Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5976_Библиотеки_им_академика_М_И_Перельмана
.pdf
biological environment upon administration, and decreasing unfavorable side effects. So, de-
livery systems modify and adjust the pha rmacokinetics of the drug by changing its elimina-
tion and distribution profiles.
Incorporating natural products such as alkaloids, phenolic compounds, terpenes, essential
oils, secondary metabolites, and others into biocompatible nanocarriers provides an option to
improve its stability, bioavailability, and release at a controlled rate. Incorporated natural
compounds from medicinal plants can improve antibacterial ability, antioxidant properties,
and biocompatibility of obtained nanomaterials. Furthermore, they can modify their physical
properties through structural and morphological changes. Additionally, using the nanocar-
riers approach, like plant metabolites, functionalized nanomaterials open a new way to use
the plant bioactive molecules against more specific targeting [53e55].
Nanocarriers are generally <200 nm in size and can carry and deliver therapeutics to
discrete sites in the cells. Due to their small size, increased stability, and sustained drug
release properties, biodegradable nanocar riers display several advantages, being more effec-
tive for cancer treatment than other nanoparticles (e.g., metallic ones) [56]. Currently, delivery
technologies using cell-targeting [57] or specific targeting of organelles inside a cell [58] are
becoming increasingly important as an area of scientific investigation. For instance, phagocy-
tosis, macropinocytosis, and micropinocytosis, which include clathrin-mediated endocytosis
(CME) and nonclathrin endocytosis (NCE), like caveolae-mediated endocytosis. Phagocytosis
mostly occurs in specialized cells that are dependent on the receptor-ligand interaction, such
as unicellular organisms and immune cells (macrophages, neutrophils, dendritic cells, etc.)
and, to a lesser extent, fibroblasts, epithelial and endothelial cells that need to internalize
big par ticles larger than 500 nm like pathogens (bacteria), dead cells, and cell debris
(apoptotic cells) [59,60]. Phagocytosis is triggered via recognition of the particle via receptors
on the phagocyte, which leads to recruitment of actin around the particle, followed by engulf-
ment [60]. The created phagosomes are believed to eventually fuse with lysosomes, creating
phagolysosomes. The acidic and enzyme-rich environment in these phagolysosomes will pro-
mote the breakdown of any biodegradable nanocarriers or sensitive drugs [60].
Macropinocytosis is an endocytic process that entails the engulfment of a large volume of
the extracellu lar milieu and is mainly responsible for the uptake of nutrients and fluids. It can
internalize cargoes that are up to 500 nm in diameter, which subsequently fuses with lyso-
somes to hydrolyze the cargo particles. Both phagocytosis and macropinocytosis involve
large rearrangements of the plasmatic membrane (PM), guided by extensive actin cytoskel-
eton remodeling and coordinated by the stepwise involvement of Rho-GTPases [59,60].
The other pathways fall under the category of micropinocytosis, which comprises a hetero-
geneous group of internalization pathways that are responsible for the uptake of small par-
ticles (<200 nm) and membrane receptors. This class of endocytic events comprises different
classes of receptor-mediated pathways. These pathways are subdivided based on certain fea-
tures, such as the presence of coatlike proteins (like clathrin and caveolin), the dependence on
dynamin (like vesicle scission, or the role of small GTPases). CME is mainly responsible for
the uptake of essential nutrients, downregulation of cell signaling, and maintaining cellular
homeostasis [59,60]. In short, CME involves engulfment and up a concentration of transmem-
brane receptors bound to ligands on the plasma membrane. On the cytosolic side of the mem-
brane, a coated pit is formed by cytosolic proteins, with clathrin as the main unit [59,60].
These clathrin-coated pits are then pinched off the membrane by a small GTPase known as
7. Application of nanomedicine for efficient delivery of herbal bioactives168
https://t.me/med1917
dynamin, forming clathrin-coated vesicles (CCV). Once the CCV is detached from the mem-
brane, the coat will disassemble, and the vesicle will undergo further intracellular trafficking.
Nanocarriers that enter the cell through CME are mostly targeted at degradative lysosomes.
First, the cargo will be transported to early endosomes (pH w 6), which will mature into late
endosomes (pH w 5). These late endosomes will fuse with prelysosomal vesicles to form
lysosomes that have an acidic (pH w 4e5) and enzyme-rich environment (containing, e.g.,
hydrolases) for degradation [60]. Caveolae-mediated endocytosis (CvME) is another major
uptake route responsible for biological functions, such as cell signaling, lipid regulation,
and vesicular transport. The dimeric protein caveolin-1 (and caveolin-3 in muscle cells) joint
to PTRF-1/Cavin1 protein is responsible for the specific flask shape of the vesicles; caveolin
can be found as a striated coat on the cytosolic surface of the membrane, and soft invagina-
tions that need recruit PTRF-1/Cavin-1 to the plasma membrane for final caveolae formation
[61]. As in ME, dynamin is responsible for scissoring the vesicle from the membrane . These
vesicles seem to fuse with caveosomes, thereby bypassing lysosomes. Therefore, CvME could
be an interesting pathway for drug delivery systems (DDS) to avoid lysosomal degradation
[18]. In the main, the NCE form of endocytosis comprises a subset of quite heterogeneous
pathways in terms of protein and lipid requirements, as well as morphological intermediates.
Both CME and NCE are required for the endocytosis of transmembrane proteins and
signaling receptors. The impact of receptor-mediated endocytosis on cell physiology is indeed
dependent on the signaling network downstream of the internalized receptor. Thus, although
a traditional way to differentiate between the different endocytic pathways is on the basis of
cargo size, there are other important features to consider, such as type of cell and bio-
physicochemical influences on the interface between nanocarrier and biological systems
like shape, surface area, surface charge, energy, roughness and porosity, valence and conduc-
tance states, functional groups, ligands, crystallinity and defects, hydrophobicity and hydro-
philicity, membrane interactions: specific and nonspecific forces, receptor-ligand binding
interactions, membrane wrapping: resistive and promotive forces, biomolecule interactions
(lipids, proteins, DNA) leading to structural and functional effects, free energy transfer to bio-
molecules and conformational change in biomolecules, among others [62].
In cancer, nanocarriers could be used to deliver chemotherapeutics to tumor cells with
high efficiency and reduced cytotoxicity on healthy tissues [63]. The activity of the drug
carried by the nanocarrier depends on how and where the NPs are disassembled. The mech -
anism of nanocarriers’ endocytosis and trafficking is still a subject of controversy [64]. In this
context, studies have revealed a direct relationship between the size of the NPs and the endo-
cytic pathway. Particles with a size less than 200 nm were internalized into nonphag ocytic,
murine melanoma cells B16-F10 via clathrin-mediated endocytosis. The size of clathrin-
coated pits varies between different cell types within the same species [65]. The size of
clathrin-coated vesicles depends on the size of its cargo, having an upper limit of 200 nm
external diameter in the cas e of virus uptake [66].
In a similar way, 50 and 120 nm folate-decorated poly (ethylene glycol)-polycaprolactone
nanoparticles were found to be internalized via both clathrin- and caveolae-mediated endo-
cytosis in ARPE-19 cells. However, 250 nm polymeric nanoparticles were only internalized
via a caveolae-mediated pathway [67], despite some articles having described an upper limit
size of w150 nm for passage through caveolae vesicles [68]. However, glycopeptide-
engineered PLGA nanoparticles, closely related to the PHBV nanoparticles studied here,
3. Nanocarriers for control drug delivery 169
https://t.me/med1917
were investigated to determine their endocytic mechanism. As demonstrated by confocal
microscopy analysis, these nanoparticles, 170 nm in diameter, are strongly colocalized with
clathrin related-but not with caveolin related-routes [69].
Ref. [70] report the possible routes of internalization and escaping from the endosomal
sorting pathway of PHBV nanoparticles in two different cell lines: HeLa (cervix cancer)
and SKOV-3 (ovarian cancer).
Fig. 7.3 shows a scheme showing nanoparticle intracellular trafficking pathways in cells. It
reveals different endocytosis pathways depending on the cell context but the same final desti-
nation. In detail, some nanopartic les are driven by the adaptor complex, which recruits cla-
thrin to cytosolic receptor domains, initiating the formation of a clathrin-coated pit. Others
are triggered by ligand-receptor interactions and regulated by actin polymerization. Both
cases require dynamin to facilitate scission from the memb rane and involve interactions of
the intracellular domains of cell surface receptors with cytoplasmic machinery. On the other
hand, the formation of caveolae is dependent on caveolin proteins. Caveolae endocytosis
appears to be a constitutive process (that is, a continuous endocytic uptake mechanism inde-
pendent of receptor-ligand interactions) and is clathrin and dynamin independent. Macropi-
nocytosis is a pathway generally involving the uptake of large volumes of fluid. Caveolae
endocytosis and macropinocytosis might be controlled by actin dynamics. Moreover, phago-
cytosis occurs after a binding event at the cell surface triggers actin polymerization, and a
vesicle form tightly around the bound material. After internalization, pathways merge into
early endosomes before undergoing sorting to other destinations, where material may be
FIGURE 7.3 Internalization pathways in mammalian cells.
7. Application of nanomedicine for efficient delivery of herbal bioactives170
https://t.me/med1917
sent back, in some cases, to the surface or onwards to the late endosome and lysosome. How-
ever, in some cases, nanoparticles might be incorporated by an independent pathway (not yet
described). In the case of curcumin delivery, the most common way of delivery is via PLGA,
which is incorporated via the classical clathrin-dependent pathway [71]. Other ways for cur-
cumin intracellular delivery are based on chitosan polymers which are endocytosed via both
clathrin-dependent and clathrin-independent pathways [72].
3.1 Classification and synthesis of nanocarriers for control of drug delivery
Nanomaterials have been obtained by many different pathways, being grouped into three
big lines of synthesis, the top-down, bottom-up (see Fig. 7.4), and a subarea of bottom-up
newly recognized as an alternative synthesis line established as the green synthesis. Even
when top-down synthesis is the most employed by industrial interest and the most extended
in natural nanomaterials related to natural environmental damage and erosions of big blocks
of materials. Green synthesis is acquiring attention as a cheap, precise alternative that, in nat-
ural condition, has been related to cellular biological environments [73,74].
Top-down synthesis is simpler and cheaper for industrial approaches; these techniques
involve the breaking down of bulk material into nanosized structures to produce the desired
structure with appropriate properties. Examples of such techniq ues are high-energy wet ball
milling, electron beam lithography, atomic force manipulation, gas-phase condensation, aero-
sol spray, and others. Nevertheless, the imperfection over surfaces of obtained structures
limits more detailed uses such as precision biomedical approaches. For more precision in
similar nanostructures, bottom-up synthesis is an alternative more employed by healthcare
industries. This kind of synthesis refers to the build-up of nanomaterial from the unit mate-
rial, such as atom-by-atom, molecule-by-molecule, or cluster-by-cluster, and, for this reason,
FIGURE 7.4 Scheme of top-down and bottom-up strategies.
3. Nanocarriers for control drug delivery 171
https://t.me/med1917
have the potential to create more detailed nanomaterials with less waste. Certain reported
techniques include chemical routes such as organometallic chemical synthesis, revere-
micelle route, sol-gel synthesis, colloidal precipitation, hydrothermal synthesis, template-
assisted sol-gel, electrodeposition, and green synthesis [73,74]. Nevertheless, these techniques
are more expensive, still under development, or are just being used for commercial produc-
tion, but the major disadvantage with physical and chemical synthesis is the employment of
certain agents and solvents to synthesis that pose toxicity issues along with environmental
damage and high energy consumption with low yield. So, green syntheses are emerging as
new technologies where the biological synthesis methods that involve the use of organisms
such as plants, algae, fungi, or bacteria are the new biotechnological approaches even
when, yet must be solved many kinds of industrial limits such as the slow development,
the pathogenicity, and maintenance of large-scale cultures are major drawbacks associated
with the use of green synthesis for the generation of nanomaterials, these new strategies re-
sults in great industrial interest [75 ].
3.2 Potential applications of nanocarriers for herbal control drug delivery
There are over 50 clinically ap proved nanomaterials for pharmaceutical and nanomedical
approaches, all of whi ch are based on simple designs encompassing a small number of com-
ponents. In the drug delivery context, lipid-based nanomaterials are the most common in
this list of approved drugs, including various subset structures, their comprising a least
one lipid bilayer with at least one internal aqueous compartment, giving many capabilities
to incorporate different biomolecules to be employed, such as delivery system. These types
of structures include liposomes, niosomes, ethosomes, phytosomes, and transferosomes.
And the synthesis of more complex lipid-based nanostructures that resemble biological
structures with hundreds of functional components is recently in research-based on extra-
cellular vesicles (EVs) such as exosomes being obtained by biological bioreactors and by
new green [76].
3.2.1 Liposomes
Liposomes were discovered initially in 1964 by the British hematologist Dr. Alec D. Bang-
ham and collaborators at the Babraham Institute, University of Cambridge. Defined as
colloidal spherical vesicles formed by self-assembly of amphiphilic lipid molecules in solution
where an aqueous compartment is entirely enclosed by one or more lipid bilayer membranes,
mainly composed of lipids that include phospholipids (mainly phosphatidylcholine) and
cholesterol where cholesterol acts as a fluidity buffer. This organized structure offers lipo-
somes the unique ability to load and deliver molecules with different solubility. Hydrophilic
molecules in the internal aqueous core, hydrophobic molecules into the lipid bilayer, and
amphiphilic molecules at the water/lipid bilayer interface, so Liposomes have gained much
importance as potential drug carrier systems for targeted drug delivery [77,78]. Different re-
searches on liposomes as vesicular drug delivery system are presented in Table 7.2.
3.2.2 Ethosomes
Ethosomes were developed in 1997 by Touitou et al. [108] as additional novel lipid carriers
composed of ethanol, phospholipids, and water. Ref. [109] constituted a lipidic vesicular
7. Application of nanomedicine for efficient delivery of herbal bioactives172
https://t.me/med1917
TABLE 7.2 Novel formulations for herbal drug delivery.
Delivery system Composition of formulation Herbal/bioactive Purpose References
Liposome The natural saturated phospholipid
1,2-dipalmitoyl-sn-glycerol-3-
phosphocholine (DPPC), cholesterol, and
a cationic amphiphile featuring a
glucosyl moiety (GL4) (extrusión and
sonication method)
Resveratrol In this work, they were loaded with resveratrol
(RSV) in cationic liposomes, in the presence and
in the absence of glucosylated amphiphile GL4.
The antimicrobial activity of RSV-loaded
liposomes was evaluated by monitoring the
bacterial growth curves of 2 cell lines of
Staphylococcus epidermidis, a slime positive and
single-negative one. The results obtained
showed that the incorporation of GL4 into the
liposome favors antimicrobial activity
compared to free resveratrol.
[79]
Phosphatidylcholine and glycerol
(Mozafari method)
Rosemary extract
(Rosmarinus officinalis
L.)
In this study, encapsulated polyphenolic
compounds extracted from the rosemary plant
in liposomes were prepared by the Mozafari
method. With this method, it is possible to
encapsulate extracts without the utilization of
toxic solvents or detergents. The results showed
that liposomal encapsulated rosemary extract
possesses more antioxidant activity compared
to free extract.
[80]
Soy phosphatidylcholine, cholesterol.
The surface of liposome was modified
with galactose and morpholine
Curcumin In this study, dual targeting lipid materials were
designed, synthesized, and evaluated for
hepatic and lysosomal dual and conventional
hepatic liposomes.
The efficiency of hepatoma-cells targeting was
compared. The incorporation of galactose (to
enhance the hepatoma-cell selectivity) and
morpholine (that increases lysosomal
permeability) could be shown that dual
targeting lipid materials can improve
hepatoma-cell targeting and increase the
antitumoral effect of curcumin.
[81]
(Continued)
3. Nanocarriers for control drug delivery 173
https://t.me/med1917
TABLE 7.2 Novel formulations for herbal drug delivery.dcont’d
Delivery system Composition of formulation Herbal/bioactive Purpose References
Ethosome Phosphatidylcholine, cholesterol, and
Tween 80.
Chenopodium murale Transdermal delivery [82]
Lipid/ethanol/propylene glycol. (Cold
method)
Achillea millefolium L.
extract.
The study concludes that topical gel loaded
with nanoliposomes containing Achillea
millefolium extract is an encouraging approach
for topical drug delivery.
[83]
Propylenglicol/dioleoyl
phosphoethanolamine (DOPE)/
cholesterol.
Curcumin and
hyaluronic acid
Skin delivery formulations [84]
Nanocapsules MPEG-PLGA (PEG, MW 2000 da; PLGA,
MW 8000 da, mol/mol of lactide/
glycolide, 50/50) and hydroxypropyl
methylcellulose (antisolvent
precipitation method)
Resveratrol In this study, resveratrol loaded nanoparticles
were synthesized to increase their
bioavailability and permeability, favoring their
ability to cross physiological barriers and
increasing their levels in plasma and the brain.
[85]
Tween 80/maltodextrin (MD), whey
protein isolate (WPI), gum Arabic (GA).
Thyme essential oil Decreasing the cytotoxicity of ZnO NPs. [86]
Nanoemulsions Tween 80, Lanatus seed oil, sodium
alginate. (Low-energy assisted)
Phyllanthus niruri plant In this work, thermodynamically stable
nanoemulsion was obtained. The antibacterial
activity of the formulated nanoemulsion was
significant in comparison to P. niruri extract
alone. The antibacterial activity assay was
released against a variety of pathogenic
bacterial and fungal strains.
[87]
Soybean oil, Tween 20, alginate,
chitosan, gelatin, and polyethylene oxide
(high energy method, ultrasonication)
Curcumin Nanoemulsion of curcumin encapsulated in
hydrogel beads was obtained. The authors
found that the curcumin exhibited higher
antibacterial activity against Gram-positive
compared to Gram-negative bacteria and
revealed that the hydrogel beads are
appropriate for the encapsulation of curcumin
and improving its antimicrobial activity in an
effective way.
[88]
Tween 80 (ultrasonic-assisted
preparation)
Eucalyptus Eucalyptus nanoemulsion was obtained in this
study, showing higher anti-E. coli activity than
eucalyptus essential oil by simulated digestion
dings.
[89]
7. Application of nanomedicine for efficient delivery of herbal bioactives174
https://t.me/med1917
Phytosome Solvents (solvent evaporation method) Pistacia integerrima
galls
In this study, phytosomes assimilating acetone
fraction of hydroalcoholic extract of Pistacia
integerrima galls against Sarcoptes scabiei were
analyzed. Scabicidal effect of phytosomes and
acetone fraction was evaluated by mite repellent
and contact bioassay.
[90]
Phosphatidyl choline and cholesterol
(lipid film hydration method)
Nyctanthes arbor-tristis The present study isolated crocetin from the
tubular calyx of N. arbortristis and improved
stability through entrapping in vesicles,
followed by an evaluation of wound healing
activity of the topical formulation thereof.
[91]
Solid lipid
nanoparticle
(SLN)
Stearic acid and varying concentrations
of lecithin, ethyl alcohol, and poloxamer
188. (Emulsion/solvent evaporation
method).
Curcumin Cur-loaded solid lipid nanoparticles (SLNs)
were designed and evaluated for the
hepatoprotective and antioxidant effects in a
murine model of acute hepatotoxicity induced
by paracetamol (PCM).
The cur-loaded SLNs were more efficient in
preventing liver damage compared to the raw
cur and N-acetylcysteine (NAC).
[92]
Stearic acid and lipophilic surfactant
(span 60). Tween 80 (high-pressure
homogenizer method)
Zataria multiflora In this work, solid lipid nanoparticles loaded
with Zataria multiflora essential oil (SLN-
ZMEO) were synthesized in order to obtain a
green repellent. The repellent activity of SLN-
ZMEO was investigated using Klun and
Debboun method and compared to free ZMEO.
[93]
Nanofibers Poly-ε-caprolactone (PCL) Mw80,000,
gelatin type A (gel) gel strength300
bloom. (Coaxial electrospinning)
Gymnema sylvestre Coreshell nanofibrous dressings with poly-
ε-caprolactone/gelatin laden were prepared
using coaxial electrospinning. It used
minocycline hydrochloride as a shell, and
gelatin was infused with G. sylvestre extracts as
the core. It was demonstrated in a porcine
model of second-degree skin burns that wounds
treated with the antimicrobial dressing
improved reepithelialization and collagen
organization compared to untreated wounds.
[94]
(Continued)
3. Nanocarriers for control drug delivery 175
https://t.me/med1917
TABLE 7.2 Novel formulations for herbal drug delivery.dcont’d
Delivery system Composition of formulation Herbal/bioactive Purpose References
Nanomicelles Ethanol, Tween 80 Curcumin The curcumin was administered in different
water-soluble formulations, including
liposomes or embedded into nanoscaled
micelles. The high uptake rate of micellar
curcumin makes it attractive also for cancer
therapeutic strategies
[95]
Methoxy poly(ethylene glycol)-
poly(lactic acid) (MPEG-PLA) and
cyclo(Arg Gly-Asp-D-Phe-Lys) (cRGD)
polypeptide modified PEG-PLA
(cRGD-PEG-PLA) copolymers
Curcumin/doxorubicin In this work, biodegradable methoxy
poly(ethylene lycol)-poly(lactic acid), and
cyclo(Arg-Gly-Asp-D-Phe-Lys) polypeptide
modified PEG-PLA (cRGD-PEG-PLA)
copolymers were used for the codelivery of
curcumin (CUR) and doxorubicin (CUR-DOX/
cRGD-M). The combined treatment showed
increased antitumor and antimetastatic capacity
in lung cancer therapy.
[96]
Nanocrystal Cellulose nanocrystals Curcumin In this work, cellulose nanocrystals (CNC) were
used to encapsulate curcumin. The particles
loaded with curcumin were stable. Slowed
degradation and improved bioaccessibility of
curcumin were observed.
[97]
Red palm super olein, cellulose
nanocrystals
Curcumin A Pickering emulsion (PE) with different
concentrations of cellulose nanocrystal (CNC)
was prepared by ultrasonic. Good stability of
curcumin was observed with a half-life of
98.47 days under dark conditions.
[17]
Exosome Isolate exosomes from HEK293 cells Curcumin In this work, exosome-mediated peptide
delivery into the lungs was studied. The
exosomes were designed for the pulmonary
delivery of RAGE-binding peptide (RBP). To
improve anti-inflammatory properties,
curcumin was loaded in RBP-exo, achieving
greater intracellular delivery efficiency.
[98]
7. Application of nanomedicine for efficient delivery of herbal bioactives176
https://t.me/med1917
Purified exosomes Curcumin In this work, the authors demonstrated that
curcumin could induce exosome/microvesicle
release in cellular models of lipid deposition.
The decrease in intracellular lipid deposition is
mediated by increased ceramide synthesis and
exosome/microvesicle release, which may be
another of the health benefits of curcumin.
[99]
Cubosome Monoolein, monopalmitolein,
phytantriol, DPSC.
Curcumin In this study, liposomes and cubosomes were
compared as potential vehicles for curcumin
encapsulation. The obtained particles were
characterized by different solid-state
techniques. Toxicity and effectiveness in
curcumin release were also evaluated using
murine fibroblast (NIH3T3) and murine
melanoma (B16F10) cell lines.
[100]
Tween 80 (T80) and pluronic F127
(PF127)
Origanum majorana Nano-ribosomal (NC) systems were loaded
with Origanum majorana extract (OE) in order to
enhance its biological effects at lower dosages.
The results showed that OE-NCs improve the
antihyperglycemic effect of OE and ameliorated
diabetic gland alterations compared to
conventional OE.
[101]
Polymersome ε-Caprolactone (CL) in the presence of
PEG and (Sn(Oct)2). Polyethylene glycol
Curcumin The aim of this study was to develop a
biodegradable thermoresponsive, injectable
hydrogel that can improve, prolong and localize
the therapeutic effects of curcumin. In this case,
the hydrogel was composed of biodegradable
polymers and incorporated curcumin-loaded
polyethylene glycol-b-polylactide (mPEG-PLA)
nanopolymersome.
[102]
Dendrimer Polyamidoamine (PAMAM) Curcumin Curcumin was encapsulated into surface-
modified polyamidoamine (PAMAM)
dendrimers to facilitate efficient delivery of
therapeutic doses of curcumin into cells.
Viability assays were carried out on three
glioblastoma cell lines. In the presence of
nanoparticles, a decrease in cell viability was
observed.
[103]
(Continued)
3. Nanocarriers for control drug delivery 177
https://t.me/med1917
Соседние файлы в папке Библиотека им академика М.И. Перельмана