24 results found
Gonzalez-Carter DA, Ong ZY, McGilvery CM, et al., 2019, L-DOPA functionalized, multi-branched gold nanoparticles as brain-targeted nano-vehicles, Nanomedicine: Nanotechnology, Biology and Medicine, Vol: 15, Pages: 1-11, ISSN: 1549-9634
The blood-brain barrier (BBB) is a protective endothelial barrier lining the brain microvasculature which prevents brain delivery of therapies against brain diseases. Hence, there is an urgent need to develop vehicles which efficiently penetrate the BBB to deliver therapies into the brain. The drug L-DOPA efficiently and specifically crosses the BBB via the large neutral amino acid transporter (LAT)-1 protein to enter the brain. Thus, we synthesized L-DOPA-functionalized multi-branched nanoflower-like gold nanoparticles (L-DOPA-AuNFs) using a seed-mediated method involving catechols as a direct reducing-cum-capping agent, and examined their ability to cross the BBB to act as brain-penetrating nanovehicles. We show that L-DOPA-AuNFs efficiently penetrate the BBB compared to similarly sized and shaped AuNFs functionalized with a non-targeting ligand. Furthermore, we show that L-DOPA-AuNFs are efficiently internalized by brain macrophages without inducing inflammation. These results demonstrate the application of L-DOPA-AuNFs as a non-inflammatory BBB-penetrating nanovehicle to efficiently deliver therapies into the brain.
Wu P-J, Kabovka I, Ruberti J, et al., 2018, Water content, not stiffness, dominates Brillouin spectroscopy measurements in hydrated materials, Nature Methods, ISSN: 1548-7091
Loftus C, Saeed M, Davis D, et al., 2018, Activation of human Natural Killer cells by graphene oxide-templated antibody nanoclusters, Nano Letters, Vol: 18, Pages: 3282-3289, ISSN: 1530-6984
An emerging new paradigm is that immune cell activation is controlled by transient interactions between supramolecular assemblies of receptors and ligands. Current immunotherapy biologic pharmaceuticals that activate or desensitize NK cells are, however, individual molecules that do not replicate this nanoscale organization of proteins. Here, we use nanoscale graphene oxide (NGO) as a template to generate soluble nanoscale clusters of Natural Killer cell-activating antibodies. We control nanocluster size and molecular number to mimic reported values for cell surface proteins. These NGO-templated molecular nanoclusters, used to stimulate NK cells via the CD16 receptor, successfully induced cellular activation, indicated by degranulation of cytolytic granules and IFN-γ secretion. Importantly, activation significantly exceeded that induced by the same antibodies applied as a solution of individual molecules. These results demonstrate that future immunotherapies could be enhanced by assembling immunomodulatory drugs into nanoclusters and establish NGO-templating as a candidate technology.
Ong ZY, Chen S, Nabavi E, et al., 2017, Multibranched Gold Nanoparticles with Intrinsic LAT-1 Targeting Capabilities for Selective Photothermal Therapy of Breast Cancer., ACS Applied Materials and Interfaces, Vol: 9, Pages: 39259-39270, ISSN: 1944-8244
Because of the critical role of the large neutral amino acid transporter-1 (LAT-1) in promoting tumor growth and proliferation, it is fast emerging as a highly attractive biomarker for the imaging and treatment of human malignancies, including breast cancer. While multibranched gold nanoparticles (AuNPs) have emerged as a promising modality in the photothermal therapy (PTT) of cancers, some of the key challenges limiting their clinical translation lie in the need to develop reproducible and cost-effective synthetic methods as well as the selective accumulation of sufficient AuNPs at tumor sites. In this study, we report a simple and direct seed-mediated synthesis of monodispersed multibranched AuNPs using the catechol-containing LAT-1 ligands, L- and D-dopa, to confer active cancer targeting. This route obviates the need for additional conjugation with targeting moieties such as peptides or antibodies. Nanoflower-like AuNPs (AuNF) with diameters of approximately 46, 70, and 90 nm were obtained and were found to possess excellent colloidal stability and biocompatibility. A significantly higher intracellular accumulation of the L- and D-dopa functionalized AuNFs was observed in a panel of breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-468, and MDA-MB-453) when compared to the nontargeting control AuNFs synthesized with dopamine and 4-ethylcatechol. Importantly, no significant difference in uptake between the targeting and nontargeting AuNFs was observed in a non-tumorigenic MCF-10A breast epithelial cell line, hence demonstrating tumor selectivity. For PTT of breast cancer, Ag(+) was introduced during synthesis to obtain L-dopa functionalized nanourchin-like AuNPs (AuNUs) with strong near-infrared (NIR) absorbance. The L-dopa functionalized AuNUs mediated selective photothermal ablation of the triple negative MDA-MB-231 breast cancer cell line and sensitized the cells to the anticancer drugs cisplatin and docetaxel. This work brings forward an effective strategy
Luongo G, Perez JE, Kosel J, et al., 2017, Scalable high-affinity stabilization of magnetic iron oxide nanostructures by a biocompatible antifouling homopolymer, ACS Applied Materials and Interfaces, Vol: 9, Pages: 40059-40069, ISSN: 1944-8244
Iron oxide nanostructures have been widely developed for biomedical applications, due to their magnetic properties and biocompatibility. In clinical application, the stabilization of these nanostructures against aggregation and non-specific interactions is typically achieved using weakly anchored polysaccharides, with better-defined and more strongly anchored synthetic polymers not commercially adopted due to complexity of synthesis and use. Here, we show for the first time stabilization and biocompatibilization of iron oxide nanoparticles by a synthetic homopolymer with strong surface anchoring and a history of clinical use in other applications, poly(2-methacryloyloxyethy phosphorylcholine) (poly(MPC)). For the commercially important case of spherical particles, binding of poly(MPC) to iron oxide surfaces and highly effective individualization of magnetite nanoparticles (20 nm) are demonstrated. Next-generation high-aspect ratio nanowires (both magnetite/maghemite and core-shell iron/iron oxide) are furthermore stabilized by poly(MPC)-coating, with nanowire cytotoxicity at large concentrations significantly reduced. The synthesis approach is exploited to incorporate functionality into the poly(MPC) chain is demonstrated by random copolymerization with an alkyne-containing monomer for click-chemistry. Taking these results together, poly(MPC) homopolymers and random copolymers offer a significant improvement over current iron oxide nanoformulations, combining straightforward synthesis, strong surface-anchoring and well-defined molecular weight.
Delcassian D, Sattler S, Dunlop IE, 2017, T cell immunoengineering with advanced biomaterials, Integrative Biology, Vol: 9, Pages: 211-222, ISSN: 1757-9694
Recent advances in biomaterials design offer the potential to actively control immune cell activation and behaviour. Many human diseases, such as infections, cancer, and autoimmune disorders, are partly mediated by inappropriate or insufficient activation of the immune system. T cells play a central role in the host immune response to these diseases, and so constitute a promising cell type for manipulation. In vivo, T cells are stimulated by antigen presenting cells (APC), therefore to design immunoengineering biomaterials that control T cell behaviour, artificial interfaces that mimic the natural APC-T cell interaction are required. This review draws together research in the design and fabrication of such biomaterial interfaces, and highlights efforts to elucidate key parameters in T cell activation, such as substrate mechanical properties and spatial organization of receptors, illustrating how they can be manipulated by bioengineering approaches to alter T cell function.
Perez JE, Contreras MF, Vilanova E, et al., 2016, Cytotoxicity and intracellular dissolution of nickel nanowires., Nanotoxicology, Vol: 10, Pages: 871-880
The assessment of cytotoxicity of nanostructures is a fundamental step for their development as biomedical tools. As widely used nanostructures, nickel nanowires (Ni NWs) seem promising candidates for such applications. In this work, Ni NWs were synthesized and then characterized using vibrating sample magnetometry, energy dispersive X-Ray analysis, and electron microscopy. After exposure to the NWs, cytotoxicity was evaluated in terms of cell viability, cell membrane damage, and induced apoptosis/necrosis on the model human cell line HCT 116. The influence of NW to cell ratio (10:1 to 1000:1) and exposure times up to 72 hours was analyzed for Ni NWs of 5.4 μm in length, as well as for Ni ions. The results show that cytotoxicity markedly increases past 24 hours of incubation. Cellular uptake of NWs takes place through the phagocytosis pathway, with a fraction of the dose of NWs dissolved inside the cells. Cell death results from a combination of apoptosis and necrosis, where the latter is the outcome of the secondary necrosis pathway. The cytotoxicity of Ni ions and Ni NWs dissolution studies suggest a synergistic toxicity between NW aspect ratio and dissolved Ni, with the cytotoxic effects markedly increasing after 24 hours of incubation.
Podhorska L, Delcassian D, Goode AE, et al., 2016, Mechanisms of polymer-templated nanoparticle synthesis: contrasting ZnS and Au, Langmuir, Vol: 32, Pages: 9216-9222, ISSN: 0743-7463
We combine solution small-angle X-ray scattering (SAXS) and high-resolution analytical transmission electron microscopy (ATEM) to gain a full mechanistic understanding of substructure formation in nanoparticles templated by block copolymer reverse micelles, specifically poly(styrene)-block-poly(2-vinyl pyridine). We report a novel substructure for micelle-templated ZnS nanoparticles, in which small crystallites (~4 nm) exist within a larger (~20 nm) amorphous organic-inorganic hybrid matrix. The formation of this complex structure is explained via SAXS measurements that characterize in situ for the first time the intermediate state of the metal-loaded micelle core: Zn2+ ions are distributed throughout the micelle core, which solidifies as a unit on sulfidation. The nanoparticle size is thus determined by the radius of the metal-loaded core, rather than the quantity of available metal ions. This mechanism leads to particle size counter-intuitively decreasing with increasing metal content, based on the modified interactions of the metal-complexed monomers in direct contrast to gold nanoparticles templated by the same polymer.
Gonzalez-Carter D, Goode AE, Fiammengo R, et al., 2016, Inhibition of Leptin-ObR Interaction Does not Prevent Leptin Translocation Across a Human Blood-Brain Barrier Model., J Neuroendocrinol, Vol: 28
The adipocyte-derived hormone leptin regulates appetite and energy homeostasis through the activation of leptin receptors (ObR) on hypothalamic neurones; hence, leptin must be transported through the blood-brain barrier (BBB) to reach its target sites in the central nervous system. During obesity, however, leptin BBB transport is decreased, in part precluding leptin as a viable clinical therapy against obesity. Although the short isoform of the ObR (ObRa) has been implicated in the transport of leptin across the BBB as a result of its elevated expression in cerebral microvessels, accumulating evidence indicates that leptin BBB transport is independent of ObRa. In the present study, we employed an ObR-neutralising antibody (9F8) to directly examine the involvement of endothelial ObR in leptin transport across an in vitro human BBB model composed of the human endothelial cell line hCMEC/D3. Our results indicate that, although leptin transport across the endothelial monolayer was nonparacellular, and energy- and endocytosis-dependent, it was not inhibited by pre-treatment with 9F8, despite the ability of the latter to recognise hCMEC/D3-expressed ObR, prevent leptin-ObR binding and inhibit leptin-induced signal transducer and activator of transcription 3 (STAT-3) phosphorylation in hCMEC/D3 cells. Furthermore, hCMEC/D3 cells expressed the transporter protein low-density lipoprotein receptor-related protein-2 (LRP-2), which is capable of binding and endocytosing leptin. In conclusion, our results demonstrate that leptin binding to and signalling through ObR is not required for efficient transport across human endothelial monolayers, indicating that ObR is not the primary leptin transporter at the human BBB, a role which may fall upon LRP-2. A deeper understanding of leptin BBB transport will help clarify the exact causes for leptin resistance seen in obesity and aid in the development of more efficient BBB-penetrating leptin analogues.
Harrison RH, Steele JAM, Chapman R, et al., 2015, Modular and versatile spatial functionalization of tissue engineering scaffolds through fiber-initiated controlled radical polymerization, Advanced Functional Materials, Vol: 25, Pages: 5748-5757, ISSN: 1616-301X
Dunlop IE, Ryan MP, Goode AE, et al., 2014, Direct synthesis of PEG-encapsulated gold nanoparticles using branched copolymer nanoreactors, RSC Advances, Vol: 4, Pages: 27702-27707
Delcassian D, Depoil D, Rudnicka D, et al., 2013, Nanoscale ligand spacing influences receptor triggering in T cells and NK cells, Nano Letters
Bioactive nanoscale arrays were constructed to ligate activating cell surface receptors on T cells (the CD3 component of the TCR complex) and NK cells (CD16). These arrays are formed from biofunctionalized gold nanospheres with controlled interparticle spacing in the range 25 – 104 nm. Responses to these nanoarrays were assessed using the extent of membrane-localized phosphotyrosine in T cells stimulated with CD3-binding nanoarrays, and the size of cell contact area for NK cells stimulated with CD16-binding nanoarrays. In both cases, the strength of response decreased with increasing spacing, falling to background levels by 69 nm in the T cell/anti-CD3 system and 104 nm for the NK cell/anti-CD16 system. These results demonstrate that immune receptor triggering can be influenced by the nanoscale spatial organization of receptor/ligand interactions.
Leo BF, Chen S, Kyo Y, et al., 2013, The Stability of Silver Nanoparticles in a Model of Pulmonary Surfactant., Environ Sci Technol, Vol: 47, Pages: 11232-11240
The growing use of silver nanoparticles (AgNPs) in consumer products has raised concerns about their potential impact on the environment and human health. Whether AgNPs dissolve and release Ag+ ions, or coarsen to form large aggregates, is critical in determining their potential toxicity. In this work, the stability of AgNPs in dipalmitoylphosphatidylcholine (DPPC), the major component of pulmonary surfactant, was investigated as a function of pH. Spherical, citrate-capped AgNPs with average diameters of 14 ± 1.6 nm (n=200) were prepared by a chemical bath reduction. The kinetics of Ag+ ion release was strongly pH-dependent. After 14 days of incubation in sodium perchlorate (NaClO4) or perchloric acid (HClO4) solutions, the total fraction of AgNPs dissolved varied from ~10 % at pH 3, to ~2 % at pH 5, with negligible dissolution at pH 7. A decrease in pH from 7 to 3 also promoted particle aggregation and coarsening. DPPC (100 mg.L-1) delayed the release of Ag+ ions, but did not significantly alter the total amount of Ag+ released after two weeks. In addition, DPPC improved the dispersion of the AgNPs and inhibited aggregation and coarsening. TEM images revealed that the AgNPs were coated with a DPPC layer serving as a semi-permeable layer. Hence, lung lining fluid, particularly DPPC, can modify the aggregation state and kinetics of Ag+ ion release of inhaled AgNPs in the lung. These observations have important implications for predicting the potential reactivity of AgNPs in the lung and the environment.
Dunlop IE, Thomas RK, Titmus S, et al., 2012, Structure and Collapse of a Surface-Grown Strong Polyelectrolyte Brush on Sapphire, LANGMUIR, Vol: 28, Pages: 3187-3193, ISSN: 0743-7463
Shahal T, Geiger B, Dunlop IE, et al., 2012, Regulation of Integrin Adhesions by Varying the Density of Substrate-Bound Epidermal Growth Factor, Biointerphases: an open access journal for the biomaterials interface community
Substrates coated with specific bioactiveligands are important for tissue engineering, enabling the local presentation of extracellular stimulants at controlled positions and densities. In this study, we examined the cross-talk between integrin and epidermal growth factor (EGF) receptors following their interaction with surfaceimmobilized Arg-Gly-Asp (RGD) and EGF ligands, respectively. Surfaces of glass coverslips, modified with biotinylated silane-polyethylene glycol, were functionalized by either biotinylated RGD or EGF (or both) via the biotin–NeutrAvidin interaction. Fluorescent labeling of the adhering A431 epidermoid carcinoma cells for zyxin or actin indicated that EGF had a dual effect on focal adhesions (FA) and stress fibers: at low concentrations (0.1; 1 ng/ml), it stimulated their growth; whereas at higher concentrations, on surfaces with low to intermediate RGD densities, it induced their disassembly, leading to cell detachment. The EGF- dependent dissociation of FAs was, however, attenuated on higher RGD density surfaces. Simultaneous stimulation by both immobilized RGD and EGF suggest a strong synergy between integrin and EGFR signaling, in FA induction and cell spreading. A critical threshold level of EGF was required to induce significant variation in cell adhesion; beyond this critical density, the immobilized molecule had a considerably stronger effect on cell adhesion than did soluble EGF. The mechanismsunderlying this synergy
Dunlop IE, Briscoe WH, Titmuss S, et al., 2009, Direct Measurement of Normal and Shear Forces between Surface-Grown Polyelectrolyte Layers, JOURNAL OF PHYSICAL CHEMISTRY B, Vol: 113, Pages: 3947-3956, ISSN: 1520-6106
Dunlop IE, Zorn S, Richter G, et al., 2009, Titanium-silicon oxide film structures for polarization-modulated infrared reflection absorption spectroscopy, THIN SOLID FILMS, Vol: 517, Pages: 2048-2054, ISSN: 0040-6090
Dunlop IE, Spatz JP, Dustin ML, 2009, Degenerative diseases: manipulating the micro- and nanoscale architecture regulates immunological synapse function, Nanotechnolgy, Editors: Vogel, Weinheim, Publisher: Wiley-VCH
Sugiharto AB, Johnson CM, Dunlop IE, et al., 2008, Delocalized surface modes reveal three-dimensional structures of complex biomolecules, JOURNAL OF PHYSICAL CHEMISTRY C, Vol: 112, Pages: 7531-7534, ISSN: 1932-7447
Briscoe WH, Chen M, Dunlop IE, et al., 2007, Applying grazing incidence X-ray reflectometry (XRR) to characterising nanofilms on mica, JOURNAL OF COLLOID AND INTERFACE SCIENCE, Vol: 306, Pages: 459-463, ISSN: 0021-9797
Perkin S, Chai L, Kampf N, et al., 2006, Forces between mica surfaces, prepared in different ways, across aqueous and nonaqueous liquids confined to molecularly thin films, LANGMUIR, Vol: 22, Pages: 6142-6152, ISSN: 0743-7463
Dunlop IE, Briscoe WH, Titmuss S, et al., 2004, Interactions between polymer brushes: Varying the number of end-attaching groups, MACROMOLECULAR CHEMISTRY AND PHYSICS, Vol: 205, Pages: 2443-2450, ISSN: 1022-1352
Titmuss S, Briscoe WH, Dunlop IE, et al., 2004, Effect of end-group sticking energy on the properties of polymer brushes: Comparing experiment and theory, JOURNAL OF CHEMICAL PHYSICS, Vol: 121, Pages: 11408-11419, ISSN: 0021-9606
Krebs MRH, MacPhee CE, Miller AF, et al., 2004, The formation of spherulites by amyloid fibrils of bovine insulin, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 101, Pages: 14420-14424, ISSN: 0027-8424
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