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11. Ionizable Lipid Containing Nanocarriers for Antimicrobial Agent Delivery.

Author

Yu, Haitao, Sarkar, Sampa, Shaw, Z. L., Dyett, Brendan, Cai, Xudong, Yap, Sue Lyn, Conn, Charlotte E., Elbourne, Aaron, Drummond, Calum J., and Zhai, Jiali

Subjects
LYOTROPIC liquid crystals, CATIONIC lipids, SMALL-angle scattering, BACTERIAL cell walls, SURFACE charges
Abstract

Antimicrobial resistance (AMR) poses a global health crisis demanding innovative solutions. Traditional antibiotics, though pivotal over the past century in combating bacterial infections, face diminished efficacy against evolving bacterial defense mechanisms, especially in Gram‐negative strains. This study explores self‐assembled ionizable lipid nanoparticles (LNPs) with the incorporation of two ionizable lipid components (one cationic, one anionic) in nanocarriers for advanced antimicrobial drug delivery of the broad‐spectrum antibiotic Piperacillin (Pip). Incorporating cationic ionizable lipid ALC‐0315, recognized as a functional lipid in the Pfizer‐BioNTech mRNA‐based SARS‐CoV‐2 vaccine, into LNPs allowed mesophase transition, pH responsiveness, and ionization behavior in acidic environments found in sites of bacterial infections, to be studied using synchrotron small angle X‐ray scattering, dynamic light scattering, and a 2‐(p‐toluidino)‐6‐naphthalene sulfonic acid assay. Incorporating another anionic ionizable lipid, oleic acid not only modulates the LNPs' physicochemical properties, such as size, internal phase nanostructure, and surface charge but also synergistically enhances the antimicrobial potency together with ALC‐0315 with a benefit enhancing permeability and fusion with bacterial membranes. This study introduces a strategy for tailoring ionizable lipid compositions in LNPs, providing a new approach to antimicrobial treatment contributing to the fight against AMR. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Cellular uptake and in vitroantibacterial activity of lipid-based nanoantibiotics are influenced by protein corona

Author

Subramaniam, Santhni, Joyce, Paul, Conn, Charlotte E., and Prestidge, Clive A.

Abstract

Bacteria have evolved survival mechanisms that enable them to live within host cells, triggering persistent intracellular infections that present significant clinical challenges due to the inability for conventional antibiotics to permeate cell membranes. In recent years, antibiotic nanocarriers or ‘nanoantibiotics’ have presented a promising strategy for overcoming intracellular infections by facilitating cellular uptake of antibiotics, thus improving targeting to the bacteria. However, prior to reaching host cells, nanocarriers experience interactions with proteins that form a corona and alter their physiological response. The influence of this protein corona on the cellular uptake, drug release and efficacy of nanoantibiotics for intracellular infections is poorly understood and commonly overlooked in preclinical studies. In this study, protein corona influence on cellular uptake was investigated for two nanoparticles; liposomes and cubosomes in macrophage and epithelial cells that are commonly infected with pathogens. Studies were conducted in presence of fetal bovine serum (FBS) to form a biologically relevant protein corona in an in vitrosetting. Protein corona impact on cellular uptake was shown to be nanoparticle-dependent, where reduced internalization was observed for liposomes, the opposite was observed for cubosomes. Subsequently, vancomycin-loaded cubosomes were explored for their drug delivery performance against intracellular small colony variants of Staphylococcus aureus. We demonstrated improved bacterial killing in macrophages, with greater reduction in bacterial viability upon internalization of cubosomes mediated by the protein corona. However, no differences in efficacy were observed in epithelial cells. Thus, this study provides insights and evidence to the role of protein corona in modulating the performance of nanoparticles in a dynamic manner; these findings will facilitate improved understanding and translation of future investigations from in vitroto in vivo.

Published
2024
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32. Rational design of potent ultrashort antimicrobial peptides with programmable assembly into nanostructured hydrogels

Author

Cardoso, Priscila, primary, Appiah Danso, Samuel, additional, Hung, Andrew, additional, Dekiwadia, Chaitali, additional, Pradhan, Nimish, additional, Strachan, Jamie, additional, McDonald, Brody, additional, Firipis, Kate, additional, White, Jacinta F., additional, Aburto-Medina, Arturo, additional, Conn, Charlotte E., additional, and Valéry, Céline, additional

Published
2023
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35. Behavior of Citrate-Capped Ultrasmall Gold Nanoparticles on a Supported Lipid Bilayer Interface at Atomic Resolution

Author

Kariuki, Rashad, primary, Penman, Rowan, additional, Bryant, Saffron J., additional, Orrell-Trigg, Rebecca, additional, Meftahi, Nastaran, additional, Crawford, Russell J., additional, McConville, Chris F., additional, Bryant, Gary, additional, Voïtchovsky, Kislon, additional, Conn, Charlotte E., additional, Christofferson, Andrew J., additional, and Elbourne, Aaron, additional

Published
2022
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37. Observations of phase changes in monoolein during high viscous injection

Author

Wells, Daniel J., Berntsen, Peter, Balaur, Eugeniu, Kewish, Cameron M., Adams, Patrick, Aquila, Andrew, Binns, Jack, Boutet, Sebastien, Broomhall, Hayden, Caleman, Carl, Christofferson, Andrew, Conn, Charlotte E., Dahlqvist, Caroline, Flueckiger, Leonie, Roque, Francisco Gian, Greaves, Tamar L., Hejazian, Majid, Hunter, Mark, Jazi, Marjan Hadian, Jönsson, H. Olof, Pathirannahalage, Sachini Kadaoluwa, Kirian, Richard A., Kozlov, Alex, Kurta, Ruslan P., Marman, Hugh, Mendez, Derek, Morgan, Andrew, Nugent, Keith, Oberthuer, Dominik, Quiney, Harry, Reinhardt, Juliane, Saha, Saumitra, Sellberg, Jonas A., Sierra, Raymond, Wiedorn, Max, Abbey, Brian, Martin, Andrew, V, Darmanin, Connie, Wells, Daniel J., Berntsen, Peter, Balaur, Eugeniu, Kewish, Cameron M., Adams, Patrick, Aquila, Andrew, Binns, Jack, Boutet, Sebastien, Broomhall, Hayden, Caleman, Carl, Christofferson, Andrew, Conn, Charlotte E., Dahlqvist, Caroline, Flueckiger, Leonie, Roque, Francisco Gian, Greaves, Tamar L., Hejazian, Majid, Hunter, Mark, Jazi, Marjan Hadian, Jönsson, H. Olof, Pathirannahalage, Sachini Kadaoluwa, Kirian, Richard A., Kozlov, Alex, Kurta, Ruslan P., Marman, Hugh, Mendez, Derek, Morgan, Andrew, Nugent, Keith, Oberthuer, Dominik, Quiney, Harry, Reinhardt, Juliane, Saha, Saumitra, Sellberg, Jonas A., Sierra, Raymond, Wiedorn, Max, Abbey, Brian, Martin, Andrew, V, and Darmanin, Connie

Abstract

Serial crystallography of membrane proteins often employs high-viscosity injectors (HVIs) to deliver micrometre-sized crystals to the X-ray beam. Typically, the carrier medium is a lipidic cubic phase (LCP) media, which can also be used to nucleate and grow the crystals. However, despite the fact that the LCP is widely used with HVIs, the potential impact of the injection process on the LCP structure has not been reported and hence is not yet well understood. The self-assembled structure of the LCP can be affected by pressure, dehydration and temperature changes, all of which occur during continuous flow injection. These changes to the LCP structure may in turn impact the results of X-ray diffraction measurements from membrane protein crystals. To investigate the influence of HVIs on the structure of the LCP we conducted a study of the phase changes in monoolein/water and monoolein/buffer mixtures during continuous flow injection, at both atmospheric pressure and under vacuum. The reservoir pressure in the HVI was tracked to determine if there is any correlation with the phase behaviour of the LCP. The results indicated that, even though the reservoir pressure underwent (at times) significant variation, this did not appear to correlate with observed phase changes in the sample stream or correspond to shifts in the LCP lattice parameter. During vacuum injection, there was a three-way coexistence of the gyroid cubic phase, diamond cubic phase and lamellar phase. During injection at atmospheric pressure, the coexistence of a cubic phase and lamellar phase in the monoolein/water mixtures was also observed. The degree to which the lamellar phase is formed was found to be strongly dependent on the co-flowing gas conditions used to stabilize the LCP stream. A combination of laboratory-based optical polarization microscopy and simulation studies was used to investigate these observations.

Published
2022
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39. Observations of phase changes in monoolein during high viscous injection

Author

Wells, Daniel J., primary, Berntsen, Peter, additional, Balaur, Eugeniu, additional, Kewish, Cameron M., additional, Adams, Patrick, additional, Aquila, Andrew, additional, Binns, Jack, additional, Boutet, Sébastien, additional, Broomhall, Hayden, additional, Caleman, Carl, additional, Christofferson, Andrew, additional, Conn, Charlotte E., additional, Dahlqvist, Caroline, additional, Flueckiger, Leonie, additional, Gian Roque, Francisco, additional, Greaves, Tamar L., additional, Hejazian, Majid, additional, Hunter, Mark, additional, Hadian Jazi, Marjan, additional, Jönsson, H. Olof, additional, Pathirannahalage, Sachini Kadaoluwa, additional, Kirian, Richard A., additional, Kozlov, Alex, additional, Kurta, Ruslan P., additional, Marman, Hugh, additional, Mendez, Derek, additional, Morgan, Andrew, additional, Nugent, Keith, additional, Oberthuer, Dominik, additional, Quiney, Harry, additional, Reinhardt, Juliane, additional, Saha, Saumitra, additional, Sellberg, Jonas A., additional, Sierra, Raymond, additional, Wiedorn, Max, additional, Abbey, Brian, additional, Martin, Andrew V., additional, and Darmanin, Connie, additional

Published
2022
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40. Observations of phase changes in monoolein during high viscous injection

Author

Wells, Daniel, Berntsen, Peter, Balaur, Eugeniu, Kewish, Cameron, Adams, Patrick, Boutet, Sebastien, Broomhall, Hayden, Caleman, Carl, Christofferson, Andrew, Conn, Charlotte E, Dahlqvist, Caroline, Flueckiger, Leonie, Roque, Francisco Gian, Greaves, Tamar, Hejazian, Majid, Hunter, Mark, Hadian Jazi, Marjan, Jonsson, H Olof, Pathirannahalage, Sachini Kadaoluwa, Kirian, Richard, Kozlov, Alex, Kurta, Ruslan, Marman, Hugh, Mendez, Derek, Morgan, Andrew, Nugent, Keith, Oberthuer, Dominik, Quinney, Harry, Reinhardt, Juliane, Saha, Sumitra, Selberg, Jonas, Sierra, Raymond, Wiedorn, Max, Abbey, Brian, Andrew, Martin, and Darmanin, Connie

Subjects
29999 Physical Sciences not elsewhere classified, FOS: Physical sciences
Abstract

Serial crystallography of membrane proteins often employs high-viscosity injectors (HVIs) to deliver micrometre-sized crystals to the X-ray beam. Typically, the carrier medium is a lipidic cubic phase (LCP) media, which can also be used to nucleate and grow the crystals. However, despite the fact that the LCP is widely used with HVIs, the potential impact of the injection process on the LCP structure has not been reported and hence is not yet well understood. The self-assembled structure of the LCP can be affected by pressure, dehydration and temperature changes, all of which occur during continuous flow injection. These changes to the LCP structure may in turn impact the results of X-ray diffraction measurements from membrane protein crystals. To investigate the influence of HVIs on the structure of the LCP we conducted a study of the phase changes in monoolein/water and monoolein/buffer mixtures during continuous flow injection, at both atmospheric pressure and under vacuum. The reservoir pressure in the HVI was tracked to determine if there is any correlation with the phase behaviour of the LCP. The results indicated that, even though the reservoir pressure underwent (at times) significant variation, this did not appear to correlate with observed phase changes in the sample stream or correspond to shifts in the LCP lattice parameter. During vacuum injection, there was a three-way coexistence of the gyroid cubic phase, diamond cubic phase and lamellar phase. During injection at atmospheric pressure, the coexistence of a cubic phase and lamellar phase in the monoolein/water mixtures was also observed. The degree to which the lamellar phase is formed was found to be strongly dependent on the co-flowing gas conditions used to stabilize the LCP stream. A combination of laboratory-based optical polarization microscopy and simulation studies was used to investigate these observations.

Published
2022
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42. Prospective Subunit Nanovaccine against Mycobacterium tuberculosisInfection─Cubosome Lipid Nanocarriers of Cord Factor, Trehalose 6,6′ Dimycolate

Author

Sarkar, Sampa, Mishra, Abhishek, Periasamy, Selvakannan, Dyett, Brendan, Dogra, Prashant, Ball, Andrew S., Yeo, Leslie Y., White, Jacinta F., Wang, Zhihui, Cristini, Vittorio, Jagannath, Chinnaswamy, Khan, Arshad, Soni, Sarvesh K., Drummond, Calum J., and Conn, Charlotte E.

Abstract

An improved vaccine is urgently needed to replace the now more than 100-year-old Bacillus Calmette–Guérin (BCG) vaccine against tuberculosis (TB) disease, which represents a significant burden on global public health. Mycolic acid, or cord factor trehalose 6,6′ dimycolate (TDM), a lipid component abundant in the cell wall of the pathogen Mycobacterium tuberculosis(MTB), has been shown to have strong immunostimulatory activity but remains underexplored due to its high toxicity and poor solubility. Herein, we employed a novel strategy to encapsulate TDM within a cubosome lipid nanocarrier as a potential subunit nanovaccine candidate against TB. This strategy not only increased the solubility and reduced the toxicity of TDM but also elicited a protective immune response to control MTB growth in macrophages. Both pre-treatment and concurrent treatment of the TDM encapsulated in lipid monoolein (MO) cubosomes (MO–TDM) (1 mol %) induced a strong proinflammatory cytokine response in MTB-infected macrophages, due to epigenetic changes at the promoters of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in comparison to the untreated control. Furthermore, treatment with MO–TDM (1 mol %) cubosomes significantly improved antigen processing and presentation capabilities of MTB-infected macrophages to CD4 T cells. The ability of MO–TDM (1 mol %) cubosomes to induce a robust innate and adaptive response in vitro was further supported by a mathematical modeling study predicting the vaccine efficacy in vivo. Overall, these results indicate a strong immunostimulatory effect of TDM when delivered through the lipid nanocarrier, suggesting its potential as a novel TB vaccine.

Published
2023
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44. Preferred orientation and its effects on intensity-correlation measurements

Author

Binns, Jack, primary, Darmanin, Connie, additional, Kewish, Cameron M., additional, Pathirannahalge, Sachini Kadaoluwa, additional, Berntsen, Peter, additional, Adams, Patrick L. R., additional, Paporakis, Stefan, additional, Wells, Daniel, additional, Roque, Francisco Gian, additional, Abbey, Brian, additional, Bryant, Gary, additional, Conn, Charlotte E., additional, Mudie, Stephen T., additional, Hawley, Adrian M., additional, Ryan, Timothy M., additional, Greaves, Tamar L., additional, and Martin, Andrew V., additional

Published
2022
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46. Protective effect of surfactant modified phytosterol oleogels on loaded curcumin.

Author

Li, Junhua, Zhai, Jiali, Chang, Cuihua, Yang, Yanjun, Drummond, Calum J., and Conn, Charlotte E.

Subjects
PHYTOSTEROLS, CURCUMIN, COCONUT oil, X-ray scattering, SURFACE active agents, X-ray microscopy, CHEMICAL stability, MICROSCOPY
Abstract

BACKGROUND: Oleogels represent one of the most important carriers for the delivery of lipophilic nutraceuticals. Phytosterols (PS), plant‐derived natural sterol compounds, are preferred for oleogel preparation due to their self‐assembly properties and health function. However, the relationship between the physical properties of PS‐based oleogels and the chemical stability of loaded bioactive compounds is still unclear. RESULTS: The influence of lecithin (LC) and glycerol monostearate (GMS) on the physical properties of PS‐based oleogels made of liquid coconut oil and the stability of curcumin as a model bioactive loaded in the oleogels was investigated. Results showed that the flow consistency index was much higher for GMS‐containing oleogels than that for LC‐containing oleogels. The optical microscopy and X‐ray scattering analysis showed that the addition of GMS in the PS oleogels promoted the formation of a crystal mixture with different crystal polymorph structures, whereas LC addition promoted the formation of needle‐like crystals of PS. Using curcumin as a model lipophilic nutraceutical, the GMS‐enriched PS oleogels with high crystallinity and flow consistency index exhibited a good retention ratio and scavenging activity of the loaded curcumin when stored at room temperature. CONCLUSION: This study shows that enhancing the firmness of oleogels made from PS and liquid coconut oil is beneficial to the retention and chemical stability of a loaded bioactive (curcumin). The findings of the study will boost the development of PS‐based oleogel formulations for lipophilic nutraceutical delivery. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Published
2023
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50. Targeted delivery of LM22A-4 by cubosomes protects retinal ganglion cells in an experimental glaucoma model

Author

Ding, Yue, primary, Chow, Seong H., additional, Chen, Jinying, additional, Brun, Anton P. Le, additional, Wu, Chun-Ming, additional, Duff, Anthony P., additional, Wang, Yajun, additional, Song, Jiangning, additional, Wang, Jiang-Hui, additional, Wong, Vickie H.Y., additional, Zhao, Da, additional, Nishimura, Tomoharu, additional, Lee, Tzong-Hsien, additional, Conn, Charlotte E., additional, Hsu, Hsien-Yi, additional, Bui, Bang V., additional, Liu, Guei-Sheung, additional, and Shen, Hsin-Hui, additional

Published
2021
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