| 1. |
- Jõemetsa, Silver, 1990, et al.
(author)
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Independent Size and Fluorescence Emission Determination of Individual Biological Nanoparticles Reveals that Lipophilic Dye Incorporation Does Not Scale with Particle Size
- 2020
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In: Langmuir. - : American Chemical Society (ACS). - 1520-5827 .- 0743-7463. ; 36:33, s. 9693-9700
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Journal article (peer-reviewed)abstract
- Advancements in nanoparticle characterization techniques are critical for improving the understanding of how biological nanoparticles (BNPs) contribute to different cellular processes, such as cellular communication, viral infection, as well as various drug-delivery applications. Since BNPs are intrinsically heterogeneous, there is a need for characterization methods that are capable of providing information about multiple parameters simultaneously, preferably at the single-nanoparticle level. In this work, fluorescence microscopy was combined with surface-based two-dimensional flow nanometry, allowing for simultaneous and independent determination of size and fluorescence emission of individual BNPs. In this way, the dependence of the fluorescence emission of the commonly used self-inserting lipophilic dye 3,3′-dioctadecyl-5,5′-di(4-sulfophenyl)oxacarbocyanine (SP-DiO) could successfully be correlated with nanoparticle size for different types of BNPs, including synthetic lipid vesicles, lipid vesicles derived from cellular membrane extracts, and extracellular vesicles derived from human SH-SY5Y cell cultures; all vesicles had a radius, r, of ∼50 nm and similar size distributions. The results demonstrate that the dependence of fluorescence emission of SP-DiO on nanoparticle size varies significantly between the different types of BNPs, with the expected dependence on membrane area, r2, being observed for synthetic lipid vesicles, while a significant weaker dependence on size was observed for BNPs with more complex composition. The latter observation is attributed to a size-dependent difference in membrane composition, which may influence either the optical properties of the dye and/or the insertion efficiency, indicating that the fluorescence emission of this type of self-inserting dye may not be reliable for determining size or size distribution of BNPs with complex lipid compositions.
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| 2. |
- Dening, Tahnee J., et al.
(author)
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Improving Correlations Between Drug Solubilization and In Vitro Lipolysis by Monitoring the Phase Partitioning of Lipolytic Species for Lipid-Based Formulations
- 2019
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In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 1520-6017 .- 0022-3549. ; 108:1, s. 295-304
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Journal article (peer-reviewed)abstract
- Solution proton nuclear magnetic resonance analysis was used in conjunction with in vitro lipolysis to elucidate the time-dependent speciation and release of lipolytic products during the digestion of lipid-loaded inorganic particles, allowing correlations to be made between the phase partitioning of lipolytic products and an encapsulated poorly soluble drug. Silicon dioxide, montmorillonite, and laponite were used to encapsulate medium chain triglycerides into solid-state lipid-based formulations (LBFs), and coumarin 102 was selected as a model poorly soluble compound. The specific inorganic carrier material used to encapsulate medium chain triglycerides significantly impacted the release and partitioning of the solubilizing lipolytic products, that is, diglycerides, monoglycerides, and fatty acids. A strong linear correlation was obtained between drug solubilization and fatty acid release to the aqueous phase (R2 = 0.996), indicating fatty acids to be the most important lipid species for enabling solubilization and potential drug absorption in vivo. This method was developed to improve upon the use of pH-stat titration for characterizing LBF digestion during in vitro lipolysis studies and is demonstrated herein to provide useful insights into how the selected inorganic carrier material impacts LBF performance when solid-state LBF powders are fabricated via adsorption.
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| 3. |
- Dening, Tahnee J., et al.
(author)
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Inorganic surface chemistry and nanostructure controls lipolytic product speciation and partitioning during the digestion of inorganic-lipid hybrid particles
- 2018
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In: Journal of Colloid and Interface Science. - : Elsevier BV. - 1095-7103 .- 0021-9797. ; 532, s. 666-679
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Journal article (peer-reviewed)abstract
- Hypothesis: Solid-state lipid formulations, whereby liquid lipids are encapsulated in inorganic particle matrices, have attracted significant interest for drug/nutrient delivery in recent years. We hypothesized that the surface chemistry of the inorganic material used to encapsulate lipids impacts the lipase-mediated digestion and partitioning of lipolytic species between the solubilized aqueous and insoluble pellet phases. Experiments: Medium chain triglycerides were spray dried with silica nanoparticles, montmorillonite or laponite platelets to form inorganic-lipid hybrid particles. In vitro lipolysis studies were conducted under gastric (pH 1.6) and intestinal (pH 7.5) conditions, and the speciation and partitioning of lipolytic products between the aqueous and pellet phases was characterized using solution-state proton nuclear magnetic resonance and fourier transform infrared spectroscopy. Findings: Under gastric conditions, greater than 80% of all lipid species remained adsorbed within each lipolysis pellet after 60 min. Approximately 40%, 50–60% and 80–90% of all lipid species were adsorbed from solution by silica-, montmorillonite- and laponite-based particle matrices during intestinal lipolysis. Monoglycerides were preferentially adsorbed by silica, whereas triglycerides and fatty acids were adsorbed by montmorillonite and laponite. Adsorption of lipolytic products from solution is expected to impact significantly on drug/nutrient solubilization and absorption in vivo. To the best of our knowledge, this is the first report characterizing the speciation and phase behavior of lipolytic products released from solid-state lipid formulations during in vitro lipolysis studies.
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| 4. |
- Hedge, Oliver, 1991-, et al.
(author)
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Investigation of Self-Emulsifying Drug-Delivery System Interaction with a Biomimetic Membrane under Conditions Relevant to the Small Intestine
- 2021
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In: Langmuir. - : American Chemical Society (ACS). - 1520-5827 .- 0743-7463. ; 37:33, s. 10200-10213
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Journal article (peer-reviewed)abstract
- Self-emulsifying drug-delivery systems (SEDDS) have been extensively shown to increase oral absorption of solvation-limited compounds. However, there has been little clinical and commercial use of these formulations, in large part because the demonstrated advantages of SEDDS have been outweighed by our inability to precisely predict drug absorption from SEDDS using current in vitro assays. To overcome this limitation and increase the biological relevancy of in vitro assays, an absorption function can be incorporated using biomimetic membranes. However, the effects that SEDDS have on the integrity of a biomimetic membrane are not known. In this study, a quartz crystal microbalance with dissipation monitoring and total internal reflection fluorescence microscopy were employed as complementary methods to in vitro lipolysis-permeation assays to characterize the interaction of various actively digested SEDDS with a liquescent artificial membrane comprising lecithin in dodecane (LiDo). Observations from surface analysis showed that interactions between the digesting SEDDS and LiDo membrane coincided with inflection points in the digestion profiles. Importantly, no indications of membrane damage could be observed, which was supported by flux profiles of the lipophilic model drug felodipine (FEL) and impermeable marker Lucifer yellow on the basal side of the membrane. There was a correlation between the digestion kinetics of the SEDDS and the flux of FEL, but no clear correlation between solubilization and absorption profiles. Membrane interactions were dependent on the composition of lipids within each SEDDS, with the more digestible lipids leading to more pronounced interactions, but in all cases, the integrity of the membrane was maintained. These insights demonstrate that LiDo membranes are compatible with in vitro lipolysis assays for improving predictions of drug absorption from lipid-based formulations.
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| 5. |
- Hossain, Shakhawath, et al.
(author)
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Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers
- 2020
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In: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8392 .- 1543-8384. ; 17:11, s. 4226-4240
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Journal article (peer-reviewed)abstract
- Transient permeability enhancers (PEs), such as caprylate, caprate, and salcaprozate sodium (SNAC), improve the bioavailability of poorly permeable macromolecular drugs. However, the effects are variable across individuals and classes of macromolecular drugs and biologics. Here, we examined the influence of bile compositions on the ability of membrane incorporation of three transient PEs-caprylate, caprate, and SNAC-using coarse-grained molecular dynamics (CG-MD). The availability of free PE monomers, which are important near the absorption site, to become incorporated into the membrane was higher in fasted-state fluids than that in fed-state fluids. The simulations also showed that transmembrane perturbation, i.e., insertion of PEs into the membrane, is a key mechanism by which caprylate and caprate increase permeability. In contrast, SNAC was mainly adsorbed onto the membrane surface, indicating a different mode of action. Membrane incorporation of caprylate and caprate was also influenced by bile composition, with more incorporation into fasted- than fed-state fluids. The simulations of transient PE interaction with membranes were further evaluated using two experimental techniques: the quartz crystal microbalance with dissipation technique and total internal reflection fluorescence microscopy. The experimental results were in good agreement with the computational simulations. Finally, the kinetics of membrane insertion was studied with CG-MD. Variation in micelle composition affected the insertion rates of caprate monomer insertion and expulsion from the micelle surface. In conclusion, this study suggests that the bile composition and the luminal composition of the intestinal fluid are important factors contributing to the interindividual variability in the absorption of macromolecular drugs administered with transient PEs.
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| 6. |
- Joyce, Paul, 1989, et al.
(author)
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Engineering intelligent particle-lipid composites that control lipase-mediated digestion
- 2018
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In: Advances in Colloid and Interface Science. - : Elsevier BV. - 0001-8686. ; 260, s. 1-23
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Research review (peer-reviewed)abstract
- Nanostructured particle-lipid composites have emerged as state-of-the-art carrier systems for poorly water-soluble bioactive molecules due to their ability to control and enhance the lipase-mediated hydrolysis of encapsulated triglycerides, leading to a subsequent improvement in the solubilisation and absorption of encapsulated species. The first generation of particle-lipid composites (i.e. silica-lipid hybrid (SLH) microparticles) were designed and fabricated by spray drying a silica nanoparticle-stabilised Pickering emulsion, to create a novel three-dimensional architecture, whereby lipid droplets were encapsulated within a porous matrix support. The development of SLH microparticles has acted as a solid foundation for the synthesis of several next generation particle-lipid composites, including polymer-lipid hybrid (PLH) and clay-lipid hybrid systems (CLH), which present lipase with unique lipid microenvironments for optimised lipolysis. This review details the methods utilised to engineer lipid hybrid particles and the strategic investigations that have been performed to determine the influence of key material characteristics on digestion enzyme activity. In doing so, this provides insight into manipulating the mechanism of lipase action through the intelligent design of lipid-based biomaterials for their use in drug delivery formulations and novel functional foods.
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| 7. |
- Joyce, Paul, 1989, et al.
(author)
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Enhancing the cellular uptake and antibacterial activity of rifampicin through encapsulation in mesoporous silica nanoparticles
- 2020
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In: Nanomaterials. - : MDPI AG. - 2079-4991. ; 10:4
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Journal article (peer-reviewed)abstract
- An urgent demand exists for the development of novel delivery systems that efficiently transport antibacterial agents across cellular membranes for the eradication of intracellular pathogens. In this study, the clinically relevant poorly water-soluble antibiotic, rifampicin, was confined within mesoporous silica nanoparticles (MSN) to investigate their ability to serve as an efficacious nanocarrier system against small colony variants of Staphylococcus aureus (SCV S. aureus) hosted within Caco-2 cells. The surface chemistry and particle size of MSN were varied through modifications during synthesis, where 40 nm particles with high silanol group densities promoted enhanced cellular uptake. Extensive biophysical analysis was performed, using quartz crystal microbalance with dissipation (QCM-D) and total internal reflection fluorescence (TIRF) microscopy, to elucidate the mechanism of MSN adsorption onto semi-native supported lipid bilayers (snSLB) and, thus, uncover potential cellular uptake mechanisms of MSN into Caco-2 cells. Such studies revealed that MSN with reduced silanol group densities were prone to greater particle aggregation on snSLB, which was expected to restrict endocytosis. MSN adsorption and uptake into Caco-2 cells correlated well with antibacterial efficacy against SCV S. aureus, with 40 nm hydrophilic particles triggering a ~2.5-log greater reduction in colony forming units, compared to the pure rifampicin. Thus, this study provides evidence for the potential to design silica nanocarrier systems with controlled surface chemistries that can be used to re-sensitise intracellular bacteria to antibiotics by delivering them to the site of infection.
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| 8. |
- Joyce, Paul, 1989, et al.
(author)
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Modulating the Lipase-Mediated Bioactivity of Particle-Lipid Conjugates Through Changes in Nanostructure and Surface Chemistry
- 2017
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In: European Journal of Lipid Science and Technology. - : Wiley. - 1438-7697 .- 1438-9312. ; 119:12, s. 1700213-
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Journal article (peer-reviewed)abstract
- The lipase-mediated hydrolysis of triglycerides can be controlled by confining lipid droplets within highly porous nanostructured particle matrices. Novel hybrid materials with varying bioactivities toward lipase have been developed by spray drying particle-stabilized emulsions to form highly organized three-dimensional architectures. In this study, the particle size, nanostructure, and surface chemistry of hybrid particles are tailored to systematically investigate the influence of material characteristics on lipase activity. This is achieved by varying (i) the spray drying process and (ii) the structure and composition of particulate colloids employed to stabilize the precursor emulsions. In all cases, the colloidal self-assembly of particles and droplets into nanostructured conjugates during the water removal process facilitated enhanced lipase activity compared to submicron triglyceride emulsions, with lipolysis kinetics increasing in the following order: polymer-lipid hybrid (PLH)
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| 9. |
- Joyce, Paul, 1989, et al.
(author)
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Nanostructured clay particles supplement orlistat action in inhibiting lipid digestion: An in vitro evaluation for the treatment of obesity
- 2019
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In: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 135, s. 1-11
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Journal article (peer-reviewed)abstract
- Obesity is a rapidly growing epidemic, with over one-third of the global population classified as overweight or obese. Consequently, an urgent need exists to develop innovative approaches and technologies that regulate energy uptake, to curb the rising trend in obesity statistics. In this study, nanostructured clay (NSC)particles, fabricated by spray drying delaminated dispersions technologies that regulate energy uptake, to curb the rising trend in obesity statistics. In this study, nanostructured clay (NSC)particles, fabricated by spray drying delaminated dispersions of commercial clay platelets (Veegum® HS and LAPONITE® XLG), were delivered as complimentary, bioactive excipients with the potent lipase inhibitor, orlistat, for the inhibition of fat (lipid)hydrolysis. Simulated intestinal lipolysis studies were performed by observing changes in free fatty acid concentration and revealed that a combinatorial effect existed when NSC particles were co-administered with orlistat, as evidenced by a 1.2- to 1.6-fold greater inhibitory response over 60 min, compared to dosing orlistat alone. Subsequently, it was determined that a multifaceted approach to lipolysis inhibition was presented, whereby NSC particles adsorbed high degrees of lipid (up to 80% of all lipid species present in lipolysis media)and thus physically shielded the lipid-in-water interface from lipase access, while orlistat covalently attached and blocked the lipase enzyme active site. Thus, the ability for NSC particles to enhance the biopharmaceutical performance and potency of orlistat is hypothesised to translate into promising in vivo pharmacodynamics, where this novel approach is predicted to lead to considerably greater weight reductions for obese patients, compared to dosing orlistat alone.
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| 10. |
- Joyce, Paul, 1989, et al.
(author)
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Polymer lipid hybrid (PLH) formulations: A synergistic approach to oral delivery of challenging therapeutics. A synergistic approach to oral delivery of challenging therapeutics
- 2020
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In: Delivery of Drugs: Volume 2: Expectations and Realities of Multifunctional Drug Delivery Systems. ; , s. 1-27
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Book chapter (other academic/artistic)abstract
- In recent decades, lipid-based formulations and polymeric systems have emerged concurrently as the predominant approaches for overcoming low gastrointestinal stability/solubility and rate-limiting dissolution drawbacks that are associated with a wide range of therapeutics, including lipophilic small molecules and sensitive macromolecules. While these conventional approaches have demonstrated the ability to overcome drug absorption barriers and subsequently improve oral biopharmaceutical performance, a number of fundamental limitations have restricted the translation of promising preclinical and clinical findings into commercial success. Furthermore, the increasing complexity of novel therapeutics has amplified the demand for innovative and intelligent carrier systems that effectively transport drug molecules to the primary site of absorption. Consequently, recent focus has been attributed to designing and engineering polymer-lipid hybrid (PLH) formulations that combine the solubilization capacity of lipids with the stabilizing matrix of polymeric systems. This presents a synergistic approach to oral drug delivery with proven potential for overcoming limitations associated with the precursor systems. This chapter focuses specifically on the development of PLH systems, with emphasis placed on the relationship between nanostructure/surface chemistry and the physicochemical and biopharmaceutical performance of the hybrid formulation.
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