Nejvíce citovaný článek - PubMed ID 24742149
Multicompartment lipid cubic nanoparticles with high protein upload: millisecond dynamics of formation
Enabling challenging applications of nanomedicine and precision medicine in the treatment of neurodegenerative disorders requires deeper investigations of nanocarrier-mediated biomolecular delivery for neuronal targeting and recovery. The successful use of macromolecular biotherapeutics (recombinant growth factors, antibodies, enzymes, synthetic peptides, cell-penetrating peptide-drug conjugates, and RNAi sequences) in clinical developments for neuronal regeneration should benefit from the recent strategies for enhancement of their bioavailability. We highlight the advances in the development of nanoscale materials for drug delivery in neurodegenerative disorders. The emphasis is placed on nanoformulations for the delivery of brain-derived neurotrophic factor (BDNF) using different types of lipidic nanocarriers (liposomes, liquid crystalline or solid lipid nanoparticles) and polymer-based scaffolds, nanofibers and hydrogels. Self-assembled soft-matter nanoscale materials show favorable neuroprotective characteristics, safety, and efficacy profiles in drug delivery to the central and peripheral nervous systems. The advances summarized here indicate that neuroprotective biomolecule-loaded nanoparticles and injectable hydrogels can improve neuronal survival and reduce tissue injury. Certain recently reported neuronal dysfunctions in long-COVID-19 survivors represent early manifestations of neurodegenerative pathologies. Therefore, BDNF delivery systems may also help in prospective studies on recovery from long-term COVID-19 neurological complications and be considered as promising systems for personalized treatment of neuronal dysfunctions and prevention or retarding of neurodegenerative disorders.
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.
- Klíčová slova
- SAXS, cryo-TEM, docosapentaenoyl phospholipids, hexosomes, inverted hexagonal phase, lipid cubic phase, plasmalogen-loaded cubosomes,
- Publikační typ
- časopisecké články MeSH
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.
- Klíčová slova
- BioSAXS, catalase, cubosome, curcumin, fish oil, liquid crystalline nanoparticles, peroxidatic activity of catalase,
- 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
- Názvy látek
- katalasa MeSH
- kurkumin MeSH
- peroxid vodíku MeSH
- polyethylene glycol 1000 MeSH Prohlížeč
- polyethylenglykoly MeSH
- reaktivní formy kyslíku MeSH
Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are bioactive lipids with considerable impact in medicine and nutrition. These compounds exert structuring effects on the cellular membrane organization, regulate the gene expression, and modulate various signaling cascades and metabolic processes. The purpose of the present work is to demonstrate the structural features of ω-3 PUFA-containing three-dimensional supramolecular lipid assemblies suitable for pharmaceutical applications that require soft porous carriers. We investigate the liquid crystalline structures formed upon mixing of eicosapentaenoic acid (EPA, 20:5) with the lyotropic nonlamellar lipid monoolein and the formation of multicompartment assemblies. Starting with the monoolein-based lipid cubic phase, double membrane vesicles, cubosome precursors, sponge-type particles (spongosomes), mixed intermediate nonlamellar structures, and multicompartment assemblies are obtained through self-assembly at different amphiphilic compositions. The dispersions containing spongosomes as well as nanocarriers with oil and vesicular compartments are stabilized by PEGylation of the lipid/water interfaces using a phospholipid with a poly(ethylene glycol) chain. The microstructures of the bulk mixtures were examined by cross-polarized light optical microscopy. The dispersed liquid crystalline structures and intermediate states were studied by small-angle X-ray scattering, cryogenic transmission electron microscopy, and quasielastic light scattering techniques. They established that PUFA influences the phase type and the sizes of the aqueous compartments of the liquid crystalline carriers. The resulting multicompartment systems and stealth nanosponges may serve as mesoporous reservoirs for coencapsulation of ω-3 PUFA (e.g., EPA) with water-insoluble drugs and hydrophilic macromolecules toward development of combination treatment strategies of neurodegenerative and other diseases.
- Publikační typ
- časopisecké články MeSH
Among the macromolecular drug targets in neurodegenerative disorders, the neurotrophin brain-derived neurotrophic factor (BDNF) and its high-affinity tropomyosin-related kinase receptor (TrkB) present strong interest for nanomedicine development aiming at neuronal and synaptic repair. Currently, BDNF is regarded as the neurotrophic factor of highest therapeutic significance. However, BDNF has delivery problems as a protein drug. The enhanced activation of the transcription factor CREB (cAMP response element-binding protein) has been evidenced to increase the BDNF gene expression and hence the production of endogenous BDNF. We assume that BDNF delivery by nanocarriers and mitochondrial protection may provide high potential for therapeutic amelioration of the neuroregenerative strategies. Beneficial therapeutic outcomes may be expected for synergistic dual or multi-drug action aiming at (i) neurotrophic protein regulation in the central and peripheral nervous systems, and (ii) diminishment of the production of reactive oxygen species (ROS) and the oxidative damage in mitochondria. Our research strategy is based on a nanoarchitectonics approach for the design of nanomedicine assemblies by hierarchical self-assembly. We explore nanoarchitectonics concepts in soft-matter nanotechnology towards preparation of biodegradable self-assembled lipid nanostructures for safe neuro-therapeutic applications of multi-target nanomedicines.
- Klíčová slova
- BDNF delivery, CREB, combination therapy, macromolecular drugs, nanomedicine, neuroprotective lipid nanocarriers, neurotrophic factor,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
