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INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS https://doi.org/10.1080/00914037.2017.1332623
5 Overview of preparation methods of polymeric and lipid-based (noisome, solid lipid, liposome) nanoparticles: A comprehensive review Fateme Haghiralsadata,b , Ghasem Amoabedinyb,c, Samira Naderinezhadc , Marco N. Helderd, Elham Akhoundi Kharanaghie and Behrouz Zandieh-Doulabid
aDepartment of Life Science Engineering, Faculty of New Sciences & Technologies, University of Tehran, Tehran, Iran; bDepartment of Nano 10 Biotechnology, Research Center for New Technologies in Life Science Engineering, University of Tehran, Tehran, Iran; cDepartment of Biotechnology
and Pharmaceutical Engineering, School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran; dDepartment of Oral & Maxillofacial Surgery, VU University Medical Center, MOVE Research Institute Amsterdam; eDepartment of Biotechnology, Faculty of Advanced Science and Technologies, University of Isfahan, Isfahan, Iran
ABSTRACT A wide number of drug nanocarriers have emerged to improve medical therapies, and in Q2particular to achieve controlled delivery of drugs, genes or gene expression-modifying compounds, or vaccine antigens to a specific target site. Of the nanocarriers, lipid-based and polymeric nanoparticles are the most widely used. Lipid-based systems like niosomes and liposomes are non-toxic self-assembly vesicles with an unilamellar or multilamellar structure, which can encapsulate hydrophobic/hydrophilic therapeutic agents. Polymeric nanoparticles, usually applied as micelles, are colloidal carriers composed of biodegradable polymers. Characteristics such as loading capacity, drug release rate, physical and chemical stability, and vesicle size are highly dependent on experimental conditions, and material and method choices at the time of preparation. To be able to develop effective methods for large scale production and to meet the regulatory requirements for eventual clinical implementation of nanocarriers, one needs to have in-depth knowledge of the principles of nanoparticle preparation. This review paper presents an overview of different preparation methods of polymeric and novel lipid-based (niosome and solid lipid) nanoparticles.
GRAPHICAL ABSTRACT
ARTICLE HISTORY Received &�Accepted &��
KEYWORDS Drug delivery; noisome; polymeric nanoparticles; preparation method; solid lipid nanoparticles
45
1. Introduction
Despite great success in the lead optimization program, highly lipophilic drug candidates are the major outcomes of such critical drug discovery drives [1]. Although many of these drug
50candidates have exceptional in vitro potency, lack of significant solubility in water often presents challenges such as [2]: .� Poor bioavailability. .� Variations in bioavailability when in fed or fasted state.
none defined
CONTACT Ghasem Amoabediny [email protected] Department of Nano Biotechnology, Research Center for New Technologies in Life Science Engineering, University of Tehran, Tehran, Iran. Q1Color versions of one or more of the figures in the article can be found online on at www.tandfonline.com/gpom. © 2017 Taylor & Francis
3b2 Version Number : 11.0.3184/W Unicode (Apr 10 2014) File path : P:/Santype(JATS)/Journals/TandF_Production/GPOM/v0n0/GPOM1332623/GPOM_A_1332623_J.3d Date and Time : 20/7/17 and 21:47
https://doi.org/10.1080/00914037.2017.1332623http://orcid.org/0000-0002-8655-2118http://orcid.org/0000-0002-0703-2334https://crossmark.crossref.org/dialog/?doi=10.1080/00914037.2017.1332623&domain=pdf&date_stamp=2017-07-20mailto:[email protected]://www.tandfonline.com/gpom
.� Use of excipients such as co-solvents to improve water 55 solubility may prove to be harsh.
.� Drug precipitation after dosing.
.� Patient noncompliance. In recent years, the proportion of such insoluble drug
candidates has been estimated to be roughly 70% of new drug 60 discoveries. In addition, about 40% of the currently marketed
immediate-release oral drugs are practically water-insoluble [3].
A novel and successful strategy to improve solubility is drug encapsulation in a colloidal nanocarrier system, which
65 overcomes some of the problems of conventional medical treatment. Nanocarriers improve solubility, bioavailability, and biodistribution of both lipophilic and hydrophilic drugs [4].
Features such as large surface-to-mass ratio which causes 70 large functional surface, simple preparation methods, easy
engineering of targeted nanoparticles, low degradation rate, preventing harmful side-effects, and large capacity of drug loading of nanocarriers have revolutionized drug delivery systems (DDS) [5].
75 Wide number of colloidal drug nanocarriers have been discovered to improve medical therapies. Based on the material used in their preparation, they are categorized as polymer-based or lipid-based systems.
Polymer-based nanoparticles are colloidal carriers 80 composed of biodegradable polymers. They effectively carry
drugs, proteins, and DNA to target cells and tissues. Storage stability and long in vivo half-life in the blood stream are positive aspects, however, their low polymer degradation rate which may cause toxicity is a negative feature [6].
85Lipid-based colloidal carriers have been introduced to over-come the toxicological issues exhibited by polymeric systems. Prominent research has been performed on lipidic systems including liposomes, niosomes, nanoemulsions, micelles, cubosomes, and lipid nanoparticles. Lipid nanoparticulate
90DDS applications and routes of administration depend on their architecture and particle size [7]. Figure 1 shows some of the available lipid particulate DDS. Liposomes represent the first-generation of drug carriers, which were already described in the early 20th century [6]. Niosomes comprise
95vesicular systems which are more stable than liposomes due to the nonionic surfactants instead of phospholipids used for preparing them. Niosomes have recently been shown to greatly increase transdermal drug delivery and can also be used in targeted drug delivery [8]. The other useful lipid-based
100nanoparticle type are solid lipid nanoparticles which are prepared by lipids that are solid at room temperature [7].
This review article provides a summary of properties of the polymeric, and lipid-based nanoparticles (niosome and solid lipid) and the manner of their preparation methods.
105Although each section of this article can be easily expanded into a separate complete review paper, we attempted to write a general review with a global presentation of the various preparation methods of these three novel and widely used nanoparticles.
1102. Polymeric nanoparticles
Since the 1980s, polymeric nanoparticles (PNPs) have been applied as micelles in drug delivery systems, and numerous polymers have been used to carry and deliver various drugs
Figure 1. Lipid particulate drug delivery systems.
2 F. HAGHIRALSADAT ET AL.
in last few years. These nanoparticles can deliver different 115 types of molecules including: low molecular weight drugs,
proteins, plasmid and antisense DNA, and short interfering RNA [9,10].
Polymeric nanoparticles have been extensively studied as drug carriers in the pharmaceutical field [11–14] and different
120 research teams have published reviews about the nanoparticle formation mechanisms [15,16].
Polymeric micelles, varying in size between 5 and 50 nm in aqueous solutions, are prepared by self-assembly of amphiphilic biodegradable, biocompatible, and FDAQ3 -approved
125 copolymers. The drugs can be entrapped or encapsulated in the polymeric micelles and transported to the tissues. The micelles can form hydrogen bonds by their hydrophilic blocks in aqueous solution around them. The drug trapped in the hydrophobic core will be well-protected against degradation
130 (Figure 2) [9,16–18]. Biosafety and biocompatibility of the used polymers are
important characteristics in the field of novel drug delivery systems. Researchers use both natural and synthetic polymers to make polymeric micelles.
135 Chitosan, gelatin, sodium alginate, and albumin are the natural polymers which are commonly used for the preparation of PNPs [17,19]. Synthetic polymers used for this approach include: polylactides (PLA), polyglycolides, poly(ε-caprolactone) (PCL), poly(lactide-co-glycolides)
140 (PLGA), polyanhydrides, polyorthoesters, polycyanoacrylates, polycaprolactone, polyglutamic acid, poly(maleic acid), poly (N-vinyl pyrrolidone), poly(methyl methacrylate), poly(vinyl alcohol), poly(acrylic acid), polyacrylamide, poly(ethylene glycol), and poly(methacrylic acid) [16–18].
145 The chemical structure and ability of functionalization of amphiphilic block copolymers is a feature that makes poly-meric micelles particularly interesting for drug delivery. Ligands and antigens could be conjugated to block copolymers to both increase the stability of micelles and control the release
150 of drug in body in DDS [18].
2.1. Advantages of polymeric drug delivery
Using polymeric nanoparticles can increase the stability of encapsulated drugs easily, carry and deliver higher amount of pharmaceutical agents to the desired tissue, protect the
155 contents against hydrolysis and enzymatic degradation, improve efficiency and effectiveness of treatments in compari-son to traditional oral and injection methods, and reduce irritation of tissue because of the polymeric shell [17,20].
2.2. Polymeric nanoparticles preparation methods
160The method of polymeric nanoparticles preparation is depend-ing on the intended application. Polymerization and drug dispersion in preformed polymers are the most common tech-niques for preparing PNPs in drug delivery approaches [17]. Polymerization techniques have drawbacks such as toxic and
165reactive residues, unreacted remaining monomers which may cause unwanted chemical reactions and/or increase the risk of formation of undesirable oligomers. Due to these drawbacks, the preformed polymers method is widely used in drug delivery systems [21].
170In general, parameters such as release-defining features, chemical nature, charge, hydrophilicity/hydrophobicity, swell-ing/de-swelling capacity, reactivation, and pH-dependency/ independency of the polymers may determine the polymer selection [22].
175The widely reported techniques for the preparation of polymeric nanoparticles from preformed polymers are: a) Solvent evaporation. b) Nanoprecipitation. c) Emulsification/solvent diffusion (ESD).
180d) High-pressure homogenization. e) Salting out. f) Dialysis. g) Spray drying. h) Supercritical fluid technology (SCF).
185Table 1 shows a summary of some nanosized polymeric micelles used in DDS.
2.2.1. Solvent evaporation In this method, the selected polymer is dissolved in an organic volatile solvent, such as dichloromethane and chloroform to
190create an emulsion. Recently, dichloromethane and chloro-form are being substituted by less toxic organic solvents like ethyl acetate. The emulsion is exposed to a high energy source, e.g., an ultrasonicator or homogenizer, to convert it into a nanoparticle suspension (Figure 3a). This stage is the key point
195of nanoparticle formation. After the fabrication of PNPs, the volatile solvent is removed by evaporation. Stirring speed, homogenizer type, and polymer concentration all influence nanoparticle characteristics. Then, for separating solid nano-particles, the residuals of the evaporation stage can be centri-
200fuged and washed with distilled water, and finally dried by lyophilization. The best nanoparticles will be formed using a high-speed homogenizer or ultrasonicator, followed by evap-oration under continuous stirring at room temperature and reduced pressure [10,17,21].
205Bilati et al. studied the effect of sonication on PLGA nano-particles properties prepared using the solvent evaporation method. Varying intensity and duration of the sonication process will have impact on the final nanoparticle size [23].
2.2.2. Nanoprecipitation 210The other name of this method is solvent–displacement
method. This method is based on self-precipitation of polymers in the anti-solvent phase. Preformed polymer and drug are dissolved in an organic intermediate polar and water-miscible solvent. This phase is added to a stirred
Figure 2. Polymeric micelles prepared by self-assembly of block copolymers and drugs.
INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS 3
215aqueous solution which is a totally miscible solvent but is an anti-solvent for the polymers, and contains a stabilizer under ambient condition. At the interface of organic solvent and water, polymers will accumulate. Fast diffusion and surface tension of the solvents will stimulate the generation of a col-
220loidal suspension. The formed nanoparticles can be collected by solidification (Figure 3b). Concentration of polymer, stir-ring speed, and the amount and solubility of solvent and anti-solvent phases can affect the size of the nanoparticles. This technique is limited to water-miscible solvents, does
225not need the use of homogenizer or ultrasonicator, and can easily be scaled-up for industrial production. A disadvantage of the nanoprecipitation method is the complexity of selecting the appropriate solvent, anti-solvent, and polymer to produce spontaneous emulsification. Due to the water miscibility of
230both solvents, this method is not useful for encapsulating hydrophilic drugs and just appropriate for lipophilic ones [10,17,21]. Nanoprecipitation has been studied for several polymers such as PLGA, PLA, PCL, and poly(methyl vinyl ether-co-maleic anhydride) by different researchers [24–28].
2352.2.3. Emulsification/solvent diffusion In this method preformed polymer and drug are mixed with an organic solvent which is partially miscible with water. Water is added slowly to this solution to eventually reach the saturation and thermodynamic equilibrium point. By
240adding excess water, the solution becomes supersaturated, and consequently nanoparticles are formed due to the physico-chemical imbalance. The more water is added, the more nanoparticles are fabricated and incorporated in the water phase. Finally, PNPs can be separated by filtration or solvent
245evaporation (Figure 3c) [17,21]. The relative amounts of water and polymer concentration will influence particles size. The benefits of this technique are high efficiency of drug loading, no need for a homogenizer, simplicity of scalingup, and narrow size distribution. However, generating PNPs by the
250ESD method needs high volumes of water to formulate suspensions, and hydrophilic drugs encapsulation yield is low by this method [10]. Several drugs such as mesotetra (hydroxyphenyl)porphyrin, doxorubicin, coumarin, and plasmid DNA loaded in PLGA and PLA have been produced
255by the ESD technique by different researchers [29–32].
2.2.4. High-pressure homogenization High pressure milling is the main force to form nanosized particles in this technique. Preformed polymers and drugs are dispersed in medium, and passed through a high-pressure
260homogenizer (HPH) for several times. Usually the pressure is increased step by step, to eliminate clogging of the particles in the narrow homogenizer hole [33]. The common types of equipment used to produce nanoparticles in HPH method are the microfluidizer [34] and the piston-gap homogenizer
265[35]. In the microfluidizer the particle suspension, which is usually dispersed in an aqueous solvent, is pumped into a chamber where milling forces are applied to reduce particle size [36]. In the piston-gap homogenizer, dispersed particles in an aqueous or organic solvent are passed through a narrow
270gap with a diameter of 25 µm. The final size of nanoparticles Tabl
e 1.
A
sum
mar
y of
som
e po
lym
eric
nan
opar
ticle
s pr
epar
ed b
y se
vera
l tec
hniq
ues
to d
eliv
er A
PIs/
prot
eins
.
Tech
niqu
e AP
Is/pr
otei
ns
Cate
gory
Po
lym
er
Rout
e M
ean
size
or
size
rang
e (n
m)
Refe
renc
e
Solv
ent
evap
orat
ion
Mox
iflox
acin
An
tibio
tic
Poly
(lact
ic-c
o-gl
ycol
ic a
cid)
(PL
GA)
In v
itro
164–
490
[44]
Em
ulsif
icat
ion
solv
ent
evap
orat
ion
Ellip
ticin
e An
tican
cer
Poly
-(3-h
ydro
xybu
tyra
te-c
o-3-
hydr
oxyv
aler
ate)
In
vitr
o 26
5 [4
5]
Emul
sific
atio
n so
lven
t ev
apor
atio
n Ci
spla
tin
Antic
ance
r Po
ly(3
-hyd
roxy
vale
rate
-co-
4-hy
drox
ybut
yrat
e)
In v
itro
100–
200
[46]
Em
ulsif
icat
ion
solv
ent
evap
orat
ion
Etop
osid
e To
poiso
mer
ase
inhi
bito
r PL
GA
In v
itro
105
[47]
Em
ulsif
icat
ion
solv
ent
evap
orat
ion
Insu
lin
Horm
one
Dex
tran
O
ral
160–
250
[48]
Em
ulsif
icat
ion
solv
ent
evap
orat
ion
Acyc
lovi
r An
tivira
l M
etho
xy p
olye
thyl
ene
glyc
ol
In v
itro
141
[49]
17
2 Ch
itosa
n Em
ulsif
icat
ion
and
nano
prec
ipita
tion
Pacl
itaxe
l An
tican
cer
PEGy
late
d PL
GA
In v
itro
112
[50]
In
viv
o (IV
) 19
0 N
anop
reci
pita
tion
Spar
floxa
cin
Antib
iotic
PL
GA
Oph
thal
mic
18
0–19
0 [5
1]
Nan
opre
cipi
tatio
n 9-
Nitr
ocam
ptot
heci
n An
tican
cer
PLGA
In
vitr
o 20
7 [5
2]
Nan
opre
cipi
tatio
n Ci
spla
tin
Antic
ance
r PE
Gyla
ted
PLGA
In
vitr
o 14
0 [5
3]
Nan
opre
cipi
tatio
n–hi
gh-p
ress
ure
hom
ogen
izer
(HPH
) 10
-Hyd
roxy
cam
ptot
heci
n An
tican
cer
Polo
xam
er 1
88
Ora
l 13
1 [5
4]
HPH
Om
epra
zole
Pr
oton
pum
p in
hibi
tor
Polo
xam
er 1
88
Pare
nter
al
<1,
000
[55]
Sp
ray-
dryi
ng
Itrac
onaz
ole
Anti-
fuga
l Po
loxa
mer
188
—
45
0 [5
6]
Salti
ng o
ut
Savo
xepi
ne
Antip
sych
otic
Po
ly(D
,L-la
ctic
aci
d)
In v
itro
228
[57]
D
ialy
sis
VEGF
Q4
and
Bcl-2
tar
getin
g siR
NA
Gene
sile
ncin
g siR
NA
Glyc
ol c
hito
san
Intr
aven
ously
inje
ctio
n 24
3 [5
8]
Dia
lysis
D
oxor
ubic
in
Antic
ance
r Po
ly(D
,L-la
ctid
e-co
-gly
colid
e)
In v
itro
100–
200
[42]
Su
perc
ritic
al f
luid
tec
hnol
ogy
Ibup
rofe
n An
ti-in
flam
mat
ory
Poly
(N-v
inyl
-2-p
yrro
lidon
e)
—
40
[59]
4 F. HAGHIRALSADAT ET AL.
will depend on the applied pressure, and few homogenization rounds [37].
2.2.5. Salting out This technique is a modified version of the ESD method and
275 based on the separation of a water soluble solvent from an aqueous solution by salting-out agents. In the first step, preformed polymer and drug are dissolved in a water miscible organic solvent. In the second step, this solution is added to an aqueous phase which contains colloidal stabilizer as well as
280 chemical electrolyte or nonelectrolyte agents such as calcium chloride, magnesium chloride, magnesium acetate, or sucrose, to induce the salting-out effect. Stirring rate should be constant in this process. Salting-out effect prevents the interspersing of organic solvent with water. By adding excess
285 water to the emulsion, the diffusion of the organic phase will be increased and nanoparticles will be formed (Figure 4a). Afterward, PNPs can be separated by filtration and removing the excess solvents and salting-out agents. The type of salting- out agent will affect the drug encapsulation efficiency of this
290 technique. High efficiency, easy scalingup, and no need for high temperatures are the advantages of salting-out method, in particular for heat-sensitive drugs. However, it needs high quantities of water for washing, and is not applicable for hydrophilic drugs [10,17,21,38]. This method is studied by
295 Galindo-Rodriguez et al. [39] and Mendoza-Muñoz et al. [40] for fabricating PNPs.
2.2.6. Dialysis Dialysis offers a method for the generation of surfactant-free, small, and narrow size-distributed nanoparticles with high
300 efficiency. Preformed polymer and drug are mixed in an organic solvent and positioned in the dialysis tube with proper molecular size cutoff. Dialysis membrane is a semi-permeable membrane which allows passive transport of solvents and
nonsolvents. Dialysis is performed against a nonsolvent 305miscible with the first solvent. The movement of nonsolvent
inside the membrane will cause polymer formation and aggre-gation because of reduction of solvent quantity (Figure 4b). Nanoparticle sizes are influenced by the type of polymer and solvents [17,21]. PNPs preparation with PLGA by dialysis
310method is assessed by different researchers [41,42].
2.2.7. Spray drying Spray drying is a single-step method which is used for generat-ing stable nanoparticles from a liquid phase. Preformed poly-mer and drug are dissolved in water and spray-dried after
315syringe filtering. Spray-drying will occur by atomization at tem-peratures between 30 and 55°C. Solvent will evaporates under these conditions, and PNPs will precipitate (Figure 4c) [43].
2.2.8. Supercritical fluid technology Supercritical fluid technology produces PNPs by an environ-
320ment-friendly method utilizing supercritical fluids. PNPs that have been generated by this technique are pure without any residual organic solvents. Preformed polymer and drug are mixed with a supercritical fluid under ambient conditions. Afterward, the solution is transferred to a pre-expansion tank,
325and heated to 40°C isobarically under the pressure of 27.6 Pa. The solution crosses a capillary nozzle or an orifice into air. Rapid decrease of pressure causes a high degree supersatura-tion which results in the generation of particles (Figure 5a).
The obtained products by this way are microscaled instead of 330nanoscaled, which is a drawback for this technique. To resolve
this problem, a combined SCF–ESD approach can be used, where the SCF solution is dispersed into aqueous environment and afterward passed through a nozzle the nozzle, which results in the fabrication of nanoparticles (Figure 5b). The concen-
335tration of polymer and the degree of saturation will influence the shape and size of particles [10,15,17].
Figure 3. (a) Schematic of the solvent-evaporation method, (b) schematic of the nanoprecipitation method, (c) schematic of the emulsification/solvent diffusion technique.
INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS 5
3. Solid lipid nanoparticles
Solid lipid nanoparticles (SLN) were developed in the 1990s as an alternative carrier in DDS [60–64]. SLNs are colloidal drug
340 carrier systems which are prepared from lipids that are solid at both room and body temperature, such as tricaprin,
tripalmitin, trilaurin, glycerol behenate, glycerol palmitostea-rate and waxes, such as cetylpalmitate [66]. Many emulsifiers have been used to stabilize them, including poloxamers,
345Tween 80, soya lecithin, and sodium dodecyl sulfate. Selection of stabilizer depends on the chosen lipid and administration
Figure 4. (a) Schematic of the salting out technique, (b) schematic of the dialysis technique, (c) schematic of the spray drying technique.
Figure 5. (a) Experimental setup for preparation of polymer nanoparticles by rapid expansion of supercritical fluid solution, (b) experimental setup for the rapid expansion of supercritical fluid solution into liquid solvent process, (c) schematic of the spray drying technique for SLNs. Note: SLN, solid lipid nanoparticle.
6 F. HAGHIRALSADAT ET AL.
route [5]. SLNs are used to carry and deliver hydrophilic and hydrophobic drugs, macromolecules, such as proteins and peptides, genes or gene expression-modifying compounds,
350 antigens, and food molecules [66]. SLNs can carry drugs by either one of two models: solid solution model and core-shell model (Figure 6a). Drug is dispersed within the lipid matrix in the first model and in the second model drug is dispersed in the core (inside) or the shell (outside) of SLNs. In which
355 SLN made depends on the choice of the preparation method [67].Q5 SLNs provide some advantages. They (i) improve bioavailability of drugs; (ii) reduce drug mobility due to the solidness of lipid; (iii) reduce biodegradation of drugs; (iv) use biodegradable lipids; (v) can avoid the use of organic
360 solvents in preparation methods to decrease toxicity; (vi) can be functionalized for controlled drug delivery; (vii) can be easily produced in large quantities; and (viii) are more stable in in vivo application than other lipid nanocarriers. However, low drug loading capacity due to their crystalline structure,
365 change of release profiles, drug expulsion after storage- induced polymeric transition, and high water content of the dispersions are disadvantages of SLNs [7,66,68–71].
Solid lipid nanoparticles have been extensively studied as drug carriers in the pharmaceutical fields [6,72–76] and
370 different research teams have published reviews about the SLN formation mechanisms [6,71,77,78].
3.1. Solid lipid nanoparticles preparation methods
Solid lipid nanoparticles are made up of solid lipid, emulsifier, and water/solvent using different methods [79]. Selection of
375preparation method depends on solubility and stability of the drug, type of lipid, and route of administration [7]. The widely reported preparation techniques are: a) High pressure homogenization. b) Ultrasonication/high speed homogenization.
380c) Solvent evaporation method. d) Solvent emulsification–diffusion method. e) Supercritical fluid method. f) Microemulsion based method. g) Spray drying method.
385h) Double emulsion method [70,77–81]. Table 2 shows a summary of some SLNs used in DDS.
3.1.1. High-pressure homogenization High-pressure homogenization is a simple, reliable, and easy to scaleup technique for the preparation of SLNs [70,82]. This
390method was first used for SLN production by Muller and Luke [80] Q7. HPH involves high pressure (100–2,000 bar), which pushes the drug–lipid solution through a narrow gap (few micron sizes) rapidly. The particle size is decreased to submi-cron by the impact of shear stress, cavitation force, and turbu-
395lence [66,70,79,80]. HPH can be performed by two general approaches: hot or cold homogenization. In both techniques the lipid is melted at 5–10°C above its melting point, and the drug is dissolved in the molten lipid [77].
In the hot HPH method, the drug–lipid mixture is com-400bined with the aqueous surfactant solution by high speed
stirring and then passed through high pressure homogenizer at the same temperature. However, the particle sizes can be low due to the high temperature and decreased viscosity of
Figure 6. (a) Models of drug incorporation into SLN, (b) structure of niosome (Redrawn from Uchegbu and Vyas [119]), (c) classification of niosomes as a function of size and number of bilayers. MLV, multilayered vesicle; SUV, small unilamellar vesicle; LUV, large unilamellar vesicle, (d) a schematic diagram of the proniosome protocol. Note: SLN, solid lipid nanoparticle; MLV, multi-lamellar vesicles; SUV, small unilamellar vesicles; LUV, large unilamellar vesicles. Q6
INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS 7
the liquid. This technique can be used for lipophilic drugs 405 [7,80,81].
In the cold HPH method, the drug–lipid mixture is rapidly cooled by liquid nitrogen or dry ice. Then the solid mixture is ground by milling to microparticles and dispersed in cool surfactant solution. This presuspension is then passed through
410 a HPH at room or below room temperature to get desired SLNs. This method is suitable for processing heat-labile drugs or hydrophilic drugs [80,81]. It has been used by Silva et al. [83] to prepare risperidon-loaded SLNs.
3.1.2. Ultrasonication/high-speed homogenization 415 Solid lipid nanoparticles can also be prepared by ultrasonica-
tion or high-speed homogenization techniques. To accomplish smaller particle sizes, combination of both ultrasonication and high-speed homogenization can be applied. In this method, the drug is mixed with molten solid lipid and added to aque-
420 ous surfactant solution and mixed by a high speed homogeni-zer (8,000 rpm for 15 min) [66]. Afterward, the pre-emulsion solution is ultrasonicated at 0°C by a sonicator to reduce par-ticle sizes. The obtained nanoparticles are filtered and stored at 4°C [81]. This method reduces shear stress and uses com-
425 monly available equipment. However, metal contamination due to ultrasonication, and physical instability such as particle growth upon storage are likely to occur in this method [80,84].
3.1.3. Solvent evaporation Solid lipid nanoparticles can also prepared by solvent evapor-
430 ation method. The lipophilic drug is dissolved in an organic water-immiscible solvent like cyclohexane and dichloro-methane. The solution is emulsified in an aqueous solution using a high speed stirrer [7,77]. The solvent is evaporated at room temperature and reduced pressure, resulting in nano-
435 particles being formed in the aqueous phase by precipitation of the lipid. The particle sizes depend on the lipid concentration in the organic phase. This method is continuous and can be scaled up easily. However, biomolecules may be damaged and residual organic solvent may remain in this method
440 [80,81]. This technique has been studied by different research-ers for drug delivery approaches [85].
3.1.4. Solvent emulsification–diffusion In this method, a partially water-miscible solvent which dissolves the lipid, such as benzyl chloride, butyl acetate, ethyl
445acetate, etc., is used. Initially, at the temperature that lipid dissolves in solvent, water is added slowly to the solvent to arrive the saturation and thermodynamic equilibrium point. Thereafter, lipid and drug are dissolved in this saturated solvent. Subsequently, a saturated aqueous phase containing
450surfactant is added to the initial phase which contains lipid, by mixing with a stirrer to form an oil–water emulsion, followed by water addition to the system in a ratio of 1:5 to 1:10 to initiate solvent diffusion and lipid nanoparticle forma-tion. This step is performed at room temperature, or at initial
455lipid dissolving temperature. Finally, the solvent is removed by vacuum evaporation or lyophilization [81]. This method is used by researchers to prepare SLNs for different pharmaceu-tical aims [86–88].
3.1.5. Supercritical fluid method 460This is an alternative method for preparation of SLNs using a
supercritical fluid. Usually the dissolving power of fluids may be different under ambient and supercritical conditions. In this technique, lipid and drug are dissolved in a supercritical fluid and mixed under critical pressure and temperature in a
465homogenizer. Afterward, this mixture is passed through an atomizer in an expansion vessel. The fluid is allowed to evaporate and SLNs are formed [77]. Of the many candidate gases available, such as CO2, ammonia, ethane, methane, and propane, CO2 is the best choice as supercritical fluid in
470this method because (i) it is generally safe; (ii) has an easily accessible critical point; (iii) is not toxic; (iv) is not expensive; and (v) is environmentally acceptable [81]. In addition to the process describe above, nanoparticles can also be produced by other combinations: gas/supercritical anti-solvent, aerosol-
475solvent/extraction-solvent, and supercritical fluid extraction of emulsions [70]. In the latter method, the use of organic solvents is avoided, dry powder nanoparticles are obtained, and only mild pressure and temperature are needed [80]. This method is used for the preparation of SLNs in several studies
480[89–91].
Table 2. A summary of some solid lipid nanoparticles used in drug delivery systems.
Technique APIs/proteins Category Stabilizer Route Mean size or size
range (nm) Reference
HPH Risperidone Antipsychotic Imwitor1� 900K Oral 114 [83] Tagat1� S Sodium deoxycholate
HPH Clotrimazole Antifungal Dynasan1116 In vitro
3.1.6. Microemulsion-based method Microemulsions are clear solutions composed of a lipid phase in water (low melting fatty acid, drug, emulsifier, co-emulsi-fier, and water). Addition of a hot microemulsion to cold
485 water (2–3°C) while stirring leads to precipitation of lipids as fine particles. Finally, the prepared SLNs can be collected by ultracentrifugation. This method needs high volumes of water and efficiency of SLN production is low [66,80]. This method has been studied by different researchers [92,93].
490 3.1.7. Spray drying Spray drying is a cheaper alternative process to lyophilization [80]. In this method, the molten drug–lipid solution is atomized by centrifugal, pneumatic, ultrasonic, or electrostatic atomization techniques and then transferred to a spray dryer
495 which is heated by hot gas. Rapid evaporation of solvent generates dried SLNs. The obtained nanoparticles can be separated by a cyclone, an electrostatic precipitator, or a filter (Figure 5c) [84]. This method is recommended for lipids with melting points over 70°C [70].
500 3.1.8. Double emulsion This method is commonly used for hydrophilic drugs. The drug is dissolved in an aqueous solvent and is then added to the melted lipid. A stabilizer like gelatin or poloxamer-407 is added to the emulsion and then this solution is dispersed in an aque-
505 ous phase which contains hydrophilic emulsifier such as PVA. The nanodrops can be separated by evaporation or filtration of the double emulsion solution [81]. Double emulsion is used for preparing SLNs for various pharmaceutical uses [94,95].
4. Niosome
510 Niosomes are nanocarriers that have been considered by many researchers and pharmaceutical companies. Niosomes are colloidal particles formed from the self-assembly of nonionic surfactants in aqueous medium resulting in closed bilayer structures. They were introduced in the cosmetics industry
515 for the first time in the 1970s and were used as DDS from the 1980s on Nasir et al. [103]. They can accommodate light-weight molecules, proteins and genes during their bilayer membrane formation [104]. Hydrophilic molecules are embedded in the particle core, whereas hydrophobic ones will
520 localize within the bilayer shell (Figure 6b). Niosomes are single or multiple layered. They are classified in terms of size or few bilayer: (i) multi-lamellar vesicles (MLV), (ii) large unilamellar vesicles (LUV), and (iii) small unilamellar vesicles (SUV) (Figure 6c) [105]. Niosomes are fabricated from amphi-
525 philic, nonionic synthetic surfactants with or without choles-terol or other lipids [7]. Niosomes and liposomes are similar in structure and mode of drug entrapment. Biodegradability, biocompatibility, easy storage and handling, low toxicity, and the ability to functionalize for targeted drug delivery are
530 benefits of both liposomes and niosomes, but the synthetic surfactant which is used in niosome production causes lower cost and higher chemical stability than is the case for the phospholipid-containing liposomes [7,106]. In recent years, numerous researchers have studied different ways of preparing
535niosomes and their subsequent application in pharmaceutical settings [107–111].
4.1. Niosome preparation methods
The general method of preparing niosomes involves solvent evaporation to produce a lipid film, followed by hydration
540with hydration medium. However, there are variants of this method that influence few bilayers, drug entrapment efficiency, size, and size distribution of niosomes. Which prep-aration method should be selected depends on the intended niosome application [8].
545The widely reported preparation techniques are: a) Thin film hydration technique. b) Freeze-drying. c) Reverse phase evaporation. d) Ether injection.
550e) Sonication method. f) Microfluidization method. g) Proniosome application. h) Heating method. i) Freeze–Thaw method.
555j) Bubble method. Table 3 shows a summary of some niosomes used in DDS.
4.1.1. Thin film hydration technique In this technique, surfactants and cholesterol are dissolved in an organic solvent or a mixture of volatile organic solvents. Then
560the solvent is evaporated under reduced pressure. Subsequently, a great volume of aqueous buffer is added to the resulting thin layer on the inner surface of the vessel at temperature above the transition temperature of the used lipid. The hydration step in which the two phases interact, more than any other steps, will
565affect the properties of the niosomes (Figure 7a). Subsequently, the aqueous phase containing drug is added slowly to the flask at room temperature. It is possible to remove and retrieve the formed noisome particles by several techniques, such as centri-fugation, dialysis or filtration. The niosomes preparations can
570be lyophilized and packaged under aseptic conditions. This method of noisome production is currently not used,
because of deficiencies in particle size reduction, as well as ves-icle formation with many layers. The niosomes produced by this method are therefore primarily used as an intermediate product.
575Current efforts aim to resolve the mentioned deficiencies by testing alternative methods for particle size reduction such as using a HPH, or passing prepared MLVs by high pressure through appropriate size cutoff membranes [8]. Drugs which are loaded by this method include: minoxidil, nimesulide, insu-
580lin, glucocorticoid, methotrexate, antioxidants, etc [112–117].
4.1.2. Freeze-drying In this method, a surfactant, cholesterol, and other additives are dissolved in an organic solvent, after applying a thin film hydration procedure. The buffers to be used in this part of
585process must contain glucose or any other appropriate anti- freeze material (cryoprotectant). After hydration and MLV niosome formation, vesicles are chopped and converted into SUV vesicles. They are dried completely by freeze-dryer devices, after which drug enclosure inside the niosomes is
INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS 9
Figure 7. (a) Thin film hydration protocol (Redrawn from Moghassemi and Hadjizadeh [124]), (b) a schematic diagram of drug inducing to the freeze dried niosomes, (c) noisome preparation by reverse phase evaporation protocol (Redrawn from Moghassemi and Hadjizadeh [124]), (d) a schematic diagram of the ether injection protocol (Redrawn from Moghassemi and Hadjizadeh [124]).
Table 3. A summary of some niosomes used in drug delivery systems.
Technique APIs/protein Category Stabilizer Route Mean size or size
range (nm) Reference
Thin film hydration Minoxidil Antihypertensive vasodilator Brij 52, cholesterol Transdermal 976 [113] 1082 441 Brij 76, cholesterol 575 843 Span 20, Cholesterol
Span 40, Cholesterol Span 60, Cholesterol
Thin film hydration Dithranol Anti-psoriatic Span 60, cholesterol Transdermal 5,000 [133] Thin film hydration Gentamicin Antibiotic Tween 60, cholesterol Ophthalmic 1,200 [134]
1,040 Tween 80, cholesterol 760 Brij 35, cholesterol
Thin film hydration Meloxicam Anti-inflammatory Span 60, cholesterol Transdermal 187 [135] Thin film hydration Ketoconazole Antifungal Span 40, cholesterol In vitro 5,400 [136]
4,800 6,300 Span 60, cholesterol
Tween 60, cholesterol Freeze-drying Ginkgo biloba Herbal medicine Tween 80, Span 80, cholesterol Oral 661 [137] Reverse Phase
Evaporation 5-Aminolevulinic
acid Photodynamic therapy
(anticancer) Span 60, cholesterol Transdermal 611 [138]
Reverse phase evaporation
Ellagic acid Antioxidant Span 60 and Tween 60, cholesterol Transdermal 124–752 [122]
Ether injection Diclofenac sodium
Anti-inflammatory Span 60, Sorbitan monostearate, cholesterol
In vitro 3,700 [123]
Ether injection Fluconazole Antifungal Span 60, cholesterol Oral 70–78 [126] Ether injection Adriamycin Anticancer Dialkyl polyglycerol ether,
cholesterol Pulmonary — [128]
Sonication Cilexetil Antihypertensive Span 60, cholesterol Oral 242 [139] Sonication Dynorphin B Endogenous opioid peptide Span 60, cholesterol Intravenously
injection 220–250 [140]
Sonication Lornoxicam Anti-inflammatory Span 60, cholesterol Transdermal 1,125 [141]
10 F. HAGHIRALSADAT ET AL.
590 accomplished by mixing of the dried nanoparticles with a drug-containing aqueous phase (Figure 7b) [118].
4.1.3. Reverse phase evaporation This method is designed to form large monolayer niosomes (LUV). These kinds of single-layered niosomes have several
595 advantages in comparison with multilayer niosomes such as: high encapsulation capacity of water soluble drugs and savings in the amount of lipid needed.
In the first preparation step, surfactant and necessary addi-tives are dissolved in an organic solvent. Then the aqueous
600 phase, containing the drug, is added to the organic phase, whereafter the two-phase system is converted to an emulsion by sonication or other mechanical devices. In this stage, water droplets are dispersed in the organic solvent and surfactant molecules surround them. The organic solvent is removed
605 by rotary evaporation under reduced pressure. During this evaporation process, LUVs are formed (Figure 7c) [119,120]. This method has been used for the preparation of niosomes entrapping naltrexone, ellagic acid (EA), diclofenacsodium (DCS), acetazolamide, etc [120–123].
610 4.1.4. Ether injection In this method, a small amount of lipid is dissolved in diethyl ether or a mixture of ether and ethanol, followed by slow injec-tion into an aqueous phase containing water-soluble drugs and surfactant (at the transition temperature of the surfactant).
615 Subsequently, the remaining ether is removed under vacuum. Ultimately, mono-layer vesicles are produced (Figure 7d) [124]. This method has been used for the preparation of niosomes with entrapped gadobenate, DCS, fluconazole, rifampicin, adriamycin, etc [123,125–128].
620 4.1.5. Sonication method In this procedure, drug solution is added to surfactant/ cholesterol, whereafter the mixture is exposed to a sonicator probe at the surfactant transition temperature for minutes [129]. The sonication procedure has been used for diallyldisul-
625 fide loading in niosomes [130].
4.1.6. Microfluidization method This procedure has several advantages such as: more uniform-ity, smaller size, direct formation of monolayer niosomes, and
higher repeatability. In this method, high velocity jets are used 630in micrometer scale. The lipid is dissolved in isopropyl alcohol
and passed through a central channel, whereas an aqueous solution is added from out of two adjacent channels. Lipid and adjacent aqueous flows are concentrated at the intersec-tion point. Inflow velocities will determine flow concentrations
635at the intersection point and the thus created interface [129]. Niosome formation using this method depends on
penetration of lipid nanoparticles by the aqueous phase, eventually leading to self-assembly of lipid nanoparticles and finally vesicle formation. Size and size distribution of
640nanoparticles can be controlled by varying lipid concentra-tions and flow conditions.
4.1.7. Proniosome application In this method, a water-soluble carrier is coated with surfac-tant. Then the carrier is resolved during the hydration process
645at a temperature above the surfactant transition temperature, whereby niosomes are formed. Some remarkable advantages of this process are: high velocity of the production process, and easy applicability of this method in industrial productions (Figure 6d) [118].
6504.1.8. Heating method In this method, the vesicle components are hydrated separately under nitrogen atmosphere at room temperature for 1 h. Then, heating at 120°C in containers stirred at a speed less than 1,000 rpm is performed for 15 min, to completely
655melt the vesicle components. Then, the temperature is reduced to transition temperature of the surfactant, the drug, surfactant and other additives are added to each other, and stirred for a certain period of time to trap the drug into the vesicles (Figure 8a) [131].
6604.1.9. Freeze–thaw method In this method, the first step is to create empty niosomes according to the thin film hydration procedure. After reducing the size of the niosomes, they are kept at � 196°C for 5 min with an appropriate concentration of drug, followed by rapid
665transfer into a water bath at surfactant transition temperature for 5 min. This cycle is repeated two to four times so that the drug becomes efficiently enclosed in the vesicles during the
Figure 8. (a) A schematic diagram of the heating protocol (Redrawn from Moghassemi and Hadjizadeh [124]), (b) schematic diagram of the freeze–thaw protocol.
INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS 11
cycles. This method is appropriate for protein trapping in the vesicles (Figure 8b) [132].
670 4.1.10. Bubble method This method allows preparation of niosomes without using organic solvents. Surfactants and additives are mixed in an aqueous phase under nitrogen atmosphere at 70°C. They are mixed for 15 s with high speed homogenizer. Finally, nitrogen
675 bubbles are blown through the mixture at 70°C [124].
4.1.11. Liposome Liposome is a common biliary-spherical carrier composed of phospholipid for biocompatibility, cholesterol for stability and charging agent as an anti-agglomerative or for specific
680 application, e.g., gene delivery [142]. There are several advan-tages in applying liposome including the ease of synthesis, high biocompatibility and similarity with biological mem-brane, biodegradable, nonstimulating agent for the immune system, producible on a large scale, and applicable to drugs
685 with different nature [143]. However, there are a challenge in using liposome due to in
vivo and in vitro instability but it could be solving by modifi-cation of liposome (e.g., PEGylation) and still proposed as a low risk vehicle [144]. The experimental synthesis method is
690 similar to niosomal preparing. Thanks to sustained-release properties of liposomal drugs,
the toxicity activity (for cytotoxic agent) could be improving, leads to pharmaceutical benefits increase and also damage to normal tissue. Delivery of drugs to nonspecified site leads to
695 loss of drugs followed by high-dose drug [145]. To address this issue, sensitizing liposome with the unique features of target cells is a developing technique including functionalizing liposome with peptide and antibody known as active targeting, and incorporation with lipid or specific agent as passive target-
700 ing to create thermos, pH, light sensitive and liposome reduction [146–150].
The permeability of membrane containing glucose and glycerol is dependent on saturation of membrane phospholi-pids and permeability increase with increasing saturation
705 within membrane [151]. Liponiosome, combination of niosome and liposome, is
new developed particles benefits from noisome and liposome both. It could deliver high amount of hydrophilic/hydrophobic drugs and therapeutic gene. Their diameter size is less than
710 150 nm, stable and biocompatible [152]. Increasing the phase change temperature (Tc) of surfactant
will increase the entrapment efficacy and decrease the permeability [153]. Increasing the acyl chain leads to increase in hydrophobic drug encapsulation.
715 Polysorbate PEGylated with sorbitan fatty acid esters (Tween surfactant) play an important role in improving drug entrapment due to PEG agent in comparison to other surfactant [104]. Polyethylene glycol (PEG) is the hydrophilic, biocompatible and biodegradable polymer. In thin film
720 hydration technique, PEG should be added in the final step of liposome preparation, in hydration step [154,155]. By PEGylation, the cellular uptake of nanoparticles might decrease, however the blood circulation of nanoparticles is
prolonged. PEGylation enhances the steric hindrance which 725leads to agglomeration decrease of particles [156,157].
Considering the investigation result on the effect of cholesterol content, we found 30–40% cholesterol content in liposomal formulation that plays a critical role in controlling drug release and improving entrapment efficiency [145]. The
730presence of cholesterol in bilayer space in vesicle compete with drug loading, and high amount of cholesterol may decrease drug entrapment efficacy. As described by El-Laithy et al. [158], the entrapment efficiency enhanced by increasing choles-terol content due to filling the empty space between surfactant
735(phospholipid) by cholesterol, as vesicular cement, leads to strength increase and the permeability decrease of membrane.
Most important parameters involved in drug loading are solubility of drug in melted lipid, polymorphic states of lipid and physio chemical structure of solid lipid matrix [159]. Rise
740in drug release occurs by increasing effective area of particles [160].
Nowadays, nanocarriers are extensively used in food, phar-maceutical, sanitary, and cosmetic industry. Thus, improving large-scale manufacturing can be a response to growing
745indeed. There are several introduced methods for synthesis liposome in pilot or industrial scale. Liposome Producer (Ilya Co., Iran) is a developed instrument for liposome controlling and sterile producing [161].
Industrial method for nanoparticles preparation includes 750aerosol flow reactor method (dissolving drug in volatile organic
solvents followed by spraying with inert gas at 40–400°C) [162], supercritical fluid-based technologies (dissolving drug in super-critical fluid such as CO2 followed by sudden expansion and supersaturation and the deposition of the nano/microdrug)
755[163], HPH (nanodrugs were formed under the strong shear stress, and most affected parameters in size of particles are pressure of homogenizer and few homogenization cycles) [164], continuous precipitation method (by solving drug in water-soluble solvent followed by adding to water contained
760stabilizer) [165] and milling media techniques (size reduction of soluble and insoluble drugs in water with water or buffer using mill made by glass, zirconium oxide and polystyrene resins under the influence of shear force for 45 min) [166].
4.1.12. Gene delivery and liposome 765Gene therapy mainly performed by targeting delivery of thera-
peutic gene within targeted cell or tissue using viral or nonviral vehicles. Applying nonviral vehicles is preferred more because of the problem associated with the viral vehicles, such as (i) immunogenicity (stimulation of the host immune system),
770(ii) toxicity, (iii) mutagenesis, due to the arrival of the gene fragment in a misplaced position, (iv) limitation in transfec-tion of high amount of gene, and (v) costly and arduous production [166].
Applying nanoparticles instead of viral vehicle benefits 775from additional advantages, such as incorporation molecular
imaging agent. Cationic liposomes are in use as gene transfec-tion vector in drug/gene delivery system coping with the limitations of viral vector [168].
There are various methods for encapsulation/incorporation 780of nucleic acids in liposome, e.g., passive encapsulation, etha-
nol drop, reverse phase evaporation, spontaneously formed
12 F. HAGHIRALSADAT ET AL.
vesicles by ethanol injection, and encapsulation in destabilized liposome [169].
4.1.13. In vitro characterization of nanoparticles 785 Loading efficiency. The high drug/gene loading in low
amount of lipid is a positive point in delivery system. There are various methods for determination of drug loading efficacy: (i) digesting lipid membranes with alcohol (ethanol, methanol, and propanol) and Triton X-100 with the volume
790 ratio of 1:20 (suspension:solvent) followed by reading UV–vis spectrophotometer at λmax of drug and calculation the entrap-ment efficiency using the calibration curve of drug in solvent [142,145]. (ii) Centrifuging the suspension using refrigerated centrifuge (17,000g, 60 min and 4°C) followed by reading the
795 absorbance of drug in supernatant regarding to unloaded drug. The loading efficacy was then calculated by difference of initial drug and unloaded drug [142,158].
To determine the successful gene loading efficiency, various amount of liposomes was loaded with gene followed by expos-
800 ing to electrophoresis at 30 kV, unloaded gene then was migrated throughout the gel and loaded gene was entrapped in electrophoresis well. In another method, determination of entrapment efficiency is performed by spectrophotometry at 260 nm [144].
805 Drug release pattern. To study drug release pattern, the semi in vivo medium should be simulated to achieve an approximate drug release pattern close to cells and modified nanoparticle formulation to achieve a controlled release formulation. Drug release is performed by (i) dialysis tube,
810 (ii) reverse dialysis, and (iii) Franz diffusion cell [170]. The medium is contained PBS or FBSQ8 at 37°C (or 42°C for cancer-ous cells), pH 7.4 (or 4, 5.4, and 6.5 for lysosome, endosomal cells, and tumor tissue, respectively) and under gentle vibration. Drug release is calculated by online/offline reading
815 at λmax using spectrophotometer.
Chemical interaction. Therapeutic drug/gene should be entrappedQ9 into/loaded on nanoparticles physically without any chemical interaction between drugs/gene or nanoparticles composition. This means the therapeutic activity may not
820 change during encapsulation. FTIR/IR and MALDI–TOF mass spectroscopy analysis [145,171].
Size diameter, surface charge and shape. The size diameter, zeta potential, and polydispersity index (dispersion index) is monitored using dynamic light scattering technique. Vesicles
825 larger than 1 µm are instable. Decrease in the amount of surfac-tant, low temperature and high drug dose will increase the size. Increasing the ratio of surfactant to lipid and using nonionic surfactant will cause to size reduction of particles [172]. The type and density of electric charge on the surface of liposome
830 effects the interaction of cells–liposome. Neutral electric charge of liposome has low physical stability and also no interaction with cells. Negative charged liposome interacts with cells by endocytosis, and liposomes are exited from plasma and transfer to cells quickly. Positively charged liposome have high interac-
835 tion with negatively charged cytoplasm and interact with cellu-lar membrane by fusion [173]. High zeta potential leads to agglomeration reduction [145]. Surface appearance, internal
bilayers, homogeneity, approximate size diameter is obtained by microscopic imaging using cryo-transmission electron
840microscope and scanning electron microscope [145].
Stability evaluation. The stability of drug/gene delivery system is assayed in two aspects: (i) storage stability (physical stability): the nanoformulation is monitored during 6-month in terms of size diameter, zeta potential, drug/gene loading
845efficiency and PDI by determination in predetermined time intervals [174], (ii) stability of gene delivery system in plasma (biological stability): since free gene is instable serum, gene- loaded liposome is exposed to human serum and the cellular uptake images after and before exposer is compared together
850[175].
4.1.14. Therapeutic efficiency of formulation Therapeutic nanodrugs may cause toxicity on body organs. Small particles are more simply transfected to cell and cause toxicity. The surface charge of nanoparticles leads to increase
855in reactivity with cells and protein. Free oxygen radical is so reactive which leads to oxidative stress. As drug/gene is loaded on nanoparticles, the therapeutic activity should be determined and compared with free drug to specify the effect of encapsula-tion. Cytotoxicity assay (e.g., XTT, MTT, CyQUANT, Alamar
860blue) is performed to compare the cytotoxicity of blank liposome, free drug and drug-loaded liposome. By encapsula-tion of chemotherapy drug, cytotoxicity of drug may be enhanced due to sustained release feature comes by encapsula-tion. CyQUANT assay is based on DNA replication samples,
865cells are seeded in 96 well plate and treated with the following groups under study (blank liposome, free drug, and drug- loaded liposome) followed by washing with PBS and replacing PBS by CyQUANT1� lysis buffer. Then samples passed three freeze and thaw cycle and DNA of duplicate samples was deter-
870mined by fluorescence exposure [142]. Alamar blue assay is a method to measure proliferation of cells based on metabolic mitochondrial activity of cells. Cells (104 per well) were treated with samples diluted in medium. After 24, 48 or 72 h, cells were washed by PBS and Alamar blue solution was added, followed
875by 3 h incubation and cell viability reading by microplate spectrophotometer at 570 nm (excitation)/600 nm (emission) wavelength [145]. The MTT Q10assay is a colorimetric assay for evaluation of cell metabolic activity. For MTT assay, after treatment cell with samples, MTT solution (3-(4,5-
880dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) is added. After 3 h incubation, DMSO is added to dissolve crystals. Cell viability is determined by fluorescence exposure. IC50 doses is an index to determine the concentrations of inhibiting the cell growth by 50% [145].
885Cellular uptake assay is performed to determine the track of the cellular transfection in liposomal drug. Cells is seeded in -well plates (density of 2 � 105 cells/well) and treated with samples (intrinsically fluorescence or dyed with fluorescent agent) for 3 h at 37°C in humidified incubator. Then cells
890are washed three times with PBS and fixed with 4%, parafor-maldehyde solution. Before fluorescence imaging, cell’s nucleus is stained with DAPI (4′,6-diamidino-2-phenylindole) for 15 min [174]. For adherent cells in all method, cells should be transferred to well up to 24 h before starting experiment.
INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS 13
895 The antioxidant activity of encapsulated drug in liposome is determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as a simple, reversible and inexpensive test. DPPH is stable radical with purple color that changed to yellow after receiving electron from anti-oxidant sample. The absorbance
900 at 517 nm is related to anti-oxidant activity of sample. Samples are mixed with DPPH and methanol. Then, placed in a dark place for 1 h and the anti-oxidant activity is read by spectro-photometer [176].
4. Conclusion
905 Polymer-based nanocarriers (PNPs) are prepared by self- assembly of amphiphilic biodegradable copolymers in aqueous solution. Ligands and antigens can be conjugated to block copolymers for controlled DDS. The most important features of PNPs are increased stability of encapsulated drugs, ability
910 to carry, and deliver higher amounts of pharmaceutical agents to the desired tissue, and protection of its contents against hydrolysis and enzymatic degradation.
Niosomes are bilayer vesicles like liposomes which are formed by self-assembly of nonionic surfactants in the aque-
915 ous phase. These nanoparticles can encapsulate a wide range of hydrophilic, lipophilic, and amphiphilic drugs. Some of the major advantages of the niosomes compared to liposomes include their low price, high stability, and lack of necessity for special storage conditions. These advantages have led to
920 increased interest in producing and using niosomal nanopar-ticles as compared to liposomal nanoparticles.
Solid lipids nanoparticles are colloidal drug carrier systems which are prepared from lipids that are solid at room and body temperature, and utilized to carry and deliver hydrophilic and
925 hydrophobic drugs. They can be functionalized for targeted DDS, and are more stable than other lipid nanocarriers. Improving bioavailability and reducing biodegradation of drugs are the most important characteristics of SLNs.
Acknowledgments 930
The authors express their appreciation to Mohadeseh Hashemi, researcher from Department of Life Science Engineering, Faculty of New Sciences & Technologies, University of Tehran, Tehran, Iran assist-ance during the project.
935 Conflict of interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. There is no conflict of interest.
ORCID 940
Fateme Haghiralsadat http://orcid.org/0000-0002-8655-2118 Samira Naderinezhad http://orcid.org/0000-0002-0703-2334
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