REVIEW
published: 25 June 2018
doi: 10.3389/ chem.2018.00237
F on ie s in Chemis y | www. on ie sin.o g 1June 2018 | Volume 6 | A icle 237
Edi ed by:
José Mo ais Ca i a,
Fe nando Pessoa Uni e si y, Po ugal
Re iewed by:
Felisa Cilu zo,
Uni e si à degli S udi G. d’Annunzio
Chie i e Pesca a, I aly
Vic o M. Bolanos-Ga cia,
Ox o d B ookes Uni e si y,
Uni ed Kingdom
*Co espondence:
Sónia Gonçal es
[email p o ec ed]
Ma co M. Domingues
[email p o ec ed]
†These au ho s ha e con ibu ed
equally o his wo k.
Special y sec ion:
This a icle was submi ed o
Analy ical Chemis y,
a sec ion o he jou nal
F on ie s in Chemis y
Recei ed: 17 Ap il 2018
Accep ed: 04 June 2018
Published: 25 June 2018
Ci a ion:
Ca alho PM, Felício MR, San os NC,
Gonçal es S and Domingues MM
(2018) Applica ion o Ligh Sca e ing
Techniques o Nanopa icle
Cha ac e iza ion and De elopmen .
F on . Chem. 6:237.
doi: 10.3389/ chem.2018.00237
Applica ion o Ligh Sca e ing
Techniques o Nanopa icle
Cha ac e iza ion and De elopmen
Pa ícia M. Ca alho†, Má io R. Felício†, Nuno C. San os, Sónia Gonçal es*and
Ma co M. Domingues*
Ins i u o de Medicina Molecula , Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal
O e he yea s, he scien i ic impo ance o nanopa icles o biomedical applica ions
has inc eased. The high s abili y and biocompa ibili y, oge he wi h he low oxici y
o he nanopa icles de eloped lead o hei use as a ge ed d ug deli e y sys ems,
bioimaging sys ems, and biosenso s. The wide ange o nanopa icles size, om 10 nm
o 1 µm, as well as hei op ical p ope ies, allow hem o be s udied using mic oscopy
and spec oscopy echniques. In o de o be e ec i ely used, he physicochemical
p ope ies o nanopa icle o mula ions need o be aken in o accoun , namely, pa icle
size, su ace cha ge dis ibu ion, su ace de i a iza ion and/o loading capaci y, and
ela ed in e ac ions. These p ope ies need o be op imized conside ing he inal
nanopa icle in ended biodis ibu ion and a ge . In his e iew, we co e ligh sca e ing
based echniques, namely dynamic ligh sca e ing and ze a-po en ial, used o he
physicochemical cha ac e iza ion o nanopa icles. Dynamic ligh sca e ing is used o
measu e nanopa icles size, bu also o e alua e hei s abili y o e ime in suspension,
a di e en pH and empe a u e condi ions. Ze a-po en ial is used o cha ac e ize
nanopa icles su ace cha ge, ob aining in o ma ion abou hei s abili y and su ace
in e ac ion wi h o he molecules. In his e iew, we ocus on nanopa icle cha ac e iza ion
and applica ion in in ec ion, cance and ca dio ascula diseases.
Keywo ds: nanopa icles, dynamic ligh sca e ing, ze a-po en ial, an imic obial pep ides, an icance pep ides,
ca dio ascula diseases
INTRODUCTION
Nano echnology esea ch and de elopmen ha e inc eased o e he las h ee decades. The conce n
abou he bioa ailabili y and e icacy o con en ional he apeu ics by hei subop imal esul s on
a ge ed cells and high oxici y in no mal cells ha e lead he scien i ic communi y o eshape he
ision o d ug de elopmen (Geszke-Mo i z and Mo i z, 2016). Nanopa icles (NPs) ha e been
de eloped o o e come he p oblems o a ge ing and e iciency, wi h educed oxici y. In he las
decade, hei applicabili y has been ocused on he biomedical and pha maceu ical ields, used as
d ug deli e y sys ems, diagnos ic ools, and implan s (Zhang, 2015; Geszke-Mo i z and Mo i z,
2016; Aleg e e al., 2017; Ju j e al., 2017; Ramos e al., 2017; Wong e al., 2017). Nanopa icles can
be made o di e en ma e ials, o ganic o ino ganic, such as me al, polyme s, ca bon nano ubes,
and liposomes (Liu e al., 2016). The use o nanopa icle-based d ug deli e y sys ems has inc eased
due o hei con olled elease o ese oi con en , leading o a dec ease in undesi able side e ec s
(Cosco e al., 2011; Mahmoodi e al., 2016; Ju j e al., 2017; Panahi e al., 2017; Singh e al., 2017).
Ca alho e al. Ligh Sca e ing in Nanopa icle Cha ac e iza ion and De elopmen
A he same ime, he use o nanopa icles in d ug de elopmen
educes he usage o addi ional componen s on he o mula ion
o p o ec he apeu ics om deg ada ion and inc ease ci cula ion
ime.
Nanopa icle o mula ion equi es ull cha ac e iza ion o
i s size, su ace cha ge, shape, and dis ibu ion (Obe dö s e ,
2010). I is o en echnically challenging o ob ain ep oducible
suspensions o nanopa icles wi h low polydispe sion and desi ed
shape and size. The igh con ol o mixing and sepa a ion
o pa icles is c ucial o ob ain a homogeneous nanopa icle
suspension (Cosco e al., 2015b). Usually, only a small ac ion
o he nanopa icles injec ion dose (<0.7%) eaches he a ge
(Schmid and S o sbe g, 2015). This shows ha NPs ha e some
o ganism ba ie s o o e come, such as unspeci ic dis ibu ion,
in e s i ial luid p essu e, cellula in e naliza ion, and d ug
e lux pumps, be o e achie ing he apeu ic e ec (Pa k and Na,
2015).
Nanopa icles ha e size- ela ed p ope ies in luencing hei
mode o ac ion and in i o li e ime. The op imal size o
d ug deli e y sys ems is conside ed o be b oadly be ween
10 and 1000 nm (Ramos e al., 2017). Low sizes allow
NPs o c oss cell memb anes and a oid de ec ion by he
e iculoendo helial sys em (RES), inc easing he d ug ci cula ion
li e ime (Schmid and S o sbe g, 2015; Ha e e al., 2017;
Jahan e al., 2017). Howe e , hey mus no be oo small,
in o de o a oid apid dis ibu ion in o lymph nodes,
being elimina ed by as enal clea ance. On he o he hand,
nanopa icles la ge han 100 nm a e mo e p one o accumula e
a he si e o injec ion o apped by he spleen, lung,
and li e mac ophages (Ju j e al., 2017). In conclusion,
size mus be op imized aking in o accoun he amoun
o ca go o be deli e ed and he desi able biodis ibu ion
(Figu e 1).
In e ms o su ace cha ge, neu ali y may lead o nanopa icle
ins abili y, wi h agg ega ion and p ecipi a ion a e long- e m
s o age. The su ace cha ge cha ac e iza ion is an impo an
pa ame e o measu e in a NPs suspension, because he i s
in e ac ion is wi h he body luids be o e eaching a a ge .
In physiological media, he nanopa icle is co e ed by plasma
p o eins leading o su ace cha ge al e a ions and, concomi an ly,
changing i s biological ac i i y and a ini ies (Ramos e al.,
2017). Posi i e su ace cha ges may acili a e he binding o
nanopa icles o cell memb anes and migh p omo e unspeci ic
binding o no mal issues, p omo ing pla ele accumula ion
and hemoly ic e en s (Liccia di e al., 2016; Jahan e al.,
2017; Ju j e al., 2017; Jiang e al., 2018; Pe e z e al.,
2018).
The unique physicochemical p ope ies and nanoscale e ec s
ha e d awn in e es on nanopa icle as d ug deli e y sys ems
o he ea men o diseases such as cance , ca dio ascula
diseases, pa hogenic in ec ions, and diabe es. Despi e he
aised in e es in nanopa icle de elopmen , no so many
ha e been app o ed o he apeu ic use (Wang e al., 2017).
He e, we will ocus on he ligh sca e ing app oaches o
cha ac e ize nanopa icle suspensions and hei applicabili y on
nanopa icle de elopmen agains in ec ious and ca dio ascula
diseases.
LIGHT SCATTERING TECHNIQUES
Dynamic Ligh Sca e ing
The de ec ion o he ligh sca e ed om he in e ac ion o
ligh wi h ma e gi es in o ma ion ela ed o he physical
cha ac e is ics o he sample. Typically, in ligh sca e ing
expe imen s, a monoch oma ic beam is di ec ed o he sample
and hen a de ec o eco ds he sca e ed ligh a a ce ain
angle. Ea ly ligh sca e ing expe imen s s a ed in la e nine een h
cen u y, wi h John Tyndall’s esea ch in colloidal suspensions
(Tyndall, 1868). Lo d Rayleigh (John William S u ) epo ed
ano he impo an e ec o he ligh sca e ing by pa icles
smalle han i s wa eleng h, by explaining he blue colo o he
sky and he e ec o he a mosphe ic pa icles (S u , 1871). Fo
la ge pa icles ela i e o he wa eleng h o ligh , Gus a Mie
de eloped a heo y o s udy he ligh sca e ing om abso bing
and non-abso bing pa icles, conside ing pa icle shape and he
di e ence in e ac i e index be ween pa icles and he medium
whe e hey a e dispe sed (Mie, 1908). Taking in o accoun he
di e ences o he ligh sca e ing a di e en angles o de ec ion
om la ge pa icles (Mie heo y) wi h he mo e homogeneous
ligh sca e ing a each angle o small pa icles (Rayleigh heo y),
we he eby use he Rayleigh pa icle o heo e ical pu poses.
In s a ic ligh sca e ing, he in ensi y o he ligh de ec ed is
a e aged o e ime, and om his we can ob ain in o ma ion
abou he molecula weigh o he pa icle and i s adius o
gy a ion (Rg). On he o he hand, dynamic ligh sca e ing (DLS),
by measu ing o e ime he luc ua ions o he ligh in ensi y, due
o pa icle B ownian mo ion, allows o de e mine he di usion
coe icien (D), which ela es o he hyd odynamic adius (Rh) o
he pa icle h ough he S okes-Eins ein equa ion (Pusey, 1974),
D=kbT
6πηRh
(1)
whe e κbis he Bol zmann cons an (1.380 ×10−23
kg.m2.s−2.K−1), Tis he absolu e empe a u e, and ηis he
iscosi y o he medium.
As i shows up in Equa ion (1), he pa icle di usion depends
on he empe a u e, iscosi y o he media and size o he pa icle.
DLS measu es he in ensi y o he ligh sca e ed o e ime. When
he in ensi y is co ela ed a se e al ime poin s, in he beginning
he sca e ed in ensi ies a e simila , losing his simila i y o e
ime due o pa icle’s mo emen . Then, o small pa icles, he
di usion is much as e , pho on co ela ion is los as e and
he co ela ion decays a ea ly ime poin s o he measu emen
(Figu es 2A,B). Howe e , as la ge pa icles di use mo e slowly,
he simila i y o he in ensi ies o e ime pe sis s o longe
pe iods, leading o a longe ime o he pho on co ela ion
o decay (Figu es 2C,D). A digi al co ela ion measu es he
in ensi y luc ua ion and hei co ela ion in espec o ime
ames (on he ns and µs imescale). The measu ed pa ame e
is a no malized in eg a ion o he in ensi ies a he beginning and
a delayed ime τ(Chu, 1974),
g2(τ)=I( ).I( +τ)
DI( )2E(2)
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Ca alho e al. Ligh Sca e ing in Nanopa icle Cha ac e iza ion and De elopmen
FIGURE 1 | Compa ison o capilla ies and di e en nanopa icles size desc ibed in li e a u e o di e en he apeu ic applica ions. Nanopa icles we e designed in
e ms o size and ma e ial conside ing he he apeu ic a ge desi ed, wi h he size being de e mined by dynamic ligh sca e ing.
FIGURE 2 | Dynamic ligh sca e ing in ensi y signal and co ela ion unc ion
o small (A,B) and la ge pa icles (C,D). The sca e ing in ensi y signal o e
ime is ob ained di ec ly om he pa icle’s B ownian mo ion. The co ela ion
unc ion is ob ained om he in ensi y luc ua ion in he espec i e ime ames.
Small pa icles (A,B) di use as e , wi h he co ela ion decaying a ea ly ime
poin s. La ge pa icles (C,D) di use mo e slowly, which implies a longe ime
o he pho on co ela ion o decay.
Howe e , he measu emen o each pa icle posi ion in he
sca e ed olume is no possible unde he expe imen al
appa a us. Fo his eason, he e is a measu emen o he
no malized elec ical ield gene a ed by he olume o he
pa icles unde an inciden beam (Be ne and Peco a, 1976),
g1(τ)=E( ).E( +τ)
DE( )2E(3)
The no malized in ensi y in eg a ion is co ela ed wi h he
no malized elec ical ield measu ed by he Siege ela ion
(Siege , 1943),
g2(τ)=B+β|g1(τ)|2(4)
whe e, Bis he baseline (∼1) and βis he cohe ence ac o ,
which depends on de ec o a ea, op ical alignmen and sca e ing
p ope ies o mac omolecules o sup amolecula agg ega es.
Conside ing a monodispe se sample, he no malized in ensi y
in eg a ion decays exponen ially and is dependen on a decay
cons an , Γ, o mac omolecules unde going a B ownian mo ion
(Eins ein, 1905, 1906),
g2(τ)=1+βe−2Ŵτ (5)
whe e Γis ela ed o di usion coe icien o he sample pa icles,
D, by (Be ne and Peco a, 1976),
Ŵ=Dq2(6)
whe e qis he sca e ing ec o , di ec ly p opo ional o he
e ac i e index, n0, and in e sely p opo ional o he wa eleng h,
λ(Ha ding, 1997),
q=4πn0
λsin (θ/2) (7)
whe e θis he angle o he de ec o ’s posi ion. Howe e , when
conside ing a polydispe se sample, he no malized in ensi y
in eg a ion canno be desc ibed by a single exponen ial decay
(B iggs and Nicoli, 1980). Ins ead, he e is a sum o exponen ial
decays a es G(Ŵ)co esponding o each pa icle in he sample
(Be ne and Peco a, 1976),
g2(τ)=1+βZ∞
0
G(Ŵ)e−Ŵτ dŴ2
(8)
Da a can be analyzed om he i ing o he co ela ion
unc ion. Howe e , i is possible o dis inguish wo ypes
o me hods o i ing: assuming a monomodal dis ibu ion
o a non-monomodal dis ibu ion. The common monomodal
app oach is he cumulan s i ing, whe e a Taylo expansion
wi h a mean decay a e is i ed o he co ela ion unc ion,
ob aining a mean di usion coe icien (Koppel, 1972). F om
he ela ion o he second cumulan o he mean decay
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Ca alho e al. Ligh Sca e ing in Nanopa icle Cha ac e iza ion and De elopmen
a e, i is possible o ob ain he polydispe si y index (PDI),
in o ming abou he monodispe si y endency o he sample.
Rega ding non-monomodal dis ibu ion me hods, he i ing
o he co ela ion unc ion is based on mul iple decay a es,
which is mo e sui able o polydispe se samples. The common
me hodologies a e non-nega i e leas squa es (NNLS), whe e he
decay a es a e cons an s om he lis o G(Ŵ) in a de e mined
ange, bu spaced linea ly o loga i hmically (Mo ison e al.,
1985). The exponen ial sampling uses he decay a es in a
de e mined ange bu spaced exponen ially. The mos common
me hodology applied o non-monomodal dis ibu ion is he
cons ained egula iza ion me hod o in e ing da a (CONTIN)
(P o enche , 1982a,b). The CONTIN me hod is simila o
NNLS, bu ins ead o he minimiza ion o esiduals in he
NNLS me hodology, i wo ks by he minimiza ion o egula ized
esiduals and an app op ia e weighing unc ion. Fo mo e de ails
on he ma hema ical app oach used in he me hods, please e e
o Fische and Schmid (2016) and S e e eld e al. (2016).
Ze a-Po en ial
The ze a-po en ial is he po en ial measu ed a he slipping
plane o a pa icle unde an elec ical ield. I e lec s he
po en ial di e ence be ween he elec ic double laye (EDL)
o elec opho e ic mobile pa icles and he laye o dispe san
a ound hem (aqueous o o ganic en i onmen ) a he slipping
plane (Figu e 3) (Mon es Ruiz-Cabello e al., 2014). The EDL
su ace o a pa icle in solu ion de elops ins an aneously and
is o med o wo laye s. The inne laye , he so-called S e n
laye , is composed o opposi e cha ged pa icles igh ly coupled
o he co e o he cen al pa icle. The second and ou e mos
laye is a di usi e laye consis ing o bo h opposi e and same
cha ged ions/molecules. When an elec ical ield is applied
o he sample, he pa icles mo e o he opposi e elec ode.
Wi hin he di use laye he e is a hypo he ical plane ha
ac s as he in e ace be ween he mo ing pa icles and he
laye o he su ounding dispe san while in he elec ical ield.
This plane is he cha ac e is ic slipping/shea plane and ze a-
po en ial is he po en ial a his pa icle- luid in e ace (Kaszuba
e al., 2010; Bha acha jee, 2016). The ze a-po en ial is measu ed
by he elec opho e ic mobili y o cha ged pa icles unde an
applied elec ic ield. The elec opho e ic mobili y (µe) o he
pa icles is calcula ed by Hen y’s equa ion (Kaszuba e al.,
2010),
µe=2ε ε0ζ (Ka)
3η(9)
whe e ε is he ela i e pe mi i i y/dielec ic cons an , ε0
is he pe mi i i y o acuum, ζis he ze a-po en ial alue,
(Ka) is he Hen y’s o Helmhol z-Smoluchowski unc ion,
and ηis he iscosi y a he expe imen al empe a u e.
Depending on he sol en whe e he pa icles a e dispe sed,
he alue o (Ka) is assumed o be 1 o 1.5, o o ganic
medium o aqueous medium, espec i ely (Domingues e al.,
2008).
FIGURE 3 | Schema ic ep esen a ion o he double laye ha su ounds he
nanopa icle in aqueous medium, conside ing ha i has nega i e cha ge. The
nanopa icle ep esen ed as example is composed by nega i ely cha ged
phospholipids, implying a i s laye (S e n-po en ial) mainly composed by
posi i ely cha ged coun e ions a e applica ion o an elec ic ield. The second
laye (ze a-po en ial) is a di usi e laye ha consis s o bo h coun e ions and
ions o he same cha ge as he nanopa icle, which con ac he o ganic o
aqueous en i onmen .
NANOPARTICLES IN THERAPEUTICS
Nanopa icles a e widely used in biomedical sciences o
di e en he apies, due o hei high biocompa ibili y and
chemical s abili y, ei he by di ec ac i i y o by encapsula ing
poo ly soluble d ugs/su ace inco po a ion (A akha e al., 2015;
Elzoghby e al., 2015). Among he mos no o ious examples a e
magne ic nanopa icles, wi h a me al co e o Zn, Ni, Cu, Ag,
o Au, syn he ically ob ained o na u ally isola ed (Bilal e al.,
2017; El-Ba al e al., 2018). Some o hese we e shown o ha e
an imic obial ac i i y, and we e conside ed pe ec candida es
o magne ic esonance imaging echniques, p esen ing a dual
ac i i y: he apeu ic and diagnos ic (Niemi owicz e al., 2015;
Dinali e al., 2017). Thei use in bandages, implan s o p os heses
is al eady becoming common, bu o e p oduc ion o eac i e
oxygen species (ROS) in long- e m usage has aised conce ns
ega ding he oxici y o magne ic NPs (Bilbe g e al., 2012;
Cascia o e al., 2017). Di e en au ho s ha e explo ed his issue,
e en in polyme ic-coa ed magne ic NPs, which we e conside less
oxic han he uncoa ed, bu high dosages du ing a la ge pe iod
o ime inc ease cy o oxic and geno oxic e ec s on mac ophages
(Jena e al., 2012; Mohan y e al., 2012). Wi h nanopa icles
ac i i y being dependen o hei physicochemical p ope ies,
namely size, shape, and su ace, hei oxici y owa d cells is
also dependen o hese p ope ies (Be a e al., 2014; Sun e al.,
2014; Rajchaki and Sa ojini, 2017). A s a egy ollowed o deal
wi h hese p oblems has been he de elopmen o di e en ypes
o nanopa icles, including polyme ic nanopa icles, micelles, o
liposomes, wi h he ad an age o being possible o shape hei
p ope ies o inc ease he e icacy in a ge ing o d ug deli e ing
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Ca alho e al. Ligh Sca e ing in Nanopa icle Cha ac e iza ion and De elopmen
(Xie e al., 2014; Bilal e al., 2017; Solai aj e al., 2017). Wi h
he objec i e o educing oxici y wi hou educing NP ac i i y,
ano he adop ed s a egy was he inco po a ion o su ace
de i a iza ion wi h di e en ligands, such as an ibodies, small
o ganic molecules, o p o eins/pep ides (Chen e al., 2012; Gao
e al., 2017). This las hypo hesis was shown o educe oxici y,
imp o ing pep ide p ope ies/ac i i y, and enhancing solubili y,
leading o a gene al imp o emen o he pha macokine ic p o ile
and he apeu ic index (Molina o e al., 2013; Gao e al., 2014,
2017; Cosco e al., 2015a; Lib ala o e al., 2017). As a ma e
o ac , di e en p o eins ha e al eady been es ed o di e en
ac i i ies, including albumin, casein o elas in-like polypep ides,
explo ing ei he an ac i e a ge ing (di ec ac i i y on a ge cells)
o a passi e a ge ing (p olonged blood ci cula ion and ac i i y)
(Sneha ani e al., 2010; Zhao e al., 2010; Bacha e al., 2012; K a z,
2014; MacEwan and Chilko i, 2014). Wi h di e en possibili ies
o su ace modi ica ion, hese p o ein nanopa icles apidly
e ol ed o pep ide nanopa icles, due o an easie manu ac u e
p ocess and educed p oduc ion cos s (Elzoghby e al., 2015).
Pep ide he apeu ics is a ield ha is as g owing since he
beginning o he cen u y, wi h a la ge numbe o scien i ic
pape s explo ing hei po en ial use in heal hca e (Albe icio and
K uge , 2012). Mo eo e , wi h esis ance inc ease in di e en
pa hologies, including in ec ious diseases and cance , he u gency
o new al e na i es has p omo ed a signi ican numbe o
s udies aiming a imp o ing he e icacy o pep ides as d ugs
o applied in diagnos ic echniques (Hamil on e al., 2015;
Gomes e al., 2018). Se e al in i o and in i o s udies ha e
been published ocusing on he e iciency o pa icula pep ide
classes, namely an imic obial and an icance pep ides (AMPs
and ACPs, espec i ely), due o hei p omising applica ions
as d ugs in he ma ke (Hancock e al., 2016; Felício e al.,
2017). E en so, downsides o hei use ha e been poin ed
ou , including low enzyma ic s abili y, low pe meabili y ac oss
biological ba ie s, low solubili y, apid me abolic exc e ion,
and high oxici y (Tam e al., 2002; Rajchaki and Sa ojini,
2017; Se na e al., 2017). S a egies o o e come hese pep ide
he apeu ic applicabili y p oblems include in silico s uc u e
design (conside ing hei sequence, using na u al and non-
na u al amino acids), pep idomime ics, lipida ion and, na u ally,
nanopa icle conjuga ion, which will be u he explo ed
(Rajchaki and Sa ojini, 2017; P ima e a e al., 2018).
Nanopa icles Wi h An imic obial Ac i i y
As men ioned abo e, an inc ease in mul i esis an pa hogens
(bac e ia, ungi, and i uses) has been epo ed on he las
decades, wi h se e al easons al eady explo ed being held
esponsible o his (Dickey e al., 2017; Llewelyn e al., 2017).
The Wo ld Heal h O ganiza ion has inclusi ely poin ed ou
di e en bac e ia s ains whe e esea che s should ocus on, due
o he high incidence o esis ance in pa ien s (Wo ld Heal h
O ganiza ion, 2015). AMPs a e conside ed one o he majo
p omises o o e come his g owing public heal hca e p oblem.
Due o his, s udies on hei isola ion, pu i ica ion, design, and
applicabili y, bo h in i o and in i o, ha e inc eased in ecen
yea s (Dias e al., 2017; Unubol e al., 2017). These pep ides
a e usually cha ac e ized by a sho amino acid sequence (less
han 50 amino acid esidues), high amphipa hic and hyd ophobic
con en , and a posi i e ne cha ge (de la Fuen e-Núñez e al.,
2017; Haney e al., 2017). Thei mechanisms o ac ion, equen ly
a he memb ane le el, a e no well-de ined, bu i is clea
ha hei physicochemical p ope ies a e essen ial o he
pep ide-memb ane in e ac ion (Neelay e al., 2017). Ini ially,
hey we e hough o a ge speci ically di e en pa hogens bu ,
nowadays, i is clea ha hei ac ion is mo e complex han ha ,
pa icipa ing in he ec ui men o immune cells o he si e o
in ec ion, o modula ing he immune esponse by p omo ing
pa hogen cell dea h (Hancock e al., 2016). Also, hey ha e a
b oad-spec um ac i i y (Vigan e al., 2015), being ac i e owa d
bac e ia (including bio ilms), ungi o i uses, wi h p ope ies
o he a ge memb ane d i ing he in e ac ions (Ribei o e al.,
2016). E en so, hei limi a ions became also no o ious in a
la ge numbe o s udies, limi ing hei po en ial as he apeu ic
molecules (Gomes e al., 2018).
A he same ime, nano echnology (pa icula ly using
nanopa icles) has also ocused i s esea ch in hese applica ions,
ha ing eached a highe success in clinical applica ions.
Wi h he ad an age o he possible use o di e en me als,
magne ic nanopa icles wi h in insic an imic obial ac i i y we e
de eloped and medically applied (Bilal e al., 2017; Dinali e al.,
2017; Pham e al., 2018). The ac ha hese NPs ha e in
hei co e a me al p edisposing o elec os a ic in e ac ions,
p omo es hei a achmen o bac e ial memb anes, leading
o he loss o in eg i y and bac e ia cell dea h (Fang e al.,
2015; Bilal e al., 2017). A high numbe o sys ems ha e been
es ed wi h epo ed ac i i y owa d pa hogens, using di e en
an ibio ic molecules conjuga ed ei he on he su ace o by
encapsula ion (Pa k e al., 2011; Gaspa e al., 2016; Mo ales e al.,
2017). An impo an example is sil e nanopa icles (AgNPs)
conjuga ed wi h polymixin B o gold nanopa icles (AuNPs)
conjuga ed wi h ancomycin, bo h showing a syne gis ic e ec ,
wi h imp o ed ac i i y (Fayaz e al., 2011; Pa k e al., 2011).
Me al nanopa icles chosen o an ibio ic conjuga ion include
i anium, zinc o coope , and as o an ibio ic molecules,
gen amicin, s ep omycin, cec opin-meli in, among o he s, ha e
shown imp o ed ac i i y (Gu e al., 2003; Bi la e al., 2009;
Allah e diye e al., 2011; Lai e al., 2015). Howe e , as al eady
s a ed, he use o me als o nanopa icle de elopmen aised
some doub s due o inhe en oxici y owa d heal hy cells, o cing
esea che s o ind al e na i es. An example was es ing NPs
o local/ opic applica ions, lowe ing he dosage amoun and
oxici y e ec s (Gao e al., 2014; A akha e al., 2015; de Oli ei a
e al., 2017). In a pH-sensi i e sys em, Picha an e al. de eloped
an ibio ic (gen amicin sul a e and/o ancomycin) unc ionalized
nanopa icles ha we e co alen ly g a ed in o i anium su aces
(Picha an e al., 2016). The nanopa icle cha ac e iza ion was
achie ed using nuclea magne ic esonance (NMR) and dynamic
ligh sca e ing measu emen s, con i ming hei size and s abili y
in di e en media (Picha an e al., 2011, 2012). Besides he
enhanced an imic obial ac i i y, hese NPs also p esen ed o he
ad an ages, such as he possibili y o be used in o he su aces
and p omo ing an inc ease in he a ge issue/cell d ug densi y
(Picha an e al., 2011, 2012). Ano he s udy, by Di F ancesco
e al. showed he ad an ages o using pH-sensi i e nanopa icles
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Ca alho e al. Ligh Sca e ing in Nanopa icle Cha ac e iza ion and De elopmen
as a usogenic d ug deli e y sys em (Di F ancesco e al., 2017).
The nanopa icles we e o mula ed acco ding o hei a ge
cells, and physicochemical p ope ies we e measu ed by DLS and
luo escence spec oscopy.
The applica ion o nanolipid sys ems (like liposomes o
micelles) o polyme ic NPs (chi osan based o conjuga ed
wi h polye hylene glycol, PEG) had special success (Hann and
P en ice, 2001; Allen and Cullis, 2013; Cosco e al., 2014;
Paolino e al., 2017). These NPs ha e he ad an age o being
mo e biocompa ible, wi h he e ec s owa d heal hy cells being
educed and ha ing an imp o ed a ge ed-o ien ed ac i i y
(Solai aj e al., 2017). Wa e e al. de eloped poly(lac ic-co-
glycolic acid) nanopa icles (PLGaNPs) ha we e used as d ug
deli e y sys em o plec asin, an an ibio ic speci ic o ai way
S aphylococcus au eus in ec ion (Wa e e al., 2015). They used
DLS and ze a-po en ial measu emen s o assu e ha plec asin
was e icien ly loaded on he NP. O he au ho s used chi osan-
sodium phy a e NPs and es ed hem agains G am-nega i e and
G am-posi i e bac e ia, showing a high an imic obial ac i i y,
wi h he ad an age o hese NPs could also be used o d ug
deli e y, combining hei e icacy wi h an an ibio ic (Yang e al.,
2017). In o de o iden i y he op imal chi osan/sodium phy a e
a io o hei ac i i y, DLS and ze a-po en ial measu emen s
we e pe o med o de e mine he NPs size, su ace cha ge, and
s abili y a di e en pH alues. As o liposomes, o he au ho s
ha e de eloped lipid NPs composed o phospha idylcholine
(zwi e ionic phospholipid) and phospha idylse ine (nega i ely
cha ged phospholipid), in e cala ed wi h Plu onic-P85 (HLB 16),
a polyme ha a o s he up ake o he NP (Fidle , 1988; Zhang
e al., 1998). By inco po a ing gen amycin in hei co e, his
sys em was es ed o d ug deli e y, wi h a high e iciency a e
(Xie e al., 2014).
Despi e all he s a egies s udied along he yea s, one
has gained special a en ion nowadays, when con en ional
he apeu ic molecules a e acing a new esis ance pa adigm. This
s a egy consis s in he combina ion o nanopa icles (liposomes,
polyme ic, o me allic) wi h an imic obial pep ides, ei he o
pep ide deli e y o o a di ec ac ion owa d he a ge cells
(Niemi owicz e al., 2015; Wa e e al., 2015). The objec i e was
o o e come he limi a ions on AMPs applica ion, bu , la e on,
i was s a ed ha he na u e o nanopa icle-AMP in e ac ion
is essen ial o he sys em ac i i y (Pal e al., 2016). Ac ually,
weake in e ac ions be ween he AMP and he nanopa icle
p omo e a dec ease in NP oxici y and, a he same ime,
inc ease AMP ac i i y, because i allows he pep ide o adop
a o able s uc u e and/o cha ge p ope ies essen ial o he
in e ac ion wi h biomemb anes (Liu e al., 2013; Rajchaki and
Sa ojini, 2017). These AMP-NP complexes also allow a highe
concen a ion o he d ug in he si e o ac ion, wi h a selec i e
ac i i y, including a di e en ial in e ac ion be ween he complex
and he ou e and inne -memb anes o he a ge bac e ial
pa hogens, implying a d ug-deli e y and di ec ac i i y sys em
(Pa k e al., 2017; Rajchaki and Sa ojini, 2017).
Di e en AMP-NP complexes ha e been es ed h oughou
he yea s, ying o es ablish one wi h high ac i i y owa d he
a ge pa hogens, wi hou ha ing a signi ican oxici y o he
o he cells, a common law o AMPs and me al NPs (Galdie o
and Gomes, 2017). Di e en me als we e es ed, as al eady
desc ibed, such as i on oxide, coupled wi h LL-37, a na u al hos -
de ense pep ide wi h an imic obial ac i i y (Niemi owicz e al.,
2015). O he examples include sil e nanopa icles su ounded
by AMPs, o gold NPs wi h bac enecin molecules on hei su ace
(Allah e diye e al., 2011; Golube a e al., 2011). All hese
sys ems we e shown o ha e less oxici y and highe e iciency,
including agains clinical isola ed mul i esis an pa hogens,
bu hei pha macokine ic and pha macodynamic p o iles s ill
need o be imp o ed (Ruden e al., 2009). Conside ing his
scena io, me hods o imp o e hese p ope ies we e designed,
including he use o na u al isola ed nanopa icles om biomass
(Mohan y e al., 2013). Thei biogenic AgNPs combined wi h
wo di e en AMPs (NK-2 and LLKK-18), cha ac e ized by
DLS and ze a-po en ial, we e shown o ha e syne gis ic e ec
and imp o ed applicabili y in clinical scena ios (Mohan y e al.,
2013). In ano he s udy, polyme ic nanopa icles (chi osan-
algina e polyelec oly e complex NPs) combined wi h pexiganan
(a syn he ic AMP) had an imp o ed p o ile o he apeu ic
applica ion (Zhang e al., 2015). Ano he s a egy es ed was he
use o PEG: nanopa icle su ace was co e ed wi h PEG and
AMPs, inc easing biocompa ibili y and an imic obial p ope ies
(Pal e al., 2016; Cascia o e al., 2017). Ze a-po en ial was used
o con i m ha he pep ide was a ached o he NP su ace
a e coupling syn hesis, wi h an o e all cha ge inc ease a e
in e ac ion wi h posi i e pep ides such as AMPs.
Besides an imic obial pep ides, nanopa icles can also be
combined wi h cell-pene a ing pep ides (CPPs) (Guido i e al.,
2017). The e is no a igid bounda y be ween hese wo classes
o pep ides, wi h epo ed AMPs ha ing a CPP unc ion, as
well as CPPs wi h desc ibed an imic obial ac i i y, besides he
capaci y o deli e ca go in o di e en cells (Bahnsen e al.,
2015; K is ensen e al., 2016). One example is he combina ion
o micelles wi h TAT, a HIV-de i ed CPP wi h an imic obial
ac i i y, conjuga ed wi h choles e ol, a space and six a ginine
esidues (Liu e al., 2009). These sel -assembly micelles, besides
enhanced ac i i y and low oxici y, we e able o c oss he blood
b ain ba ie , which in oduced a g ea ad an age o b ain
in ec ion diseases (Liu e al., 2009). On ano he s udy om
he same au ho s, hey used he same CPP, wi h a space o
h ee glycine and six a ginine esidues, bu conjuga ed o colloid
AgNPs su ace (Liu e al., 2013). Imp o ed an imic obial ac i i y
and educed hemolysis we e obse ed. In bo h cases, DLS and
ze a-po en ial we e essen ial o cha ac e ize he NPs, ega ding
size and su ace cha ge, bu also o assess colloidal s abili y (Liu
e al., 2009, 2013).
I is impo an o e e ha hese complexes o AMPs/CPPs-
NPs ha e high po en ial o he ea men o bac e ial in ec ion,
including hose leading o bio ilm o ma ion (Ribei o e al.,
2016). Bio ilms a e complex pa hogen agg ega es, encased in a
ma ix composed o ex acellula polyme ic subs ances (EPS),
ha no mally end o o m when bac e ia aces s ess adap a ion
(Flemming e al., 2016). Due o his ma ix, AMPs e icien
agains plank onic ( ee) bac e ia can be ine ec i e agains
bio ilms (Ba oni e al., 2016). Nanopa icles by hemsel es
ha e small size, wi h an eno mous su ace a ea and easy
pene abili y p ope ies, including on bio ilms. These p ope ies
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Ca alho e al. Ligh Sca e ing in Nanopa icle Cha ac e iza ion and De elopmen
and associa ion wi h AMP in oduce ad an ages o ackle bio ilm
in ec ion, and should be conside ed in u u e wo ks (Qayyum
and Khan, 2016).
The use o pep ides in nano echnology has been la gely
inc easing, as desc ibed abo e. A his le el, o he s uc u es
wi h p omising esul s a e sel -assembling pep ide NPs, which
a e o med by small pep ides ha sel -agg ega e, o ming
clus e s, o oligome s (Se na e al., 2017). The idea came om
dend ime ic pep ides, small nanosys ems wi h a size ange om
2 o 50 nm, wi h g ea ad an ages in e ms o biocompa ibili y,
s uc u al/ unc ional e sa ili y and d ug deli e y e iciency
(Tam, 1988; Tam e al., 2002; Se na e al., 2017). These
sys ems a e cha ac e ized by a hype -b anched and almos
pe ec geome ical 3D a chi ec u e, ha g ow om he co e
in o a globula shape, wi h epo ed ac i i y agains in ec ious
pa hogens and cance cells (Tam e al., 2002; Iono e al., 2013;
Ga cía-Gallego e al., 2017). Examples o sys ems al eady s udied
a e di e se, wi h each au ho explo ing di e en mechanisms o
p omo e he assembling o ac i i y owa d he a ge cells. They
include AMPs conjuga ed o he N- e minal o his idine- agged
p o eins, o ming oligome s wi h an imic obial ac i i y (Se na
e al., 2017). As he syn hesis o sel -assembly NPs s a s wi h
small agg ega es, DLS was used o de e mine he e olu ion o
he size dis ibu ion, con i ming he oligome s o ma ion (Se na
e al., 2017). Lipida ion o AMPs, besides he inc eased ac i i y
al eady explo ed, can also p omo e he o ma ion o dend ime ic
pep ide NPs (Si iwa dena e al., 2018). Using pa en al sys ems,
hese au ho s de eloped a new one, wi h highe an imic obial
ac i i y and p o-angiogenic p ope ies in biological bu n-wound
bandages, named TNS18 (Si iwa dena e al., 2018). Finally, o he
au ho s ecen ly ocused in sel -assembling pep ide nanopa icles
ha only ac on he a ge cell a e ac i a ion, using o ha
speci ic cha ac e is ics o he a ge issue, such as o e exp essed
memb ane p o eins o en iched p o eases concen a ion (Yu
e al., 2018; Zhang e al., 2018). This ield is now expanding
and, he e o e, mo e esea ch is needed o unde s and how his
s a egy can bene i cu en he apies ela i e o o he sys ems
ha a e easie o manipula e.
Nanopa icles Wi h An icance Ac i i y
The apies o deal wi h cance ha e e ol ed in esponse o
he human need, bu esis ance o he apy is a public heal h
conce n (A nold e al., 2015). Nano echnology has o long
ied o igh his bu den, by imp o ing he pha macokine ic
and pha macodynamics o he chemo he apeu ic agen s ha
a ge solid umo s. Fo ha , d ug encapsula ion was s udied
and es ed in i o, wi h he i s molecules being FDA app o ed
in he middle o he 1990s, namely Doxil and DaunoXome
(Ee wegh e al., 2006). Bo h he apeu ics consis o liposomes
wi h encapsula ed d ugs, doxo ubicin (DOX) and a mix u e o
an h acycline and dauno ubicin, espec i ely (Ee wegh e al.,
2006; Allen and Cullis, 2013). Cance d ugs ace di e se
challenges, c ea ing he need o de eloping new d ugs acco ding
o he ype o a ge : solid umo s o ci cula ing cance cells
(Pea ce e al., 2012). Fo solid umo s, e ading he mononuclea
phagocy e sys em (MPS) and emaining in he umo issue is
essen ial o d ug e icacy, while o ci cula ing cance cells he e
is he need o he d ug o be in e nalized o ensu e i s ac ion a
he a ge si e (S ylianopoulos and Jain, 2015).
Conside ing he cu en scena io, di e en s a egies ha e
been ollowed ying o o e come hese limi a ions. Me al
nanopa icles wi h gold o sil e co e ha e been es ed and
showed o ha e na u al an icance ac i i y, ei he in i o o
in i o agains umo s and cance cells (Shanmugasunda am
e al., 2017; Shma ako e al., 2017). Following he imp o emen s
on he de elopmen o nanopa icles, combina ions o coppe
and chi osan we e also es ed, wi h obse able an icance
ac i i y and less oxic e ec s (Solai aj e al., 2017). DLS was
used he e no only as a me e cha ac e iza ion echnique, bu
as a ool o iden i y me al s uc u es wi h highe colloidal
s abili y and be e size dis ibu ion (Shma ako e al., 2017).
Di F ancesco e al., using non-ionic su ac an esicles (NSVs)
loaded wi h DOX, de eloped nanosys ems wi h di e en a ios
o Tween21/Tween80, p omo ing a pH- esponsi e app oach
wi h an icance p ope ies (Di F ancesco e al., 2017). These
NSVs showed a usogenic beha io and an inc eased a ge ing
e iciency, which ansla ed in highe an icance ac i i y.
Nanopa icles wi h di ec ac i i y can also be used as d ug
ca ie s, as men ioned be o e. Zake zadeh e al. designed silica
NPs wi h encapsula ed e azole, a cyclic/a oma ic molecule wi h
an imic obial, an i ungal and an icance ac i i y (Zake zadeh
e al., 2017).
Despi e p e ious ad ances, imp o emen s in he a ge ing
we e s ill necessa y. As in in ec ion he apies, also he e he
use o pep ides was conside ed, ei he o inc ease ac i i y o
o p omo e speci ic a ge ing o cance cells and solid umo s
(Pea ce e al., 2012). As an example, Chang e al. designed
NPs ha we e able o bind o he umo mass (o al, b eas ,
lung, colon, o panc ea ic umo s) by coa ing hem wi h he
small an imic obial pep ides PIVO-8 and PIVO-24 (also ac ing
a he ascula iza ion p ocess), which a e signi ican ly inc eased
a ound umo s (Chang e al., 2009). To con i m NP coa ing
wi h bo h pep ides, au ho s used DLS, e alua ing a e wa ds he
di e ences in ac i i y (Lee e al., 2004). Also a ge ing umo s,
i on oxide NPs coa ed wi h an hep apep ide ha ecognize
ib in- ib onec in complexes o chi osan NPs wi h an iangiogenic
pep ide endos a in (ES) imp o ed an icance ac i i y by a ge ing
he ascula iza ion o he umo (Agemy e al., 2010; Xie e al.,
2017). Coa ing nanopa icle su aces wi h wo o mo e di e en
pep ides was also epo ed (Colombo e al., 2002; Ma chiò e al.,
2004). E en so, ideally, an icance he apies would be able o
elimina e umo s and malignan cance cells, including hose
ha a e no longe associa ed wi h he main umo , wi hou
oxici y owa d heal hy cells. NPs ha ac as d ug ca ie s ( o
d ugs like doxo ubicin, 5- luo o acil o cispla in), wi h good
pha macokine ic and pha macodynamic p o iles (using PEG
on hei su ace o polyme NPs), speci ic (by using small
pep ides) and wi h enhanced cellula up ake would be he desi ed
candida es (Sa a, 2003; Paolino e al., 2013; Ribei o e al., 2016;
Gomes e al., 2018). Fo his sys em, he missing poin is he
enhanced up ake, which was possible wi h he a achmen o
CPPs o he nanopa icle su ace, besides he AMPs necessa y
o hei ac i i y. Au ho s es ed he use o TAT, he HIV-1
de i ed CPP, by coupling i o NPs wi h PEG on hei su ace,
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Ca alho e al. Ligh Sca e ing in Nanopa icle Cha ac e iza ion and De elopmen
and demons a ed he imp o ed cellula up ake (Kuai e al.,
2010, 2011). Besides he CPP, hese au ho s also es ed he
possible applicabili y o di e en PEG molecules, due o hei
conce n o inc easing NPs dis ibu ion nea he umo , bu
loss o in e naliza ion abili y (Kuai e al., 2010). Using DLS and
ze a-po en ial measu emen s, Kuai e al. s udied he op imal
p opo ion o clea able PEG o main ain hei accessibili y
and ac i i y. Taka a e al. also es ed he inco po a ion o a
CPP (STR-R8) on he nanopa icle su ace, ha was al eady
coa ed wi h NGR mo i pep ides ( ecognizes CD13 p esence in
endo helial umo cells) and PEG, showing ha a syne gic e ec
be ween all he molecules inco po a ed occu ed (Taka a e al.,
2010). Fo ha , DLS and ze a-po en ial we e used o e alua e
he bes CPP amino acid esidue o use o he ancho ing,
conside ing ha size should be s able, and ha su ace cha ge
is essen ial o NP a ge ing memb ane in e ac ion. Recen ly,
Xia e al. u he inc eased he complexi y wi h a high e iciency
cons uc : using selenium NPs, which ha e ad an ages in e ms o
dosage, biocompa ibili y, oxici y, and d ug deli e y, hey coa ed
hem wi h an an icance pep ide (RGDFC hep apep ide) and
inco po a ed DOX and siRNA (an i-Nanog, a human homeobox
p o ein ha is essen ial o cance cell p oli e a ion) (Xia e al.,
2018). This SeNPs@DOX/siRNA sys em showed o be e y
e ec i e on he a ge ing and ea men o cance , p esen ing
a new hypo hesis as syne gis ic sys em. Ne e heless, ega ding
cance he apies, he e is a lo o imp o e in e ms o a ge ing
and e iciency o cance e adica ion in i o, because mos o he
sys ems es ed in i o ha e been ailing on clinical ials (Pea ce
e al., 2012).
Nanopa icles in Ca dio ascula Diseases
Al hough a eas like cance and an imic obial esis ance d aw
mos o he a en ion om he public and scien i ic communi y,
ca dio ascula diseases (CVD) a e he majo epidemic o he
mode n e a, claiming a highe numbe o dea hs han cance ,
mala ia, AIDS, o ube culosis. Indeed, CVD emains he mos
common cause o dea h wo ldwide (Pa k e al., 2008). Jus in
Eu ope, CVD a e esponsible o 45% o all dea hs, eaching 4
million dea hs pe yea (Townsend e al., 2015). Co ona y hea
disease is he mos common single cause o dea h, esul ing
in 19% o dea hs in men and 20% o dea hs in women, much
highe han b eas cance in women (2%) and lung cance in men
(6%) (Townsend e al., 2015). Mos con en ional he apeu ics
and clinical app oaches a e ou da ed, and esea che s a e pu ing
hei e o s in o as employing all he po en ial o “nano” in he
CVD managemen , app oaching s a egies o bo h imaging and
ea men o hese condi ions.
De eloping New Agen s o CVD Imaging
Con en ional medical ools s ill ail on he de ec ion o
a he oscle o ic lesions and plaque up u e, while in e en ions
wi h a ca he e ul asound o magne ic esonance imaging
(MRI) gi e pu ely mo phological in o ma ion, wi hou s a ing
he p og ession o in lamma ion and he occu ing o unc ional
changes (Pa k e al., 2008). New imaging echniques and
agen s a e in high demand. Con as agen s inco po a ing
nanopa icles and pep ides ha e signi ican ly e ol ed and a e
now capable o de ec ing and quan i ying mic o h ombus.
None heless, hey mainly consis o ha d pa icles, which p esen
exc e ion di icul ies and slow o inexis en me aboliza ion. The
endency is o look o mo e complian pa icles, like sel -
assembling and small molecules, capable o lowing h ough he
mic o ascula u e o clea ance o gans (Pan e al., 2009), wi h low
oxici y, good biodeg adabili y, and biocompa ibili y (Pa k e al.,
2008). The e ha e been ad ances in he de elopmen o ib in-
speci ic manganese nanocolloids, ha success ully each he low
nanomola ange o de ec ion and p esen a high elaxi i i y
(Pan e al., 2009). These esul s a e di ec ly compa ed o he
mic omola ange only o he mos ly used gadolinium-based
agen s.
In ecen yea s, some app oaches p e iously used mainly o
oncology imaging ha e been adap ed o ca dio ascula imaging,
as i is he case o i on oxide nanopa icles, especially in he o m
o ul a-small supe magne ic i on oxide (USPIO) nanopa icles
(<50 nm) (Ploussi e al., 2015). Ea ly use o hese NPs o medical
imaging was desc ibed as a solu ion o he limi ing ac o in
MRI, he backg ound signal p oduced by he hos issue, bu
hey can also be used o magne ic pa icle imaging (MPI), being
capable o p o iding a highe sensi i i y and a be e spa ial
esolu ion (Gleich and Weizenecke , 2005). Due o he high
in e es in hese pa icles, se e al a ia ions o supe pa amagne ic
i on oxide nanopa icles (SPIONs) can be ound, as well as
he cha ac e iza ion o hei beha io in di e en si ua ions.
Pa k e al. ha e subjec ed h ee o mula ions o SPIONs o pH
a ia ions (5, 7, 9, and 11) and ime p og ession (30 days) (Pa k
e al., 2012). By ligh sca e ing analysis a pH 11, a signi ican
inc ease in hyd odynamic diame e was obse ed, leading o he
conclusion ha nanopa icle agg ega ion is occu ing, especially
when PEG was one o he componen s (Figu e 4A). Unde
u he analysis, au ho s concluded ha he PEG coa ing was
deso bed om he su ace, leading o an uns able NP suspension
and igge ing agg ega ion. A pH 7, he e we e no al e a ions in
measu ed sizes o he pa icle.
SPIONs can ha e mul iple coa ing op ions. Thus, au ho s
can play wi h ei he PEG o o he biocompa ible molecules,
like chi osan. Szpak e al. s udied he s abili y o i on oxide
nanopa icles coa ed wi h a hin laye o cha ged chi osan
de i a i es (Szpak e al., 2013). Pe o ming DLS measu emen s,
hey concluded ha he diame e o he nega i ely cha ged NPs
was sligh ly smalle , indica ing an e ec o he cha ge in he
beha io o i s milieu. Fu he cha ac e iza ion o he coa ing
cha ge was pe o med by ze a-po en ial measu emen s. Au ho s
emphasized ha , o biological applica ions, SPIONs mus be
esis an o adso p ion o biomac omolecules and ha chi osan
migh be he ideal candida e o acili a ing se e al deg ees o
physical p ope ies manipula ion, such as he ailo ing o su ace
cha ge. Ano he s udy has analyzed he s abili y o SPIONs a
37◦C, bu his ime wi h a dex an coa ing (Obe le and Lüd ke-
Buzug, 2013). The nanopa icles we e s able a pH 7.2 o as
long as 6 weeks, while a pH 6.2 he hyd odynamic diame e
s ongly inc eased, deno ing pa icle agg ega ion, also isible by
p ecipi a ion (Figu e 4B). This s ongly sugges s ha dex an is
no only a biocompa ible polyme , bu also an excellen solu ion
o keep a SPION o mula ion s able a physiological condi ions.
F on ie s in Chemis y | www. on ie sin.o g 8June 2018 | Volume 6 | A icle 237
Ca alho e al. Ligh Sca e ing in Nanopa icle Cha ac e iza ion and De elopmen
FIGURE 4 | Example o dynamic ligh sca e ing applica ions o s udy
nanopa icle s abili y a di e en pH alues (A,B) and empe a u es (C).(A) I on
nanopa icles (FeNPs) agg ega ion s abili y s udied o e ime a ou di e en
pH alues. A he op, FeNPs wi hou su ace polyme ; in he middle FeNPs,
coupled wi h PEG2000 and a he bo om FeNPs couple wi h PEG5000.
Adap ed wi h pe mission om Pa k e al. (2012). Copy igh 2018 Ame ican
Chemical Socie y. (B) SPIONs agg ega ion s abili y s udied o e ime a wo pH
alues. Adap ed om Obe le and Lüd ke-Buzug (2013).(C) Pe luo open ane
(PFP) micelles size s abili y s udied a di e en empe a u es. Micelles we e
p epa ed wi h di e en pe cen ages o PFP (Rapopo e al., 2007).
I on oxide agen s ha e been es ed o he de ec ion o
abdominal ao ic aneu ism (Richa ds e al., 2011; Sada e al.,
2011), a he oscle o ic plaques (Schmi z e al., 2001; Kooi e al.,
2003), and acu e myoca dial in a c ion (Alam e al., 2012;
Yilmaz e al., 2012, 2013a,b). Tang e al. also ex ensi ely s udied
he use o e umox an-10 o imaging ca o id plaques (Tang
e al., 2009a,b), ca o id s enosis (Tang e al., 2006) and ca o id
a he omas (Tang e al., 2007, 2008). Mo eo e , se e al o hese
es s a e basically gi ing a new use o e uca bo an (Reso is ),
an agen i s ly used o de ec ei he benign o malign hepa ic
lesions (Namkung e al., 2007). The pa icles usually ha e a
co e o magne i e (Fe3O4)/maghemi e (γFe2O3) coa ed wi h
ca boxydex an, and an o e all hyd odynamic diame e o 62 nm
(Reime e al., 1995). By 2015, only Reso is was a ailable in e y
limi ed coun ies, wi h o he agen s being s opped o u he
de elopmen . This is he case o e umox an-10 (Sine em), also
widely es ed in he ci ed s udies o ca dio ascula condi ions,
al hough ini ially de eloped o lymph node imaging. He e, he
co e is a c ys alline in e se spinel s uc u e o magne i e, coa ed
wi h dex an, wi h 20 nm diame e (Shen e al., 1993).
A he same ime, he ield is also ac i ely looking o new
disease bioma ke s and in ensi ely explo ing agen s in ol ed in
he in lamma o y esponse in CVD. In an e o o p o ide be e
quan i a i e mac ophage imaging in ascula issue, Kelihe e al.
de eloped a class o modi ied polyglucose nanopa icles, wi h a
size below he limi o enal exc e ion (Kelihe e al., 2017).
When mac ophages ail in emo ing choles e ol deposi s om
he a e ial wall, an in lamma o y esponse is igge ed, wi h
ec ui men o mo e cells, which enhances in lamma ion and
comp omises blood low and issue in eg i y. Animal s udies
succeeded in de ec ing a he oscle o ic egions wi h p ac ically no
in e ac ion wi h o he lymphocy es. The same happened when
using mice wi h pe manen co ona y liga ion (Kelihe e al.,
2017).
Wi h CVD p e en ion being he ocus o signi ican a en ion
om he scien i ic communi y, and s udies poin ing o new
disease bioma ke s s eadily eaching publica ions (Hijazi e al.,
2016; Wal e s e al., 2016), some au ho s explo ed CVD
ela ionship wi h o he medical condi ions (Ge des e al.,
2014; Pa o e al., 2015). Following he wo k on sc eening
o a pep ide o bind o a he oscle o ic plaques (Hong e al.,
2008), o he au ho s ha e ca ied ou i s inco po a ion as a
a ge ing moie y in chi osan nanopa icles (Pa k e al., 2008).
A e wo king on hyd ophobic modi ied glycol chi osan (HGC)
nanopa icles as cance imaging p obes (Pa k e al., 2007) and
o o he he apeu ic pu poses (Kwon e al., 2003; Pa k e al.,
2004; Kim e al., 2006), he eam was able o conjuga e he
pep ide on he NP su ace and de ec he selec i e binding o
a he oscle o ic plaques in i o, by adhe ing o he IL-4 ecep o
on endo helial cells, mac ophages and smoo h muscle cells (Pa k
e al., 2008). The au ho s highligh ed ha hese 270 nm sel -
assembled nanopa icles ha e a long esidence ime e en in
low condi ions. In ac , he luo escence in he ao ic a ch
o he Ldl −/−mice exhibi ed a mo e p ominen luo escence
signal han he ao ic a ch o heal hy mice, e en a e 6 h om
in a enous adminis a ion.
D ug Deli e ing Nanopa icles o CVD T ea men
The deli e y o a he apeu ic d ug h ough a nanopa icle
ehicle allows high d ug concen a ions in he in ended local
en i onmen s, while he o al d ug concen a ion and side e ec s
a e signi ican ly educed (Chen e al., 2015). In CVD, he
in oduc ion o hese he apeu ic agen s can be done ei he
wi h su gical in e en ion o h ough sys emic adminis a ion.
In cases o co ona y a e y disease, a common app oach
is a pe cu aneous co ona y in e en ion. This p ocedu e is
pe o med unde local anes hesia and in ol es he inse ion
o a guidewi e in o he ao a, o hen pass o he he apeu ic
ools, such as in la able balloons, s en s, and ca he e s (Chen
e al., 2015). An usual side e ec is es enosis, which is a
na owing o he a e y, ei he by emodeling and ecoiling o
he essel lumen, o by p oli e a ion o smoo h muscle cells in
esponse o he inju y caused by he inse ed de ices (Cy us
e al., 2008). The inse ion o a s en is indica ed o p e en
he si ua ion, bu i may i sel be a igge o a p oli e a i e
esponse, and also a ehicle o cell mig a ion, dec easing he
in e nal diame e o he ea ed essel. Fo his eason, i is
impo an o de elop modi ied coa ings. The eal ad an ages o
using nanopa icle in used polyme s a e s ill unde e alua ion,
wi h some s udies concluding ha he use o d ug-elu ing s en s
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