Liposomes are lipid‐based nanoparticles that have been used to deliver encapsulated drugs for a variety of applications, including treatment of life‐threatening fungal infections. By understanding the effect of composition on liposome interactions with both fungal and mammalian cells, new effective antifungal liposomes can be developed. In this study, we investigated the impact of lipid saturation and cholesterol content on fungal and mammalian cell interactions with liposomes. We used three phospholipids with different saturation levels (saturated hydrogenated soy phosphatidylcholine (HSPC), mono‐unsaturated 1‐palmitoyl‐2‐oleoyl‐glycero‐3‐phosphocholine (POPC), and di‐unsaturated 1‐palmitoyl‐2‐linoleoyl‐sn‐glycero‐3‐phosphocholine (PLPC)) and cholesterol concentrations ranging from 15% to 40% (w/w) in our liposome formulations. Using flow cytometry, >80% of
Molecular interactions of phospholipid monolayers with a model phospholipase
The intrinsic overexpression of secretory phospholipase A2 (sPLA 2 ) in various pro-inflammatory diseases and cancers has the potential to be exploited as a therapeutic strategy for diagnostics and treatment. To explore this potential and advance our knowledge of the role of sPLA 2 in related diseases, it is necessary to systematically investigate the molecular interaction of the enzyme with lipids. By employing a Langmuir trough integrated with X-ray reflectivity and grazing incidence X-ray diffraction techniques, this study examined the molecular packing structure of 1,2-palmitoyl- sn-glycero -3-phosphocholine (DPPC) films before and after enzyme adsorption and enzyme-catalyzed degradation. Molecular interaction of sPLA 2 (from bee venom) with the DPPC monolayer exhibited Ca 2+ dependence. DPPC molecules at the interface without Ca 2+ retained a monolayer organization; upon adsorption of sPLA 2 to the monolayer the packing became tighter. In contrast, sPLA 2 -catalyzed degradation of DPPC occurred in the presence of Ca 2+ , leading to disruption of the ordered monolayer structure of DPPC. The interfacial film became a mixture of highly ordered multilayer domains of palmitic acid (PA) and loosely packed monolayer phase of 1-palmitoyl-2-hydroxy- sn-glycero -3-phosphocholine (lysoPC) that potentially contained the remaining un-degraded DPPC. The redistribution of lipid degradation products into the third dimension, which produced multilayer PA domains, damaged the structural integrity of the original lipid layer and may explain the bursting of liposomes observed in other studies after a latency period of mixing liposomes with sPLA 2 . A quantitative understanding of the lipid packing and lipid-enzyme interaction provides an intuitive means of designing and optimizing lipid-related drug delivery systems.
more »
« less
- Award ID(s):
- 1834750
- PAR ID:
- 10135132
- Date Published:
- Journal Name:
- Soft Matter
- Volume:
- 15
- Issue:
- 20
- ISSN:
- 1744-683X
- Page Range / eLocation ID:
- 4068 to 4077
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract Candida albicans SC5314 cells were found to interact with all liposome formulations developed, while >50% of clinical isolates tested exhibited interaction with these liposomes. In contrast, POPC‐containing formulations exhibited low levels of interaction with murine fibroblasts and human umbilical vein endothelial cells (<30%), while HSPC and PLPC formulations had >50% and >80% interaction, respectively. Further, PLPC formulations caused a significant decrease in mammalian cell viability. Formulations that resulted in low levels of mammalian cell interaction, minimal cytotoxicity, and high levels of fungal cell interaction were then used to encapsulate the antifungal drug, amphotericin B. These liposomes eradicated planktonicC. albicans at drug concentrations lower than free drug, potentially due to the high levels of liposome‐C. albicans interaction. Overall, this study provides new insights into the design of liposome formulations towards the development of new antifungal therapeutics. -
Presented herein is the first report on dipolar Janus liposomes–liposomes that contain opposite surface charges decorating the two hemispheres of the same colloidal body. Such heterogeneous organization of surface charge is achieved through cholesterol-modulated lipid phase separation, which sorts anionic/cationic lipids into coexisting liquid-ordered/liquid-disordered domains. We present optimized experimental conditions to produce these liposomes in high yields, based on the gel-assisted hydration of ternary lipid systems consisting of cholesterol, 1,2-dipalmitoyl- sn-glycero -3-phosphocholine, and 1,2-dioleoyl- sn-glycero -3-phosphocholine. The size/charge distribution and domain configuration of these liposomes are characterized in detail by confocal fluorescence microscopy, nanosphere binding and zeta potential measurements. Using confocal fluorescence microscopy, we also follow the electrokinetic motion as well as the electrostatic self-assembly of these new dipolar Janus particles.more » « less
-
Aggregation of misfolded oligomeric amyloid-beta (Aβ) peptides on lipid membranes has been identified as a primary event in Alzheimer's pathogenesis. However, the structural and dynamical features of this membrane assisted Aβ aggregation have not been well characterized. The microscopic characterization of dynamic molecular-level interactions in peptide aggregation pathways has been challenging both computationally and experimentally. In this work, we explore differential patterns of membrane-induced Aβ 16–22 (K–L–V–F–F–A–E) aggregation from the microscopic perspective of molecular interactions. Physics-based coarse-grained molecular dynamics (CG-MD) simulations were employed to investigate the effect of lipid headgroup charge – zwitterionic (1-palmitoyl-2-oleoyl- sn-glycero -3-phosphocholine: POPC) and anionic (1-palmitoyl-2-oleoyl- sn-glycero -3-phospho- l -serine: POPS) – on Aβ 16–22 peptide aggregation. Our analyses present an extensive overview of multiple pathways for peptide absorption and biomechanical forces governing peptide folding and aggregation. In agreement with experimental observations, anionic POPS molecules promote extended configurations in Aβ peptides that contribute towards faster emergence of ordered β-sheet-rich peptide assemblies compared to POPC, suggesting faster fibrillation. In addition, lower cumulative rates of peptide aggregation in POPS due to higher peptide–lipid interactions and slower lipid diffusion result in multiple distinct ordered peptide aggregates that can serve as nucleation seeds for subsequent Aβ aggregation. This study provides an in-silico assessment of experimentally observed aggregation patterns, presents new morphological insights and highlights the importance of lipid headgroup chemistry in modulating the peptide absorption and aggregation process.more » « less
-
null (Ed.)Antimicrobial pentatopic 2,2′:6′,2′′-terpyridines that form 3-D supramolecular hexagonal prisms with Cd 2+ through coordination driven self-assembly can be entrapped by lipid discoidal bicelles, composed of 1,2-dipalmitoyl- sn-glycero -3-phosphocholine, 1,2-dihexanoyl- sn-glycero -3-phosphocholine and 1,2-dipalmitoyl- sn-glycero -3-phospho-(1′-rac-glycerol) lipid, forming a well-defined nanocomplex. Structural characterization performed by very small angle neutron scattering, small angle X-ray scattering and transmission electron microscopy suggests that the hexagonal prisms are preferably located at the rim of bicellar discs with the hexagonal face in parallel with the bilayers, instead of face-to-face stacking. Such a configuration reduces the π−π interaction and consequently enhances the fluorescence emission. Since novel supramolecules were reported to have antibiotic functions, this study provides insight into the interactions of antimicrobial supermolecules with lipid membranes, leading to potential theranostic applications.more » « less
-
The structure and dynamics of lipid membranes in the presence of extracellular macromolecules are critical for cell membrane functions and many pharmaceutical applications. The pathogen virulence-suppressing end-phosphorylated polyethylene glycol (PEG) triblock copolymer ( Pi-ABAPEG ) markedly changes the interactions with lipid vesicle membranes and prevents PEG-induced vesicle phase separation in contrast to the unphosphorylated copolymer ( ABAPEG ). Pi-ABAPEG weakly absorbs on the surface of lipid vesicle membranes and slightly changes the structure of 1,2-dimyristoyl- sn-glycero -3-phosphocholine ( DMPC ) unilamellar vesicles at 37 °C, as evidenced by small angle neutron scattering. X-ray reflectivity measurements confirm the weak adsorption of Pi-ABAPEG on DMPC monolayer, resulting in a more compact DMPC monolayer structure. Neutron spin-echo results show that the adsorption of Pi-ABAPEG on DMPC vesicle membranes increases the membrane bending modulus κ .more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/C8SM01154K
