Chemical and Biomolecular Engineering - Research Publications

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    Self-assembly of "patchy" nanoparticles: a versatile approach to functional hierarchical materials
    Lunn, DJ ; Finnegan, JR ; Manners, I (ROYAL SOC CHEMISTRY, 2015-01-01)
    The solution-phase self-assembly or "polymerization" of discrete colloidal building blocks, such as "patchy" nanoparticles and multicompartment micelles, is attracting growing attention with respect to the creation of complex hierarchical materials. This approach represents a versatile method with which to transfer functionality at the molecular level to the nano- and microscale, and is often accompanied by the emergence of new material properties. In this perspective we highlight selected recent examples of the self-assembly of anisotropic nanoparticles which exploit directional interactions introduced through their shape or surface chemistry to afford a variety of hierarchical materials. We focus in particular on the solution self-assembly of block copolymers as a means to prepare multicompartment or "patchy" micelles. Due to their potential for synthetic modification, these constructs represent highly tuneable building blocks for the fabrication of a wide variety of functional assemblies.
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    The within-day behaviour of 6 minute rainfall intensity in Australia
    Western, AW ; Anderson, B ; Siriwardena, L ; Chiew, FHS ; Seed, A ; Bloeschl, G (COPERNICUS GESELLSCHAFT MBH, 2011-01-01)
    Abstract. The statistical behaviour and distribution of high-resolution (6 min) rainfall intensity within the wet part of rainy days (total rainfall depth >10 mm) is investigated for 42 stations across Australia. This paper compares nine theoretical distribution functions (TDFs) in representing these data. Two goodness-of-fit statistics are reported: the Root Mean Square Error (RMSE) between the fitted and observed within-day distribution; and the coefficient of efficiency for the fit to the highest rainfall intensities (average intensity of the 5 highest intensity intervals) across all days at a site. The three-parameter Generalised Pareto distribution was clearly the best performer. Good results were also obtained from Exponential, Gamma, and two-parameter Generalized Pareto distributions, each of which are two parameter functions, which may be advantageous when predicting parameter values. Results of different fitting methods are compared for different estimation techniques. The behaviour of the statistical properties of the within-day intensity distributions was also investigated and trends with latitude, Köppen climate zone (strongly related to latitude) and daily rainfall amount were identified. The latitudinal trends are likely related to a changing mix of rainfall generation mechanisms across the Australian continent.
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    Enhancing dendritic cell activation and HIV vaccine effectiveness through nanoparticle vaccination
    Glass, JJ ; Kent, SJ ; De Rose, R (TAYLOR & FRANCIS LTD, 2016-01-01)
    Novel vaccination approaches are needed to prevent and control human immunodeficiency virus (HIV) infection. A growing body of literature demonstrates the potential of nanotechnology to modulate the human immune system and generate targeted, controlled immune responses. In this Review, we summarize important advances in how 'nanovaccinology' can be used to develop safe and effective vaccines for HIV. We highlight the central role of dendritic cells in the immune response to vaccination and describe how nanotechnology can be used to enhance delivery to and activation of these important antigen-presenting cells. Strategies employed to improve biodistribution are discussed, including improved lymph node delivery and mucosal penetration concepts, before detailing methods to enhance the humoral and/or cellular immune response to vaccines. We conclude with a commentary on the current state of nanovaccinology.
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    Human immune cell targeting of protein nanoparticles - caveospheres
    Glass, JJ ; Yuen, D ; Rae, J ; Johnston, APR ; Parton, RG ; Kent, SJ ; De Rose, R (ROYAL SOC CHEMISTRY, 2016-01-01)
    Nanotechnology has the power to transform vaccine and drug delivery through protection of payloads from both metabolism and off-target effects, while facilitating specific delivery of cargo to immune cells. However, evaluation of immune cell nanoparticle targeting is conventionally restricted to monocultured cell line models. We generated human caveolin-1 nanoparticles, termed caveospheres, which were efficiently functionalized with monoclonal antibodies. Using this platform, we investigated CD4+ T cell and CD20+ B cell targeting within physiological mixtures of primary human blood immune cells using flow cytometry, imaging flow cytometry and confocal microscopy. Antibody-functionalization enhanced caveosphere binding to targeted immune cells (6.6 to 43.9-fold) within mixed populations and in the presence of protein-containing fluids. Moreover, targeting caveospheres to CCR5 enabled caveosphere internalization by non-phagocytic CD4+ T cells--an important therapeutic target for HIV treatment. This efficient and flexible system of immune cell-targeted caveosphere nanoparticles holds promise for the development of advanced immunotherapeutics and vaccines.
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    Tuning the properties of pH responsive nanoparticles to control cellular interactions in vitro and ex vivo
    Mann, SK ; Dufour, A ; Glass, JJ ; De Rose, R ; Kent, SJ ; Such, GK ; Johnston, APR (ROYAL SOC CHEMISTRY, 2016-01-01)
    Engineering the properties of nanoparticles to limit non-specific cellular interactions is critical for developing effective drug delivery systems. Differences between interactions with cultured cells and human blood highlights the need for appropriate assays
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    Recombinant influenza virus expressing HIV-1 p24 capsid protein induces mucosal HIV-specific CD8 T-cell responses
    Tan, H-X ; Gilbertson, BP ; Jegaskanda, S ; Alcantara, S ; Amarasena, T ; Stambas, J ; McAuley, JL ; Kent, SJ ; De Rose, R (ELSEVIER SCI LTD, 2016-02-24)
    Influenza viruses are promising mucosal vaccine vectors for HIV but their use has been limited by difficulties in engineering the expression of large amounts of foreign protein. We developed recombinant influenza viruses incorporating the HIV-1 p24 gag capsid into the NS-segment of PR8 (H1N1) and X31 (H3N2) influenza viruses with the use of multiple 2A ribosomal skip sequences. Despite the insertion of a sizable HIV-1 gene into the influenza genome, recombinant viruses were readily rescued to high titers. Intracellular expression of p24 capsid was confirmed by in vitro infection assays. The recombinant influenza viruses were subsequently tested as mucosal vaccines in BALB/c mice. Recombinant viruses were attenuated and safe in immunized mice. Systemic and mucosal HIV-specific CD8 T-cell responses were elicited in mice that were immunized via intranasal route with a prime-boost regimen. Isolated HIV-specific CD8 T-cells displayed polyfunctional cytokine and degranulation profiles. Mice boosted via intravaginal route induced recall responses from the distal lung mucosa and developed heightened HIV-specific CD8 T-cell responses in the vaginal mucosa. These findings demonstrate the potential utility of recombinant influenza viruses as vaccines for mucosal immunity against HIV-1 infection.
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    High fidelity simian immunodeficiency virus reverse transcriptase mutants have impaired replication in vitro and in vivo
    Lloyd, SB ; Lichtfuss, M ; Amarasena, TH ; Alcantara, S ; De Rose, R ; Tachedjian, G ; Alinejad-Rokny, H ; Venturi, V ; Davenport, MP ; Winnall, WR ; Kent, SJ (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2016-05-01)
    The low fidelity of HIV replication facilitates immune and drug escape. Some reverse transcriptase (RT) inhibitor drug-resistance mutations increase RT fidelity in biochemical assays but their effect during viral replication is unclear. We investigated the effect of RT mutations K65R, Q151N and V148I on SIV replication and fidelity in vitro, along with SIV replication in pigtailed macaques. SIVmac239-K65R and SIVmac239-V148I viruses had reduced replication capacity compared to wild-type SIVmac239. Direct virus competition assays demonstrated a rank order of wild-type>K65R>V148I mutants in terms of viral fitness. In single round in vitro-replication assays, SIVmac239-K65R demonstrated significantly higher fidelity than wild-type, and rapidly reverted to wild-type following infection of macaques. In contrast, SIVmac239-Q151N was replication incompetent in vitro and in pigtailed macaques. Thus, we showed that RT mutants, and specifically the common K65R drug-resistance mutation, had impaired replication capacity and higher fidelity. These results have implications for the pathogenesis of drug-resistant HIV.
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    Charge Has a Marked Influence on Hyperbranched Polymer Nanoparticle Association in Whole Human Blood
    Glass, JJ ; Chen, L ; Alcantara, S ; Crampin, EJ ; Thurecht, KJ ; De Rose, R ; Kent, SJ (AMER CHEMICAL SOC, 2017-06-01)
    In this study, we synthesize charge-varied hyperbranched polymers (HBPs) and demonstrate surface charge as a key parameter directing their association with specific human blood cell types. Using fresh human blood, we investigate the association of 5 nm HBPs with six white blood cell populations in their natural milieu by flow cytometry. While most cell types associate with cationic HBPs at 4 °C, at 37 °C phagocytic cells display similar (monocyte, dendritic cell) or greater (granulocyte) association with anionic HBPs compared to cationic HBPs. Neutral HBPs display remarkable stealth properties. Notably, these charge-association patterns are not solely defined by the plasma protein corona and are material and/or size dependent. As HBPs progress toward clinical use as imaging and drug delivery agents, the ability to engineer HBPs with defined biological properties is increasingly important. This knowledge can be used in the rational design of HBPs for more effective delivery to desired cell targets.
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    Thiol-Reactive Star Polymers Display Enhanced Association with Distinct Human Blood Components
    Glass, JJ ; Li, Y ; De Rose, R ; Johnston, APR ; Czuba, EI ; Khor, SY ; Quinn, JF ; Whittaker, MR ; Davis, TP ; Kent, SJ (AMER CHEMICAL SOC, 2017-04-12)
    Directing nanoparticles to specific cell types using nonantibody-based methods is of increasing interest. Thiol-reactive nanoparticles can enhance the efficiency of cargo delivery into specific cells through interactions with cell-surface proteins. However, studies to date using this technique have been largely limited to immortalized cell lines or rodents, and the utility of this technology on primary human cells is unknown. Herein, we used RAFT polymerization to prepare pyridyl disulfide (PDS)-functionalized star polymers with a methoxy-poly(ethylene glycol) brush corona and a fluorescently labeled cross-linked core using an arm-first method. PDS star polymers were examined for their interaction with primary human blood components: six separate white blood cell subsets, as well as red blood cells and platelets. Compared with control star polymers, thiol-reactive nanoparticles displayed enhanced association with white blood cells at 37 °C, particularly the phagocytic monocyte, granulocyte, and dendritic cell subsets. Platelets associated with more PDS than control nanoparticles at both 37 °C and on ice, but they were not activated in the duration examined. Association with red blood cells was minor but still enhanced with PDS nanoparticles. Thiol-reactive nanoparticles represent a useful strategy to target primary human immune cell subsets for improved nanoparticle delivery.
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    Induction of vaginal-resident HIV-specific CD8 T cells with mucosal prime-boost immunization
    Tan, H-X ; Wheatley, AK ; Esterbauer, R ; Jegaskanda, S ; Glass, JJ ; Masopust, D ; De Rose, R ; Kent, SJ (NATURE PUBLISHING GROUP, 2018-05-01)
    Tissue-resident memory (TRM) CD8 T cells survey a range of non-lymphoid mucosal tissues where they rapidly mediate clearance of viral infections at the entry portals. Vaccines that establish CD8 TRM cells in the cervicovaginal mucosa hold promise for effective immunity against sexually transmitted HIV. We demonstrate that HIV-specific CD8 TRM cells can be established in the murine vaginal mucosa using a combined intranasal and intravaginal mucosal immunization with recombinant influenza-HIV vectors. Using in situ tetramer immunofluorescence microscopy, we found that this mucosally administered prime-boost immunization also resulted in the durable seeding of CD8 T cells in the frontline vaginal epithelial compartment as opposed to the vaginal submucosa. Upon cognate antigen recognition within the vaginal mucosa, these HIV-specific CD8 TRM cells rapidly initiated a tissue-wide state of immunity. The activation of HIV-specific CD8 TRM cells resulted in the upregulation of endothelial vessel addressin expression and substantial recruitment of both adaptive and innate immune cells in the vaginal mucosa. These findings suggest that the epithelial localization of HIV-specific CD8 TRM cell populations and their capacity to rapidly activate both arms of the immune system could significantly augment frontline defenses against vaginal HIV infection.