processes such as porogen leaching, gas foaming, and emulsion-templating have been adapted to generate macroporosity in injectable CPCs, hydrogels, and hydrophobic polymers. While some of the more mature injectable foam technologies have been evaluated in clinical trials, there are challenges remaining to be addressed, such as the biocompatibility and ultimate fate of the sacrificial phase used to generate pores within the foam after it sets in situ. Furthermore, while implantable scaffolds can be washed extensively to remove undesirable impurities, all of the components required to synthesize injectable foams must be injected into the defect. Thus, every compound in the foam must be biocompatible and noncytotoxic at the concentrations utilized. As future research addresses these critical challenges, injectable macroporous foams are anticipated to have an increasingly significant impact on improving patient outcomes for a number of clinical procedures.
© 2013 Wiley Periodicals, Inc.
1 Communities
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7 MeSH Terms