Cubosome
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The development of nanomedicines for the treatment of neurodegenerative disorders demands innovative nanoarchitectures for combined loading of multiple neuroprotective compounds. We report dual-drug loaded monoolein-based liquid crystalline architectures designed for the encapsulation of a therapeutic protein and a small molecule antioxidant. Catalase (CAT) is chosen as a metalloprotein, which provides enzymatic defense against oxidative stress caused by reactive oxygen species (ROS) such as hydrogen peroxide (H2O2). Curcumin (CU), solubilized in fish oil, is co-encapsulated as a chosen drug with multiple therapeutic activities, which may favor neuro-regeneration. The prepared self-assembled biomolecular nanoarchitectures are characterized by biological synchrotron small-angle X-ray scattering (BioSAXS) at multiple compositions of the lipid/co-lipid/water phase diagram. Constant fractions of curcumin (an antioxidant) and a PEGylated agent (TPEG1000) are included with regard to the lipid fraction. Stable cubosome architectures are obtained for several ratios of the lipid ingredients monoolein (MO) and fish oil (FO). The impact of catalase on the structural organization of the cubosome nanocarriers is revealed by the variations of the cubic lattice parameters deduced by BioSAXS. The outcome of the cellular uptake of the dual drug-loaded nanocarriers is assessed by performing a bioassay of catalase peroxidatic activity in lysates of nanoparticle-treated differentiated SH-SY5Y human cells. The obtained results reveal the neuroprotective potential of the in vitro studied cubosomes in terms of enhanced peroxidatic activity of the catalase enzyme, which enables the inhibition of H2O2 accumulation in degenerating neuronal cells.
- MeSH
- kapalné krystaly chemie MeSH
- katalasa chemie MeSH
- kurkumin chemie MeSH
- lidé MeSH
- maloúhlový rozptyl MeSH
- nanostruktury chemie MeSH
- peroxid vodíku chemie MeSH
- polyethylenglykoly chemie MeSH
- reaktivní formy kyslíku MeSH
- synchrotrony MeSH
- zobrazování trojrozměrné MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Lipid nitroalkenes - nitro-fatty acids (NO2-FAs) are formed in vivo via the interaction of reactive nitrogen species with unsaturated fatty acids. The resulting electrophilic NO2-FAs play an important role in redox homeostasis and cellular stress response. This study investigated the physicochemical properties and reactivity of two NO2-FAs: 9/10-nitrooleic acid (1) and its newly prepared 1-monoacyl ester, (E)-2,3-hydroxypropyl 9/10-nitrooctadec-9-enoate (2), both synthesized by a direct radical nitration approach. Compounds 1 and 2 were investigated in an aqueous medium and after incorporation into lipid nanoparticles prepared from 1-monoolein, cubosomes 1@CUB and 2@CUB. Using an electrochemical analysis and LC-MS, free 1 and 2 were found to be unstable under acidic conditions, and their degradation occurred in an aqueous environment within a few minutes or hours. This degradation was associated with the production of the NO radical, as confirmed by fluorescence assay. In contrast, preparations 1@CUB and 2@CUB exhibited a significant increase in the stability of the loaded 1 and 2 up to several days to weeks. In addition to experimental data, density functional theory-based calculation results on the electronic structure and structural variability (open and closed configuration) of 1 and 2 were obtained. Finally, experiments with a human HaCaT keratinocyte cell line demonstrated the ability of 1@CUB and 2@CUB to penetrate through the cytoplasmic membrane and modulate cellular pathways, which was exemplified by the Keap1 protein level monitoring. Free 1 and 2 and the cubosomes prepared from them showed cytotoxic effect on HaCaT cells with IC50 values ranging from 1 to 8 μM after 24 h. The further development of cubosomal preparations with embedded electrophilic NO2-FAs may not only contribute to the field of fundamental research, but also to their application using an optimized lipid delivery vehicle.
- MeSH
- dusíkaté sloučeniny MeSH
- faktor 2 související s NF-E2 MeSH
- KEAP-1 MeSH
- lidé MeSH
- mastné kyseliny * MeSH
- oxid dusnatý * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The present work highlights recent achievements in development of nanostructured dispersions and biocolloids for drug delivery applications. We emphasize the key role of biological small-angle X-ray scattering (BioSAXS) investigations for the nanomedicine design. A focus is given on controlled encapsulation of small molecular weight phytochemical drugs in lipid-based nanocarriers as well as on encapsulation of macromolecular siRNA, plasmid DNA, peptide and protein pharmaceuticals in nanostructured nanoparticles that may provide efficient intracellular delivery and triggered drug release. Selected examples of utilisation of the BioSAXS method for characterization of various types of liquid crystalline nanoorganizations (liposome, spongosome, cubosome, hexosome, and nanostructured lipid carriers) are discussed in view of the successful encapsulation and protection of phytochemicals and therapeutic biomolecules in the hydrophobic or the hydrophilic compartments of the nanocarriers. We conclude that the structural design of the nanoparticulate carriers is of crucial importance for the therapeutic outcome and the triggered drug release from biocolloids.
- MeSH
- difrakce rentgenového záření MeSH
- fytonutrienty chemie farmakologie MeSH
- hydrofobní a hydrofilní interakce MeSH
- koloidy MeSH
- lidé MeSH
- malá interferující RNA genetika metabolismus MeSH
- maloúhlový rozptyl MeSH
- nanočástice chemie MeSH
- nosiče léků * MeSH
- peptidy chemie metabolismus MeSH
- plazmidy chemie metabolismus MeSH
- příprava léků metody MeSH
- protinádorové látky chemie farmakologie MeSH
- uvolňování léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Lipid nanocarriers are among the most employed systems for drug delivery purposes in several research and industrial sectors, since their favorable properties ensure broad applicability. The design and characterization of these nanosystems are of paramount importance to obtain controlled outcome, since the supramolecular structure and molecular interactions deeply impact the functionality of the resulting aggregates. The choice of the most appropriate formulation for the target of interest relies on in-depth physico-chemical characterization in order to optimize stability, loading rates and sustained release. Several supramolecular architectures suited for carrier development can be obtained from lipid building blocks, by varying lipid composition and packing parameter. In particular, cubosome and liposome aggregates are often used as drug vectors thanks to their high cargo capability and biocompatibility. Moreover, the possibility to employ lipids from natural sources i.e. biomasses to prepare nanosystems makes them especially attractive. In this work, two aggregate types were characterized and compared as drug vectors for poorly water-soluble antioxidants, particularly curcumin and two adjuvants (i.e. tocopherol and piperine). The nanovectors were obtained by extracting lipids from algal biomasses with different lipid composition, and characterized by advanced structural (DLS, SAXS, Cryo-TEM) techniques, spectroscopy (NMR) and calorimetry (ITC). Finally, the structural stability of both aggregate types was evaluated.
Structural properties of plasmenyl-glycerophospholipids (plasmalogens) have been scarcely studied for plasmalogens with long polyunsaturated fatty acid (PUFA) chains, despite of their significance for the organization and functions of the cellular membranes. Elaboration of supramolecular assemblies involving PUFA-chain plasmalogens in nanostructured mixtures with lyotropic lipids may accelerate the development of nanomedicines for certain severe pathologies (e.g., peroxisomal disorders, cardiometabolic impairments, and neurodegenerative Alzheimer's and Parkinson's diseases). Here, we investigate the spontaneous self-assembly of bioinspired, custom-produced docosapentaenoyl (DPA) plasmenyl (ether) and ester phospholipids in aqueous environment (pH 7) by synchrotron small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM). A coexistence of a liquid crystalline primitive cubic Im3m phase and an inverted hexagonal (HII) phase is observed for the DPA-ethanolamine plasmalogen (C16:1p-22:5n6 PE) derivative. A double-diamond cubic Pn3m phase is formed in mixed assemblies of the phosphoethanolamine plasmalogen (C16:1p-22:5n6 PE) and monoolein (MO), whereas a coexistence of cubic and lamellar liquid crystalline phases is established for the DPA-plasmenyl phosphocholine (C16:1p-22:5n6 PC)/MO mixture at ambient temperature. The DPA-diacyl phosphoinositol (22:5n6-22:5n6 PI) ester lipid displays a propensity for a lamellar phase formation. Double membrane vesicles and multilamellar onion topologies with inhomogeneous distribution of interfacial curvature are formed upon incorporation of the phosphoethanolamine plasmalogen (C16:1p-22:5n6 PE) into dioleoylphosphocholine (DOPC) bilayers. Nanoparticulate formulations of plasmalogen-loaded cubosomes, hexosomes, and various multiphase cubosome- and hexosome-derived architectures and mixed type nano-objects (e.g., oil droplet-embedding vesicles or core-shell particles with soft corona) are produced with PUFA-chain phospholipids and lipophilic antioxidant-containing membrane compositions that are characterized by synchrotron SAXS and cryo-TEM imaging. The obtained multiphase nanostructures reflect the changes in the membrane curvature induced by the inclusion of DPA-based PE and PC plasmalogens, as well as DPA-PI ester derivative, and open new opportunities for exploration of these bioinspired nanoassemblies.
- Publikační typ
- časopisecké články MeSH
Nanomedicine for treating post-viral infectious disease syndrome is at an emerging stage. Despite promising results from preclinical studies on conventional antioxidants, their clinical translation as a therapy for treating post-COVID conditions remains challenging. The limitations are due to their low bioavailability, instability, limited transport to the target tissues, and short half-life, requiring frequent and high doses. Activating the immune system during coronavirus (SARS-CoV-2) infection can lead to increased production of reactive oxygen species (ROS), depleted antioxidant reserve, and finally, oxidative stress and neuroinflammation. To tackle this problem, we developed an antioxidant nanotherapy based on lipid (vesicular and cubosomal types) nanoparticles (LNPs) co-encapsulating ginkgolide B and quercetin. The antioxidant-loaded nanocarriers were prepared by a self-assembly method via hydration of a lyophilized mixed thin lipid film. We evaluated the LNPs in a new in vitro model for studying neuronal dysfunction caused by oxidative stress in coronavirus infection. We examined the key downstream signaling pathways that are triggered in response to potassium persulfate (KPS) causing oxidative stress-mediated neurotoxicity. Treatment of neuronally-derived cells (SH-SY5Y) with KPS (50 mM) for 30 min markedly increased mitochondrial dysfunction while depleting the levels of both glutathione peroxidase (GSH-Px) and tyrosine hydroxylase (TH). This led to the sequential activation of apoptotic and necrotic cell death processes, which corroborates with the crucial implication of the two proteins (GSH-Px and TH) in the long-COVID syndrome. Nanomedicine-mediated treatment with ginkgolide B-loaded cubosomes and vesicular LNPs showed minimal cytotoxicity and completely attenuated the KPS-induced cell death process, decreasing apoptosis from 32.6% (KPS) to 19.0% (MO-GB), 12.8% (MO-GB-Quer), 14.8% (DMPC-PEG-GB), and 23.6% (DMPC-PEG-GB-Quer) via free radical scavenging and replenished GSH-Px levels. These findings indicated that GB-LNPs-based nanomedicines may protect against KPS-induced apoptosis by regulating intracellular redox homeostasis.
- MeSH
- antioxidancia * farmakologie MeSH
- COVID-19 metabolismus MeSH
- farmakoterapie COVID-19 * MeSH
- ginkgolidy * farmakologie MeSH
- glutathionperoxidasa * metabolismus MeSH
- laktony farmakologie MeSH
- lidé MeSH
- nanočástice * MeSH
- nanomedicína * metody MeSH
- neurony účinky léků virologie MeSH
- oxidační stres * účinky léků MeSH
- quercetin farmakologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- SARS-CoV-2 účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
