Advances of Non-Ionic Surfactant Vesicles (Niosomes) and Their Application in Drug Delivery

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Advances of Non-Ionic Surfactant Vesicles
(Niosomes) and Their Application in Drug Delivery
Xuemei Ge 1,† , Minyan Wei 2,†, Suna He 3 and Wei-En Yuan 2,*

1 School of Light Industry and Food Engineering, Nanjing Forestry University, Nanjing 210037, China;
[email protected]

2 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, and School of
Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; [email protected]

3 Department of Pharmaceutical Sciences, Medical College, Henan University of Science and Technology,
Luoyang 471023, China; [email protected]

* Correspondence: [email protected]; Tel.: +86-21-3420572
† These authors contributed equally to this work.

Received: 20 December 2018; Accepted: 27 January 2019; Published: 29 January 2019

Abstract: Non-Ionic surfactant based vesicles, also known as niosomes, have attracted much attention
in pharmaceutical fields due to their excellent behavior in encapsulating both hydrophilic and
hydrophobic agents. In recent years, it has been discovered that these vesicles can improve the
bioavailability of drugs, and may function as a new strategy for delivering several typical of
therapeutic agents, such as chemical drugs, protein drugs and gene materials with low toxicity
and desired targeting efficiency. Compared with liposomes, niosomes are much more stable during
the formulation process and storage. The required pharmacokinetic properties can be achieved by
optimizing components or by surface modification. This novel delivery system is also easy to prepare
and scale up with low production costs. In this paper, we summarize the structure, components,
formulation methods, quality control of niosome and its applications in chemical drugs, protein
drugs and gene delivery.

Keywords: niosome; drug delivery; non-ionic surfactant; carrier; stability

1. Introduction

Nano-carriers such as liposomes, polymersomes, niosomes, micelles and polymer-based vesicles
can provide an ideal approach for the delivery of therapeutic agents to target sites in the treatment
of diseases [1]. They have attracted attention from researchers because of their advantages, e.g.,
nanocarriers may prolong the half-life of drugs in serum, avoid uptake by reticulo-endothelial systems
(RESs) and reduce non-specific adsorption by optimizing its components or building a multi-functional
surface. And they can also protect the drug from degradation in storage and in in vivo circulation [2,3].
Nano vesicles are widely used as carriers in delivering (or co-delivering) chemical drugs, protein
drugs and gene medicines. Although numerous research works have focused on how to increase the
therapeutic efficacy of drugs with low side effects, only a few of them have been approved for clinical
use. Our goal in this field is to develop a feasible way to generate therapeutically and clinically useful
nano vesicle formulations [4].

Non-ionic surfactant vesicles (Niosomes), which are formulated with non-ionic amphiphiles
in certain aqueous solutions by self-assemble technology, were first used in the development of
cosmetics. In structure, Niosomes are usually multilamerllar or unilamellar vesicles which possess
closed bilayers with hydrophilic cavities as both the internal and hydrophobic shells as the outer
layers to accommodate the active agents. In recent years, with the development of nanotechnologies

Pharmaceutics 2019, 11, 55; doi:10.3390/pharmaceutics11020055 www.mdpi.com/journal/pharmaceutics

 

Pharmaceutics 2019, 11, 55 2 of 16

in the field of pharmaceutics, more and more studies have focused on niosomes as nanocarriers
for drug delivery. Niosomes can be an alternative to liposomes and polymersomes due to their
ability to encapsulate different kinds of drugs for the purpose of increasing their stability and
efficacy. Unlike other nanoparticles, structurally, liposomes, polymersomes and niosomes have many
similarities, and they can all be loaded with both hydrophilic and hydrophobic drugs; therefore,
they could co-deliver both hydrophilic and hydrophobic drugs in one vesicle. Due to excellent
biocompatibility and relatively low toxicity, liposomes have attracted much attention, especially after
Doxil®was approved by Food and Drug Administration (FDA) and used in clinical trials [5]. Compared
with liposomes, niosomes have advantages such as good stability, low cost, easy formulation and
scaling-up. Niosomes are much more stable because their forming materials, non-ionic surfactants,
are more stable than those of lipids both in terms of physical and chemical stability. Also, the PEG on the
surface of liposomes which could prolong the half-life after being administrated was limited because
the lipid bilayer can maximally tolerate about 5%–6% mol% of PEG, and may cause some stability
problems such as the lysis of liposomes at high concentrations. The formulation processing was much
easier due to the good stability of the niosomes. And niosomes are much cheaper than liposomes [6–8].
Polymersomes could serve as a promising nano carrier technology, but the membrane-forming material
needs lots of synthesis work to obtain the amphipathic block copolymer. The size, Zeta potential
and in vivo performance of niosomes can be optimized by selecting its components and formulation
methods according to the requirements [9]. Some niosomes are commercially available, and clinical
trials have indicated the successful application of niosomes as drug carriers [10,11]. Furthermore,
Niosomes can be prepared for many kinds of formulations for different clinical uses. For example, one
study aiming to investigate novel niosomes based on nano vesicles for the treatment of pulmonary
diseases by inhalation completed its Phase 1 study in 2017. Melatonin niosome oral gel was formulated
in order to overcome the problem of absorption and stability. Their pharmacokinetic properties,
sleep induction effect and adverse events will be determined in clinical study [12]. Based on these
developments and the advantages of niosomes, the structure, components and formulation methods
are introduced in this paper and their potential clinical applications are also discussed.

2. The Structure and Components of Niosomes

2.1. The Structure of the Niosomes

It is important to understand the basic structural units of niosomes, because that may determine
which substances can form niosomes and the loading mechanism of drugs for delivery. Similar
to the liposomes, niosomes are non-ionic surfactant vesicles with a bilayer structure (Figure 1).
Hydrophilic heads are opposite to aqueous solutions and hydrophobic heads are opposite to
organic solutions [13]. Bilayer vesicles can be divided into unilamellar and multilamellar vesicles
(Figure 1) [12,14]. Multilamellar vesicles are concentric circles constructed by at least 2 bilayer
vesicles or a large vesicle embodying one or more small vesicles (Figure 1b,c). Therefore, the particle
size of multilamellar vesicles is usually larger than that of unilamellar vesicles. As for unilamellar
sorbitan monostearate (C18-sorbitan monoester)-cholesterol niosomes, X-ray scattering data showed
a bilayer spacing of 15 nm and a thickness of 3.3–3.4 nm. Generally, niosomes are in the sub-micron
(colloidal) size range. The particle sizes of small unilamellar vesicles (SUV) were about 10–100 nm,
large unilamellar vesicles (LUV) 100–3000 nm, and multi-lamellar vesicles (MLV) greater than 5 µm,
while a few “giant” (> 15 um) vesicles have been reported [13–15].

 

PPhharamrmacaecueutitciscs2 2001198, ,1 110, ,5 x5 FOR PEER REVIEW 33 ooff 1166

Figure 1. Schematic structures of non-ionic surfactant vesicle. (a) unilamellar vesicle, (b,c).
mFuigltui-rlea m1.e Sllcahrevmesaitcilce .structures of non-ionic surfactant vesicle. (a) unilamellar vesicle, (b,c). multi-
lamellar vesicle.

2.2. The Components of the Niosomes
2.2. The Components of the Niosomes

A niosome consists of drugs, cholesterol or its derivatives, non-ionic surfactants and, sometimes,
ionic Aam nipohsiopmheil ecos.nsTihstes odfr durgusg, sb, ochtholehsytderolp ohri liitcs daenrdivahtyivderso,p nhoonb-ioc,nicca snurbfeacteannctasp asnudla, tseodmeintimthees,
niioonsiocm aems.pHhyipdhroilpehs.i liTchder udgrsuagrse, ebnocathp suhyladterodpinhitlhice caonrdre shpyodnrdoipnhgocboirce, , wcahni lebeh yednrcoapphsoubliacteddru gins atrhee
enitorsaopmp eds. iHn ythderohpyhdirloicp dhroubgics raergei oencoafptshuelabtielady ienr .tTheh ecoprrroepseproanmdionugn ctoorfec, hwohleilset ehryodl risopadhdobedic tdortuhges
nairoes oemnterasptopeadch inie vtheet heydmrospthsotbabicl erefgoriomnu olaf ttihoen bdiluaeyteor.i Ttshien tperroapcteiro anmwoiuthntn ofn c-ihoonliecssteurrofal cist aandtdse[1d6 t]o.
Othnely nciohsoolmesetesr tool accahnineovte ftohrem mtohset ssttraubclteu froeromfuthlaetiboinla dyuere, tbou ittsit icnatenrmacitxiown iwthitth enobnil-aiyonericm suemrfabcrtaanet,s
p[l1a6y]i.n Og nthlye rcohloeloefstreergoul lactainngotth efosrtmru ctthuer esatrnudctfluerxei boifli ttyheo fbthileaymere,m bburta nite caasna dmeipxe nwditahb ltehbeu bffielar.yer
memInbrnainoes,o mpleasy,inogn -tihoen ircoslue rfoafc traengtuslarteintgh ethmea isntriuncgtruerdei eannt,dr aftlheexribtihliatny pohfo sthpeh omlipemidbs,rawnhei cahsi sa

tdheppernimdaabrlye cboumffpero.n ent in liposomes. Non-ionic surfactants used in the niosomes are amphipathic,
includInin ngiotesorpmeenso, indosn[-1io7]n,icp osulyrsfaocrtbaanttess a[r1e8 t]h, eS pmaanisn [i1n9g]r,eadlikeynlt,o rxaytheethr ythleanne sph(uosuphalolylipfirdosm, wCh1i2cht ois
Cth18e )p[r2i0m,2a1r]ya cnodmspooonne.nStq iuna lliepnoes,oams easm. Nemonb-eiornoifct shuertfearcptaentosi dusfeadm inly ,thisea nnioastoumraelsl iapried .aImt ipshuipseadthtioc,
pirnecpluardeingio tseormpeenso, iwdist h[1t7h]e, paodlvyasnotrabgaeteosf [e1n8h],a Snpcaings [t1h9e]r, iaglikdyilt yoxaynedthstyalbeinlietsy (oufsuniaollsyo mfroemfo rCm12u ltaot iCo1n8s)
w[2it0h,2m1]i nainmda lscoy otont.o Sxiqcuitayleinev, itarso a nmdeimn bveivr oo[f1 t7h].e Ptoelrypseonrobiadte fiasmoinlye,o ifs tha enmatousrtailm lippoirdt.a nItt inso uns-ieodn itco
spurefapcatraen ntsioesmompleosy, wedithin thneio asdovmaentfaogrem ouf leantihoannsc.inFgo rtheex arimgipdliety, nainods osmtabesilictoyn otfa ninioinsogmpeo lfyosromrublaatteio8n0s
owffietrhe mxcienlilmenatl pcryotpoteorxtiiecsitfyo ring evniterod ealnivde riny ivnivfo r[m17u]l.a Ptiolnysaonrdbattrea nis foenctei oonf ethffiec imenocsyt ,ibmepcaourtsaenot fntohne-
piolnyiec tshuyrlfeancetagnltysc eoml (pPloEyGe)dc ihna inniosspormesee fnotrimnuitlsatsiotrnusc. tFuorer e[1x7a,m18p]l.e,S nimioislaormlye,sn cionsotamineisncgo pnosliystsionrgbaotfe
p8o0l yosfoferbr aetxec2e0lleanlsto pdriospelartyiessu fpoerr igoernpee drfeolrimvearnyc ieni nfovrmitruol.aTtihoenP aEnGd ctrhaaninsfseoctfipoonl yefsfoircbieantecy2,0 bmecaakuesteh oef
stuhref apcoelpyreothpyelretinees galnydcoclo m(PpEoGs)i tciohnaionfs npioressoemnte sins iimtsi lsatrutocttuhraet [o1f7P,1E8G].y Slaimteidlanrlayn, onpioarstoicmleess, cwohniscihstdinog
nooft paofflyecstorthbeatien 2te0g arlistoy dofistphleayC saucop-e2r-icoerl lpmerofonromlaaynecrei innv viittrroo,.a Tllhoew PiEnGg tchheaaindsh oefs ipoonlyosfonrabnatoep 2a0r tmicalekse
ttohteh seuirnftaecset ipnraolpeeprittihees laiunmd c, oamndpaocstiitvioanti onfg ntihoesotrmanes csyimtoisliasr ptoa tthwata oyf. PTEhGeryelfaotreed, niaonsopmaersticloenss, iwsthinicgh
odfop onlyost orabffaetcet 20thcea ninptaesgsritnyt aocft tthhreo uCghactoh-e2-Ccealclo -m2-ocnelollmayoenr oliany evritarnod, tahlleonwinincgre atshee thaedthreasniospno rotf
onfatnhoepraprteiculteisc atog etnhtes ainctreostsinianlt eesptiinthael leiupmith, ealinadl baacrtriiveartitnog otbhtea intranbsceyttteorsitsh epratphewuatiyc. eTffheecrte[f1o8r]e.,
Tnhieosnoimoseos mcoanl sciastrirniegr o(fS poalnys6o0r/bTawte e2e0n c6a0n/ pcahsosl einst etaroctl )thcraonusgihg nthifiec Canatcloy-2i-nccerlel amseontohleayeenrt raanpdm tehnetn
eifnficcrieanscey tohfe tthreandsrpuogrst boef ctahuesreapoefutthice iangteenratsc taiocrnobsse tiwnteeesntinthael edpriutghselaianld btahrreiearc ytol cohbatianisn oaf Sbpetatner
6t0he[1r9a]p.eutic effect [18]. The niosomal carrier (Span 60/Tween 60/cholesterol) can significantly increase
the eAndtrdaiptimoneanllty ,esffoimciencchya rogfe dthme odlreucgusle bseocraiuosnei coafm thpeh iipnhteilreasc,tsiounch baestwdieceenty tlhpeh dosrpuhgas tean(Dd CthPe) aancdyl

pchoasinpsh aotfi dSpicanac 6id0 ([n1e9g].a tively charged molecules), stearylamine (SA) and cetylpyridinium chloride
(positAivdeldyitcihoanraglleyd, msoomleec uchleasr)gaerde umsoedlecinultehse onri oiosonmice asmfoprhtihprheielepsu, rspuocshe sa:sl odaicdeitnygl dprhuogssp,hinactere (aDsiCnPg)
tahnede fpfihcaocsyphantidiec nahcaindc(ninegasttiavbeillyi tych[a1r2g]e. dF omr oelxeacmulpesle),, sthteearcyaltaimoninice li(pSiAd), 2a,n3d-d ic(etetytrlapdyericdyilnoixuym)
pcrholpoarind-e1 -(apmosiniteiv, eislyc ochmabrgineedd mwoiltehcunloens)- iaornei cusuedrf ainc ttahnet sntiospormepesa rfeorc athtiroenei cpunriopsoosmese: slo. aTdhiengfo drmruegds,
ciantciorenaiscingio stohme esefwfiictahcya paonsdit iveenhchaanrcginegc anstainbtileirtayc t[e1l2e]c. trFoostra tiecxaalmlypwlei,t htthhee ncaetgiaotnivice lyli-pcihda,r g2e,d3-
pdhio(tsepthraadtecgyrloouxpys) opf rtohpeaDnN-1A-amanidnei,n cirse acsoemthbeintreadn swfeictthio noenffi-icoiennic ys[u1r7f]a.cAtanndtst hteo captrioepniacren iocsaotimonesic
cnainosinocmr eass. eTthhee fdorumgeden ccaatpiosnuilca tnioionsoefmfiecise wnciyth, s ak ipnopsietrivmee cahtiaorngee ncahna nincetemraecntt ,ealencdtrboestuatsiecdaltloy pwrietpha trhee
hnyebgraidtivneiloys-ochmaarlgceodm pphloesxp[h2a2t]e. gArdoduiptiso onfa tlhlye, cDhNarAg eadndm ionlcerceualsees tthoet htreanbsilfaeycteironca enffaiclsieonicnyc r[e1a7s].e Athned
stthaeb iclaittyioonficn nioiososommesesd cuaen tioncaresausieta tbhle dzreutag (eζn)-cpaoptseunlatitaiol.nG eeffniceireanllcyy,,f suklilny peleercmtreoasttiaotnic esnthabanilcizeamtieonnt,
naened sbea uζ-speodt eton tpiarel pofaroev heryb+r3i0dm niVosoormbaelo cwom−p3l0exm [V22, ]b.e Acadudsietipoanratlilcyle, schwairtghead hmigohleζc-uploetse tnot itahlea breilaleysesr
lickaenl yatlosoa gingrceregaste dthue tsotaebleilcitryi coafl rneipouslosmioens[ 2d3u,2e4 ]t.o a suitable zeta (ζ)-potential. Generally, fully
electrostatic stabilization needs a ζ-potential of over +30 mV or below −30 mV, because particles with
a high ζ-potential are less likely to aggregate due to electrical repulsion [23,24].

 

 

Pharmaceutics 2019, 11, 55 4 of 16

Pharmaceutics 2018, 10, x FOR PEER REVIEW 4 of 16
3. Methods for Formulation and Evaluation of Niosomes
3. Methods for Formulation and Evaluation of Niosomes
3.1. Formation of Niosome by the Proniosomes Method
3.1. Formation of Niosome by the Proniosomes Method

Proniosomes, also called dry niosomes, are dry-form formulations of the non-ionic surfactant
vesicPlersownihoiscohmceasn, ablesoc ocnavlleerdt eddryin ntoionsioomsoems, easrea fdterry-hfyodrmra tfioornmiunlaatsiohnosr totfi mthee, annodn-aioreninco swurwfaicdtaenlyt
uvesesidcliens twhehifcohr mcaunl abteio cnonovf enritoesdo minetos dniuoesotomtehse airftgero ohdydsrtaabtiiolinty in[ 6a,2 s5h,2o6r]t. tiPmroen, iaonsdo marees ncoowns wistidoeflya
wusaetder -inso tlhueb lfeocramrruilearticoona toefd nwioitshomnoens -diounei ctosu trhfeaicrt agnotos,da nstdabairleityea [s6il,2y5h,2y6d]r. aPtreodniinotsoomnioess ocmonessibste foofr ea
uwsaatgeer-s(Foilguubrlee c2a)r.riTehr icsomateedth wodithp nososne-siosensics seuvrefraacltaandtvsa, anntadg aerses euacshilya shygdoroadtepdh iynstoic anlioasnodmcehs ebmefiocrael
sutsaabgilei t(yFfiogrurloen 2g)-.t eTrhmiss mtoerathgoed, c opnovsseensiseensc esefvoerrtarla nasdpvoarnttaatgioens, sauncdhe aass egtooosdc aplehyuspic[a2l7 ,a2n8d]. cAhnedmtihcaisl
tsetachbinliotlyo gfoyr mloanyg-oteffremr mstaonraygme, ocroenovpentiioennscef ofrorn tiorasnosmpeosrttaotiboen,f uanrtdh eerasfoe rtmo usclaaltee dupin [2d7if,2fe8r]e. nAtnfdor tmhiss,
steucchhnaoslotagbyl emtsayan odffgeer lm[2a9n,3y0 m]. oErxet eonpstiivoensre fsoera nrcihoshoamseasl stoo rbeep ofurtrethdetrh faotrpmruonlaitoesdo mine ds icfofeurlednbt efoursmesd,
ssuuccche asss ftualblyletisn atnhde gapelp [l2ic9a,3ti0o]n. Eoxftednrsuivged reelsiveaerrcyht hharos uaglsho dreifpfeorretendt rtohuatt epsr,osnuicohsoamseosr caol,uplda rbeen tuesreadl,
dsuecrmceasls,fturlalyn sidne rtmhea laapnpdlicoactuiolanr [o6f] .dTruhgis disetlhiveebryes tthwroauygtho mdiifnfiemreinzte rthoeutwesa,t esruccohn ates notrianl,n pioasroemnteesrainl,
odredrmeratlo, tirmanpsrdoveremthael iarnsdta obciluitlya,ra.[n6d] Tmhaisy isp rthove ibdeesta wsoalyu ttioo mn fionrimloinzeg -ttheer mwastteorr acgoen.tent in niosomes in
order to improve their stability, and may provide a solution for long-term storage.

FFiigguurree 22.. FFoorrmmaattiioonn ooff nniioossoommeess bbyy pprroonniioossoommeess mmeetthhooddss..

3.2. Sonication
3.2. Sonication

Sonication is a conventional method for the preparation of niosomes. This method is easy to
Sonication is a conventional method for the preparation of niosomes. This method is easy to

operate; the drug solution (in buffer) must simply be added to the proper mixture of non-ionic
souprefraacttea;n tthaet odprutigm sizoeludtrioatni o(iann dbuthffeenr)s omnuicsat tseidmaptltyh ebed eatderdmedin etod tfhreeq uperonpcye,r temmixpteurraet uorfe naonnd-itoimniec,
surfactant at optimized ratio and then sonicated at the determined frequency, temperature and time,
to obtain the desired niosomes. This is also a suitable way to control the particle sizes of the niosomes.
Dto. oPbatnadino tehte adl.esrierpeodr nteiodstohmatesr.e Tsvheisr aistr aollson iao ssuoimtaebslew weraeyp tore cpoanrterdolw thiteh paanrteicnlec aspizseusl aotfe tdher antieosoofm43e%s.
D. Pando et al. reported that resveratrol niosomes were prepared with an encapsulated rate of 43%
by using two-stage technologies: mechanical agitation and sonication. Sonication can decrease the
dbyia museitnegrs towfon-isotsaogme etsecwhintholnoagrireosw: msiezcehdainsitcraibl uatgioitnat[i3o1n] .aBnudt psoronbiceastoionnic. aStioonniciantvioonlv ecsanth deeucsreeaosfeh itghhe
diameters of niosomes with narrow size distribution [31]. But probe sonication involves the use of
levels of energy, and may cause a sudden increase of temperature and the shedding of titanium [7].
high levels of energy, and may cause a sudden increase of temperature and the shedding of titanium
3[7.3].. Micro Fluidization

3.3. MMicicroro Fflluuididiziaztaiotino n is a new method for the formulation of niosomes, which is based on the jet
principle, i.e., by mixing two kinds of fluids such as alcohol and water in microchannels. Niosomes
can bMe fiocrrom fululaitdeidzawtiiotnh tihs ea dneeswir emdeptharotdic lfeors itzhees faonrdmsuizlaetidoinst roifb unitoiosnombyeso, pwtihmicihzi nisg btahseepda oranm theete jrest,
spuricnhciapslem, ii.xei.n, gbyc omnidxiitnigo ntws,os ukrifnadcst aonft sfluaindds osuthcehr ams aaltceorihaolsl a[3n2d] .wTahteer fionr mmiuclraotciohnanonfenlsi.o Nsoiomseosmbeys
tchaen mbee tfhoromduolfamtedic rwoi-tflhu tihdei zdaetsioirnedis pwaridtiecllye suiszeeds .aIntdi ssirzeep doristetrdibtuhtaitonM boyh oamptmimaidziAng. Othbee pidareatmael t[e3r3s],.
ssuuccche asssf mulilxyinpgre cpoanrdeditinoonns,- isounrifcacstuarnfatsc taanndt voethsiecrl ems afoterrtihales p[3u2r]p. oTsheeo ffodrmeliuvleartiionng othf enriaopseoumtiecs sbiRy NthAe
imnteothcoadn coefr mceilclsrou-fsliunigdimzaictiroonfl uisd iwcsiddeelvy icueseNda. nIot Aiss sreempobrlteed(B tehnacth Mtopoh, Pamremcisaido nAN. OanboeSidy setet mals [I3n3c]..,
Csuacncaedssaf)u. lTlyh eprseizpearoefdt hneonn-iioosnoimc seusrwfaacstabnetl ovwesi6c0lens mfo,rw thiteh pruelraptoivseel oyfn daerlriovweridnigs ttrhibeuratpioenutainc dsigRoNoAd
sintatob icliatyncfeorr coevllesr u8swinege kmsiacrto2f5lu°dCic[s3 3d,3e4v]i.ceD NueantooAthseseamdvbalen t(aBgeenschotfotph,e Pmreiccrisoioflnu iNdaiznaotSioynstmemetsh Iondcs.,,
sCuacnhaadsa)t.h Tehfoe rsmizaet ioofn tohfe nniioossoommeess wwitahs sbmelaolwle r6s0i znems,, bwetittehr rreelpatriovdeulyc inbailrirtyowan ddisetarsibeuotfiofonr amnudl agtoioond,
tshtaebyilhitayv feorb eoevnerw 8i dweelyekus saetd 25in ℃th [e33f,o3r4m]. uDlauteio tno othfen aiodsvoamnteasgiens oref ctehnet myeicarros .flAuinddizathtiiosnm meeththooddiss,
csounchsi dase rtehde afoprmroamtiiosinn gofw naioysfoomr eths ewinitdhu ssmtraiallledr esvizeelos,p bmetetnetr orefpnrioodsoumciebsi.lity and ease of formulation,
they have been widely used in the formulation of niosomes in recent years. And this method is
3co.4n.sTidhienr-eFdil am pHroymdriastiinong Mwaetyh ofodr the industrial development of niosomes.

3.4. TThhinin-Fifilmlm Hhyydrdartaiotino Mn e(tThFoHd ) is one of the most widely-used methods for the preparation of
liposomes. This method could be also used in the formulation of niosomes. It is a simple method

Thin film hydration (TFH) is one of the most widely-used methods for the preparation of
liposomes. This method could be also used in the formulation of niosomes. It is a simple method
which involves dissolving the membrane-forming materials in an organic solvent in a flask. As shown

 

PPhhaarrmmaacceeuuttiiccss 22001198,, 1110,, 5×5 FOR PEER REVIEW 55 ooff 1166

iPnh aFrmigacueureti c3s ,2 0a1f8t,e 1r0 ,r xe FmOoRv PiEnEgR t RhEeV oIErWga nic solvent by vacuum evaporation, a layer of dried thin5 -ofifl m16
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tddhoiissxtortierbucuhbtniicoiiqnnu. aeTnhidsi sou mtsheeedtrh teooxdgtr eiatshc wtesr i[dw2e1il,ty3h 5u,s3so6end].i ctaot ifoonrmtoulaactqe uniiroesnomioseos mloeasdwedit wh inthar droruwgss iszuecdhi satsr iibnusutiloinn,.
Tdhoixsomruebthicoidn iasnwdi dotehlyeru esxetdratoctfso [r2m1,u3l5a,t3e6n].i osomes loaded with drugs such as insulin, doxorubicin and
other extracts [21,35,36].

Figure 3. Preparation of niosomes by the thin-film hydration method. Reproduced with permission
Ffriogmur e[133.],P preupbalirsahteiodn boyf Enlisoesvoimere, s20b1y4t. he thin-film hydration method. Reproduced with permission
fFroigmur[e1 33]., Ppruebplaisrhateidonb yofE nlsioevsoiemr,e2s0 b1y4. the thin-film hydration method. Reproduced with permission

3.5. Rfervomers [e1d3 ]P, hpausbel iEshvaedpo brya tEiolsne vier, 2014.
3.5. Reversed Phase Evaporation
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Figure 4. Preparation of niosomes by the reversed phase evaporation method. Reproduced with
pFeigrmuriess 4io. nPrferpomara[t1i3o]n, pouf bnliiosshoemdebsy bEyl stehvei erer,v2e0r1se4d. phase evaporation method. Reproduced with
permission from [13], published by Elsevier, 2014.

3.6. OFtihgeurrse 4. Preparation of niosomes by the reversed phase evaporation method. Reproduced with

3.6. Opermission from [13], published by Elsevier, 2014.
Stohmeres other conventional methods are also used for the preparation of niosomes, such as

e3t.h6e. rOSitonhmjeercest oiotnh,erm ciocnelvlaerntsiolnuatli omne, thraonds- marem albsroa nuesepdH fogrr tahdei epnrtepanardatihoenh oefa ntiinogsomeetsh, osduc[h12 a,4s 0e–t4h3e]r.
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Pharmaceutics 2019, 11, 55 6 of 16

This new module may provide a promising strategy for scale-up in industry for the production of
niosomes [12,44]. The formulation method, components and other properties are summarized in
Table 1.

Table 1. Formulation method of niosomes.

Formulation
Method Components Structures Size Zeta Potential Encapsulate Rate

(nm) (mV) (%) Application

Span 60 Unilamellar
4400 ± 210 / 99.2 ± 5.1 Analgesic,

anti-inflammation [45]
Proniosomes

Disorders
Sugar esters 1620 ± 170 / 98.74 ± 0.51 cerebrovascular/cerebral

degenerative diseases [46]

Span 40 and chol or multi-lamellar 1
DCP or lecithin more than 20 / 16.7 ± 1.0

(highest) antihistaminic [47]
µm

Sonication Span 60 cholesterol Multi-lamellar (probably
35.77 higher zeta 29.2 % anti-inflammation [48]

potential)

Monopalmitin From 60.96 ± From −76.83 ±
Micro fluidization glycerol cholesterol 0.36 to 168.40 ± 0.81 to −30.63

dicetyl phosphate 2.26 in different ± 2.06 in / [34]
buffer different buffer

Polyoxyethylene 79.8 ± 3.5%
Thin-film alkyl ethers or From 214 to From −26.73 to (Span 40) Treatment of Androgenetic

hydration method sorbitan 1368 −41.31 76.56 ± 2.1% alopecia [49]
(TFH) monoesters (Span 20)

2.05 ± 0.043/210
Span 60 and ment level
cholesterol 5000 ± 1500 / Entrap

(mg)/total lipid Treatment of psoriasis [50]
(mg)

Reversed phase
evaporation (REV) Span 40 or Span 60 3460, 3610 / 26.27% ± 1.96

(highest) Treatment of glaucoma [51]

3.7. Characterization of Niosomes

Usually, niosomes are evaluated according to their surface morphology, size distribution,
zeta potential, drug loading efficiency and stability during the formulation process and storage.
These characteristics are very important for niosomes because these factors not only affect the
encapsulation rate and stability of the niosomes, but also relate to their performance in vivo. With the
development of detection technology, more and more methods are used in the measurement of
niosomes. Some commonly-used technologies for the characterization of niosomes are summarized in
Table 2.

Table 2. Methods for characterization of niosomes.

Niosome Parameter Measurement
Size DLS, SEM, AFM, STM, CLS

ζ-potential DLS, Electrophoretic mobility

Encapsulation efficiency Encapsulated amount
= total amount × 100%

Encapsulation efficiency (%) The amount of the loaded drug is determined by HPLC,
UV/VIS, Fluorescence

Stability DLS (determine size and zeta potential in 37 ◦C, or in serum to
mimic the in vivo situation), Leaky of the loaded drugs

Abbreviations: DLS (Diameter laser scatter), SEM (scanning electron microscope), AFM (Atomic Force Microscope),
STM (Scanning Tunneling Microscope), HPLC (High Performance Liquid Chromatography).

3.7.1. Sizes and Zeta Potential of Niosomes

Niosomes are spherical in shape and their size may be determined by several techniques,
as summarized in Table 1. Their size distribution and polydispersity index are usually determined

 

Pharmaceutics 2018, 10, x FOR PEER REVIEW 7 of 16

Niosomes are spherical in shape and their size may be determined by several techniques, as
summarized in Table 1. Their size distribution and polydispersity index are usually determined by
laser scattering (DLS) particle size analyzer. To better observe the sharp of the niosomes, SEM, TEM,
AFM and STC are used to determine the morphology of the niosomes. As shown in Figure 5, the
morphology of the blank niosomes and three kinds of drugs, rifampicin (RIF), isoniazid (INH) and
Pphyarrmazacienuatimcs i2d01e9 (,P11Z, A55)-loaded niosomes were observed by SEM and TEM images. No aggregates 7woefr1e6
observed and the nature of blank or drug-loaded niosomes was spherical [52]. The self-assembly of
bnyioslaosmeress cias trtaerreinlyg s(pDoLnSt)anpeaortuisc laensdiz neeaendasl yezneerr.gyTo asb eat tderrivoibnsge rfvoercteh, esuschha raps ohfeathtiengn ioors ommeecsh,aSnEicMal,
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tlihkeem nioorspohmoleosg, yalosfo tnhaembleadn kdinsicoosmomese, smaanyd ftohrrmee, kwinitdhs ao sfidzeru rgasn,greif aomf 1p1i–ci6n0 (μRmIF )w, ihsoenn iianzcidub(aINteHd )waintdh
pnyorisaozminea mdiisdpee(rPsiZoAn )w-liotahd tehde npiroospoemr elesvwele oref sooblsuelravne dC2b4y. STEhMesea anrde TaElsMo aipmpalgieeds. inN dorauggg dreegliavteersyw deuree
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sinticrlruindge: [15)3 ]N. oCnr-yioon-SicE Msurcfoauctldanbt estursuecdtufroers l(acmhoellelasrteitryold iest eursmedin taot ioanvo. iAd nadggitreisgarteipoonr)t. eHdytdhraotplahrigliec
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dsou eonto.[1th0]e iAr FuMni qaulseos tcrouucltdu rbee. uCsoendf otoca ml leaasseurrsec athnen imngormpihcorolosgcyop oyf (nCioLsSoMm)ecso, uasld rebpeoursteedd.[t5o4i]d Ietn wtiafys
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ztaertgaesitzinegr, mefifcicroieenleccyt.r oWphe ohreospise atnod foDrLmSuilnastter uvmeseincltess[ 5w6]i.th narrow size distributions and uniform
morphologies to control their in vivo distribution.

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Sizes and Zeta potential very critical to the pharmacokinetics, bio-distribution, toxicity and
3.7.2. Encapsulation Efficiency of Niosomes
stability of niosomes. It was found that larger vesicles are likely to accumulate in the lung, liver and
spleeTnhwe itehncsahposrut lsaetriuonm ehfafilcf-ileinfecsya fotfe rthsyes tneimosaotmiceins jercetpiorens.eInmtsp rtohpe ecraZpeatbailpitoyt eonft iavlemsicalyesc atuos elotahde
athgegrraepgeautitoicn aogfetnhtes.n Tiohseo mdefsi,naitnidonm oafy nailossooimnve oeknecasopmsuelautniowna enftfeicdieenffceyc tis ssuhcohwans itnox Ticaibtyle, d1e, carneads itnhge
t“atorgtaelt inagmeofufincti”e nicny . thWe efohrompue ltao rfeofremrsu ltaot ethve siacmleosuwnti thofn adrrruogws suizsedd iisnt ritbhuet ifoonrsmaunladtiuon.i foTrhme
menocraphsouloagtiioens teoffcicoinetnrcoyl tohfe nirioinsovmiveos dmisotsritblyu tdioepne. nds on the type of non-ionic surfactant, synthesis

3.7.2. Encapsulation Efficiency of Niosomes

The encapsulation efficiency of the niosomes represents the capability of vesicles to load
therapeutic agents. The definition of niosome encapsulation efficiency is shown in Table 1, and the
“total amount” in the formula refers to the amount of drugs used in the formulation. The encapsulation

 

Pharmaceutics 2019, 11, 55 8 of 16

efficiency of niosomes mostly depends on the type of non-ionic surfactant, synthesis method and other
agents used in the formulation process, such as cholesterol. It is reported that the encapsulation rate
could reach 75%~90% (but that it is commonly in the range of 10%~40%) [57]. For gene materials,
we can also label the DNA/RNA with a fluorescent dye such as calcein for florescence measurements
to determine the loading efficiency.

3.7.3. Stability of Niosomes

The stability of the niosomes plays an important role in their formulation development. It is
affected by the preparation method, loaded drugs, and types of the membrane forming materials.
For their storage, the changes of particle size, zeta potential, morphology and loaded drug leaky rate
may be measured to evaluate the stability. To determine the stability of niosomes during circulation,
we may incubate these drug-loaded vesicles at 37 ◦C and in serum (or even in harsh conditions) to
mimic situations in vivo [58]. The sizes, zeta potential and leakiness of the loaded drugs in niosomes
are measured as a fraction of time to evaluate the stability of these vesicles. The stability of the
nano carriers, such as liposomes, polymersomes and some other lipid- or polymer-based particulates
remains a big concern for drug delivery. How to improve their stability during formulation/storage
and to prevent premature disassembly before reaching the target sites still needs to be addressed.
Compared with liposomes, niosomes possess better stability and have the potential for clinical uses.

4. The Application of the Niosomes in Chemical Drugs, Protein Drugs and Gene Delivery

Niosomes first emerged in the field of cosmetics, and are now attracting extensive attention
as a vesicle delivery system in pharmaceutics. Due to their ability to entrap both hydrophobic and
hydrophilic drugs, niosomes are reported as ideal carriers for the delivery of drugs such as doxorubicin,
vaccines, insulin, siRNA and so on. Their therapeutic effects are widely applicable (e.g. anti-Alzheimer,
anti-cancer, antioxidant, diabetes and antimicrobial) and can be administrated via different methods,
such as intravenously, orally and transdermally [59] (Table 3). Here we summarize three types of the
drugs which can be encapsulated into niosomes and delivered to target sites.

Table 3. The application of niosomes in delivering of drugs.

Surfactant Formulation
Method Loaded Drug Encapsulation

Rate (%) Administrated Application Ref

1 Pluronic L64 REV Doxonrubicin 38.73 ± 1.58 /(cell level) Anti-caner [21]

2 Span 60
Tween 60 REV Ellagic acid 38.73 ± 1.58 Transdermal Antioxidant [60]

Anti-cancer
3 Tween 20 TFH and

Sonication Curcumin 74.5 ± 3.2 / Antioxidant [61]
Anti-inflammatory

150µg/16 mg
4 Tween61 TFH and Tyrosinase l

Sonication Plasmid of niosomal Transderma
(pMEL34) compositions (in vitro) Treatment of vitiligo [62]

5 Polysorbate O1-hBMP-7
Cationic lipid REV pUN

plasmid / / Bone regeneration [63]

Cationic lipid
6 Tween 80 REV pCMSEGFP / Ocular Gene delivery [17]

squalene

7 Polyoxyethylene
alkyl ethers THF Insulin / Oral Diabetes [35]

Vasoactive Anti-inflammatory
8 N-Palmitoyl-glucosamine

Span 60 Sonication Intestinal 24.07 ± 0.83 Intravenous Immunomodulatory ]
peptide administration neurological [64

Disorders and so on
H3N2

9 Monopalmitoyl Melt l
glycerol method antigen / Ora

(Radio-labellin) Intramuscular Flu [65]

 

Pharmaceutics 2019, 11, 55 9 of 16

4.1. Chemical Drugs

For nano-vesicle-based delivery systems, niosomes can be used as an alternative to liposomes and
polymersomes for chemical drug delivery. They possess both a hydrophilic cavity and hydrophobic
shell, and are suitable for chemical drug loading. They can also provide a way for the co-delivery
of two different kinds of drugs to achieve the desired therapeutic effects. As with liposomes and
polymersomes, niosomes have some advantages such as biocompatibility, low toxicity, biodegradability,
etc. Furthermore, their good stability, low cost and ease of storage make them an alternative to
liposomes. Niosomes were developed as carriers of chemical drugs for the treatment of various
diseases such as cancer, diabetes, inflammation and so on.

One application of niosomes in delivering chemical drugs is the use of this formulation to
improve oral bioavailability. Carvedilol is a kind of clinical drug that is widely used in the treatment of
congestive heart failure and coronary artery diseases. But its systemic availability is limited due to the
first-pass metabolism and short half-life after administrated. Numerous studies have worked on ways
of developing new formulations to improve the bioavailability of carvedilol. Niosome is considered as
one solution, because it can protect the loaded drug from degradation, control the releasing profiles
by optimizing its components and avoid first-pass metabolism [66]. It was reported that carvedilol
niosomes can be prepared by a film hydration method with a minimal size of 167 nm (PDI 0.6) and
highest encapsulation rate 77.7% in different formulations. And it has been proved that the release of
all formulations could reach almost 100% with no significant difference after 20 h. The best stability of
the vesicle was observed in two different kinds of formulations (C50S6025T6025 and C40S6030T6030)
by determining the sizes changes [67]. All these results show that niosomes might be developed and
used as a nano-carriers for the oral delivery of therapeutic agents to improve their bioavailability.
Niosomes can be also used as carriers for the delivery of chemical drugs for the treatment of cancer due
to their smaller size, offering a possibility of enhanced permeability and retention in tumor tissue [68].
Niosomes are also incorporated into hydrogels and chitosan/glyceryl monooleate (CH/GMO) as a pH
sensitive formulation for the efficient treatment of cancer [69].

4.2. Protein and Peptide Drugs

Protein and peptides such as insulin and bacitracin may function as important therapeutic agents
for the treatment of diseases. But their clinical application is hindered due to poor bioavailability,
instability during storage and after administration, and also some side effects during the application.
To overcome these problems, niosomes may serve as good carriers for the delivery of various protein
and peptide drugs, and also show good performance in vaccine formulation and application [70,71].

The oral delivery of protein and peptide drugs is still a challenge for macro-biological molecules.
For decades, the non-invasive administration of insulin formulations has attracted extensive attention
and much research. But until now, no truly non-invasive drug formulation is available. It is reported
that niosome was investigated for the delivery of insulin via the parenteral and vaginal routes, and that
it showed a good ability to protect insulin from degradation [72,73]. Pardakhty investigated a method
for the formulation of insulin niosomes (composed of polyoxyethylene alkyl ether surfactant Brij 52 and
Brij 92 or sorbitan monistearate Span 60 and cholesterol) and studied the pharmacokinetic properties of
the insulin encapsulated in niosomes in diabetic rats [74]. The insulin niosome was administrated orally
and its release profile was measured in simulated intestinal fluid (SIF) and simulated gastric fluid (SCF).
The results showed that niosomes could protect insulin from degradation. The insulin niosomes could
reduce the blood sugar as expected, and the relative bioavailabilities (F) were 1.88 ± 0.43, 1.46 ± 0.43
and 1.12 ± 0.57 (%) respectively for three different formulations Brij 92, Span 60 and Brij 52 orally [74].
Another example for the successful delivery of protein/peptide drug is H. Yoshida’s investigation
into the possibility of peroral administration of 9-desglycinamide 8-arginine vasopressin (DGAVP)
by choosing stable noisome-forming materials such as polyoxyethylenealkylethers. In vitro intestinal
absorption of encapsulated DGAVP in niosomes was performed using an intestinal loop model to
mimic an in vivo situation. The results showed that the DGAVP entrapped in niosomes could achieve

 

Pharmaceutics 2019, 11, 55 10 of 16

relatively high concentrations in the acceptor phase of the rat intestinal lumen compared with a
DGAVP solution and DGAVP in the presence of empty niosomes after 120 min [75].

Another application of niosomes is their usage in vaccine formulations. It is known that vaccines
are a powerful tool to prevent and eradicate diseases, but their safety and efficacy are still big problems
for their application. Protein subunit vaccines, which have been proven to be much safer than live
organism-based vaccines, may provide an alternative for vaccine development [76]. Anil Vangala
and colleagues developed a non-ionic surfactant involving a nano-vector which aimed to improve
the physical stability of a dimethyldioctadecylammonium vesicular adjuvant system. The non-ionic
surfactants, such as 1-monopalmitoyl glycerol (MP), cholesterol (Chol) and trehalose 6,6’–dibehenate
(TDB) were added to investigate the changes in stability by measuring the changes of vesicle size and
zeta-potential in two different temperatures. The results showed that the sizes of MP-Chol-DDA-TDB
and MP-Chol-DDA were slightly changed at 25 ◦C. The efficacy of the formed vaccine formulation
was also investigated in this study, and the adjuvant activity was determined in mice against three
subunit antigens. Both MP- and DDA-based vesicle formulations could induce antibody responses [24].
These results could provide a way for the development of noisome-based vaccine formulations for
disease prevention and therapy.

4.3. Gene Delivery

Gene therapy, as a new modality for the treatment of diseases, has emerged as a powerful tool in
recent years. But delivery remains a problem for clinical applications. Non-viral gene carriers which
are mainly based on polymers and lipids are employed as two approaches for the delivery of gene
materials. Lipoplex function is a widely-used gene delivery carrier which may cause toxicity and
non-specific attachment during the circulation in vivo [77,78].

Instead, niosomes have been widely used as oligonucleotide carriers for the treatment of many
kinds of diseases in reported studies. They can be used for the delivery of gene materials due to some
advantages such as good chemical and physical stability, relatively smaller sizes, etc. G. Puras reported
a method to deliver pCMSEGFP plasmid to the retina using niosomes. They formulated the niosomes
based on cationic lipid 2,3-di(teradecyloxy)propan-1-amine, aqualene and polysorbate 80 by a method
of solvent emulsification-evaporation. The results proved that niosomes could protect DNA from
degradation and help the gene materials to enter cells [17]. For DNA vaccines, niosomes can also be
used as vectors and provide a simple, stable and cost effective solution compared with liposomes.
S.P. Vyas and colleagues found that by using niosome as gene carriers, DNA encoding hepatitis B
surface antigens (HBsAgs) could be encapsulated and invoked an immune-response to produce serum
antibodies and endogenous cytokines comparable to that of intramuscular recombinant HBsAgs and
topical liposomes [79]. Niosomes can also serve as a delivery system for targeting stem cells [80,81].
A study of niosomes proved that they could function as a platform for the delivery of RNAs to human
mesenchymal stem cells for the purpose of promoting cell differential. The design of the niosomes for
intracellular delivery of siRNA/miRNA and labelling is shown in Figure 6. These cationic niosomes
consist of Span 80, DOTA, and PEGylated lipid (TPGS). RNAs are complexed with niosomes in the
proper ratio and the surface charge is around 29.5 mV by DLS measurement, which can result in
specific gene silencing in hMSCs [80].

 

ACS Applied Materials & Interfaces Research Article
Pharmaceutics 2019, 11, 55 11 of 16

Scheme 1. Illustration Showing the Design of Theranostic Niosomes (iSPN) for Intracellular Delivery of siRNA/miRNA and
Activatable Labeling of Cells upon Dequenching

Figure 6. The design of theranostic niosomes for intracellular delivery of siRNA/miRNA and labelling
of cells upon dequenching, reproduced with permission from [80], published by American Chemical
Society, 2018.

4.4. The In Vivo Stability, Biodistribution and Formation of Protein Corona of Niosomes

The in vivo stability of the nano-carrier is an important factor for their delivery efficiency.
As described, niosomes were much more stable due to the good chemical and physical stability of
their forming materials. So, this may enhance their stability before targeting during in vivo circulation.
Their stability is also affected by their surface characteristics such as Zeta potential. It is known that
positively-charged nanoparticles may cause non-specific adsorption and accumulate in some organs
such as the liver. Some experiments were carried out to mimic in vivo situations and determine
the performance of the niosomes in biological environments by surface charge measurements,
zeta potential, gel electrophoresis and ELISA [82]. Niosomes could prolong the half life during
circulation, reduce capture by the liver and improve the uptake of the loaded drugs [83,84]. And it is
reported that niosomes could also increase the uptake of methotrexate(MTX) into the brain due to the
possibility that niosome components could permeate the blood brain barrier [85]. Animal experiments
were also performed to investigate the pharmacokinetics of niosomes. In one study regarding niosome

Figure 1.dCishtarriabctuertiizoatnionanodf iSaPnNti.-(tAu)mHoyrdraocdytinvamityic, siitzewanads (fBo)uznedta tphotaetnttihaleofairSePaNuand eiSrPtNh/esiRpNlaAsmcomaplleevxeesl-mtiemasuerecdubryvDeLS. Data
represent mean ± SD (n = 3). (C) Gel retardation assay for analysis of siRNA complexation by iSPN. Lanes 1 and 7, free siRNA as control; lanes 2−
6, iSPN/siinRcNrAeacsoemdpl6exfeos lpdrewpahreednatdwoexigohrturabtiiocsin(iSnPiNos/soiRmNeAs,ww/ewr)eoafd2m.5, i5n, i1s0t,e1r5e,dan, dco2m0, preaspreecdtivteoly.d(oDx)oRreupbreisceinntastioveluTtEioMn,images of
SPN andainSPdNt.hSecalerebaaru, 1n0d0enrmth. e tumor level-time curve also increased significantly [84].

Nanoparticles can be administrated via different ways such as inhalation, subcutaneous injection
2.9. Osteogenic Differentiation. hMSCs were seeded in 24-well cDNA synthesis kit (Quanta) on a thermal cycler according to

plates anadnindcuinbattreadvweinthouiSsPNin/jaenctti-imoniR.-1T3h8eoyr aiSrPeNim/anmti-emdiiRa-tNeCly expomsaenduftaoctuhriegrh’s lienvsterulsctoiofnsp. roRteeail-ntimine thPCeRblowoasdspterrefoarmmed using
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0.2 mM Lk-ansocowrbnicaascihd,a1r0dmcoMroβn-galy)coerrolpohwospahfafiten, iatnyd(1d0ynnMam1,i2c5-with sfhoor r1t0emr linif,efotlilomwee,dsboyft50cocyrcolensao)f. 9T5h°eCffoorrm15esd, 5p5r°oCtefionr 15 s, and
vitamin-D3). 72 °C for 30 s. Primers used in reactions were obtained from
Matrixcomrionneraaslizmatiaoyn cwaaussevispuraolizteedinbmy iAsfloizladriningredanSd a(AgRgSr)egationIn,taegnrdateidnvDoNkAeTaenchinmomloguiens,earnedstphoensesqeu.eInncetshaeremliestaend in Table

staining. tAitmdeay, 1p4roftediinfferceonrtioatnioans, ceollus lwderme fiaxsekd aonrdbinlocucbkattehdeinfunctiSo1n. al groups on the surface of the nanoparticle.
2% ARSSsoomluteionof(tphHe =co4r.o2,nSaigmmaa-yAlcdariuchs)e faorlo1s0smoifnfuatnrcotoiomn due to2t.1h0e. cNhIRanImgaingigngofoof hriMenSCtas.tiCoenllsowredreissepeldaecdeimn 2e4n-wt ell plates
temperature, followed by two washes with water to visualize the and incubated with either free ICG or iSPN/siRNA complexes for 1, 2,
calcium odfeptoasrigtsetbymoa lemciucrloesscoopne. tMheinesrualrifzaatcioenofwatshefunrtahneropartiocrle6s [h8.6–T8h8en]., cTehllsiswmeraeywaafsfheecdt tthhreeebteimhaesviwoirthofPBS and
quantifiednabnyopexatratcitcinlegs tihnebAioRlSogsitcaianl swyitshte1m0%s. Sceot,yliptyirsidcinriuucmial to usnubdseqrsuteanntlyd itmhaegerdatiwointhalanofIhVIoSw20n0ioismoamginegs isnystteermac(tXenogen,
chloride wanidthmebaisoulroinggitchaelacbosomrpptioonneatn5ts70fonrmthbyeiarpfluatrethreeadredr.evelopCmaliepnert.LTifehSecifeonrcems,iHnogpmkinatoten,rMiaAls,,UsSiAze) uasnindg tshuerIfCaGcefilter units
The expression level of miR-138 was quantified by TaqMan small of excitation of 710−760 nm and emission of 810−875 nm and

RNA asspayro(AppeprltieiedsBmioasyystbemesk).eyToftaacl tRoNrsAtwoadseistoelramtedinfrionmg tchelelsformastciaonnneodfwciothroanutaos-e[x8p9o]s.urTe.he investigation of protein
by TRIzoclo roeangaensto(nInnvitorosgoemn)e, sancdouclDdNhAelwpasusytnothbeseitzteedrbeyvaluate to2x.i1c1it.yInanVdivoheTlrpaciknintgheofaphMplSiCcas.tiAolnl aonfimnailoesxopmeriemsents were
TaqMan iMniccrloinRiNcAalRterviaerlsse. Transcription Kit (Applied Biosystems), performed in compliance with the guidelines established by the
and qRT-PCR was performed with a TaqMan Universal PCR Master National Institutes of Health. hMSCs were incubated with iSPN/
Mix and a specific TaqMan MicroRNA assay (Applied Biosystems) siRNA complexes overnight (∼18 h) and harvested by trypsin−EDTA
according to manufacturer’s instructions. Osteogenic markers were solution (Gibco, Invitrogen) followed by three times washing with
quantified by real-time PCR. cDNA was synthesized by a qScript PBS. Female BALB/c nude mice (n = 4) at 5−6 weeks of age (Janvier

C DOI: 10.1021/acsami.8b05513
ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

 

Pharmaceutics 2019, 11, 55 12 of 16
Pharmaceutics 2018, 10, x FOR PEER REVIEW 12 of 16

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Funding: This work was financially supported by National Science Foundation of China (No. 81601596), and also
Fpuarntdlyinsgp:o Tnshoisr ewdobryk twheasIn ftienradniscciaiplllyin saurpypPorrotgerda mbyo Nf Sahtiaonngahl aSicJiieanoceT oFnoguUndnaivtieorns itoyf (CNhoi.nYa G(N20o1. 78M16S02125)9a6n),d atnhde
aTlrsaon splartitolyn aslpMonesdoirceinde bPyr othgera ImntoerfdSihsacinpglhinaairJyia PorToognrgamU noifv Sehrsaintygh(Naio J.iZaoH T20o1n8gQ UNnAiv5e6r)s. ity (No. YG2017MS22)
aCnodn flthiect TsroafnIsnlatetiroensat:l TMheedaiucitnheo Prsrodgercalamre onf oShcoannflghicatio Jfiaino tTeroensgt. University (No. ZH2018QNA56).
Conflict of Interest: The authors declare no conflict of interest.
References
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