Chitosan-based nanoscale systems for doxorubicin delivery: Exploring biomedical application in cancer therapy

REVIEW ARTICLE
Chi osan-based nanoscale sys ems o doxo ubicin deli e y:
Explo ing biomedical applica ion in cance he apy
Milad Ash a izadeh
1
| Kia ash Hushmandi
2
| Sepideh Mi zaei
3
| Saied Bokaie
2
|
Ashkan Bigham
4
| Pooyan Mak andi
5
| Na id Rabiee
6
| Vijay Kuma Thaku
7,8
|
Alan P em Kuma
9,10
| Esmaeel Sha i i
11
| Rajende S. Va ma
12
|
Ami Reza A e
13,14
| Ma cin Wojnilowicz
15,16
| Ali Za abi
17
|
Hassan Ka imi-Maleh
18,19,20
| Nicolas H. Voelcke
15,16,21
| Eb ahim Mos a a i
22,23
|
Go ka O i e
24,25,26,27
1
Facul y o Enginee ing and Na u al Sciences, Sabanci Uni e si y, Üni e si e Caddesi, Tuzla, Is anbul, Tu key
2
Depa men o Food Hygiene and Quali y Con ol, Di ision o Epidemiology, Facul y o Ve e ina y Medicine, Uni e si y o Teh an, Teh an, I an
3
Depa men o Biology, Facul y o Science, Islamic Azad Uni e si y, Science and Resea ch B anch, Teh an, I an
4
Ins i u e o Polyme s, Composi es and Bioma e ials - Na ional Resea ch Council (IPCB-CNR), Naples, I aly
5
Is i u o I aliano di Tecnologia, Cen e o Ma e ials In e aces, Pon ede a, Pisa, I aly
6
School o Enginee ing, Macqua ie Uni e si y, Sydney, New Sou h Wales, Aus alia
7
School o Enginee ing, Uni e si y o Pe oleum & Ene gy S udies (UPES), Deh adun, U a akhand, India
8
Bio e ining and Ad anced Ma e ials Resea ch Cen e , Sco land's Ru al College (SRUC), Edinbu gh, UK
9
NUS Cen e o Cance Resea ch (N2CR), Yong Loo Lin School o Medicine, Na ional Uni e si y o Singapo e, Singapo e, Singapo e
10
Depa men o Pha macology, Yong Loo Lin School o Medicine, Na ional Uni e si y o Singapo e, Ken Ridge, Singapo e
11
Depa men o Tissue Enginee ing and Bioma e ials, School o Ad anced Medical Sciences and Technologies, Hamadan Uni e si y o Medical Sciences,
Hamadan, I an
12
Regional Cen e o Ad anced Technologies and Ma e ials, Czech Ad anced Technology and Resea ch Ins i u e, Palacky Uni e si y,
Olomouc, Czech Republic
13
Bel e Cen e o Applied Cance Science, Dana-Fa be Cance Ins i u e, Ha a d Medical School, Bos on, Massachuse s, USA
14
Xsphe a Biosciences Inc., Bos on, Massachuse s, USA
15
Commonweal h Scien i ic and Indus ial Resea ch O ganisa ion (CSIRO) Manu ac u ing, Clay on, Vic o ia, Aus alia
16
Monash Ins i u e o Pha maceu ical Sciences, Pa k ille, Vic o ia, Aus alia
17
Depa men o Biomedical Enginee ing, Facul y o Enginee ing and Na u al Sciences, Is inye Uni e si y, Is anbul, Tu key
18
School o Resou ces and En i onmen , Uni e si y o Elec onic Science and Technology o China, Chengdu, PR China
19
Depa men o Chemical Enginee ing, Quchan Uni e si y o Technology, Quchan, I an
20
Depa men o Chemical Sciences, Uni e si y o Johannesbu g, Doo n on ein Campus, Johannesbu g, Sou h A ica
21
Melbou ne Cen e o Nano ab ica ion, Vic o ian Node o he Aus alian Na ional Fab ica ion Facili y, Clay on, Vic o ia, Aus alia
22
S an o d Ca dio ascula Ins i u e, S an o d Uni e si y School o Medicine, S an o d, Cali o nia, USA
23
Depa men o Medicine, S an o d Uni e si y School o Medicine, S an o d, Cali o nia, USA
24
NanoBioCel Resea ch G oup, School o Pha macy, Uni e si y o he Basque Coun y (UPV/EHU), Vi o ia-Gas eiz, Spain
Abb e ia ions: AA, ac ylic acid; ABC, ATP-binding casse e; AGO, amine- unc ionalized GO; BSA, bo ine se um albumin; CHOL, choles e ol; CMC, ca boxyme hyl CS; CSO, CS oligosaccha ide;
CXB, celecoxib; DCA, deoxycholic acid; DOX, doxo ubicin; FA, olic acid; GA, glycy he inic acid; GO, g aphene oxide; GSH, glu a hione; HA, hyalu onic acid; HSPC, hyd ogena ed soy
phospha idyl choline; IA, i aconic acid; miRNA, mic oRNA; M-MSNs, magne ic mesopo ous silica nanopa icles; MOFs, me al o ganic amewo ks; OA, oleanolic acid; P-gp, P-glycop o ein; PHA,
pheopho bide A; PTX, pacli axel; RAPA, apamycin; ROS, eac i e oxygen species; SA, s ea ic acid; shRNA, sho hai pin RNA; siRNA, small in e e ing RNA; SOC, N-succinyl-N0-oc yl chi osan.
Recei ed: 15 Feb ua y 2022 Re ised: 12 Ma ch 2022 Accep ed: 17 Ma ch 2022
DOI: 10.1002/b m2.10325
This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion License, which pe mi s use, dis ibu ion and ep oduc ion in any medium,
p o ided he o iginal wo k is p ope ly ci ed.
© 2022 The Au ho s. Bioenginee ing & T ansla ional Medicine published by Wiley Pe iodicals LLC on behal o Ame ican Ins i u e o Chemical Enginee s.
Bioeng T ansl Med. 2023;8:e10325. wileyonlinelib a y.com/jou nal/b m2 1o 29
h ps://doi.o g/10.1002/b m2.10325
23806761, 2023, 1, Downloaded om h ps://aiche.onlinelib a y.wiley.com/doi/10.1002/b m2.10325 by Uni e sidad Del Pais Vasco, Wiley Online Lib a y on [06/03/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
25
Uni e si y Ins i u e o Regene a i e Medicine and O al Implan ology–UIRMI(UPV/EHU-Fundaci
on Edua do Ani ua),
Vi o ia-Gas eiz, Spain
26
Bioa aba, NanoBioCel Resea ch G oup, Vi o ia-Gas eiz, Spain
27
Singapo e Eye Resea ch Ins i u e, Singapo e
Co espondence
Pooyan Mak andi, Is i u o I aliano di
Tecnologia, Cen e o Ma e ials In e aces,
iale Rinaldo Piaggio 34, 56025 Pon ede a,
Pisa, I aly.
Email: pooyan.mak andi@ii .i
Nicolas H. Voelcke , Monash Ins i u e o
Pha maceu ical Sciences, Pa k ille, Vic o ia
3052, Aus alia.
Email: nicolas. oelcke @monash.edu
Go ka O i e, Bioa aba, NanoBioCel Resea ch
G oup, Vi o ia-Gas eiz, Spain.
Email: [email p o ec ed]
Funding in o ma ion
Na ional Ins i u e o Biomedical Imaging and
Bioenginee ing, G an /Awa d Numbe :
5T32EB009035; Uni e si y o he Basque
Coun y; Minis y o Economy, G an /Awa d
Numbe : PID2019-106094RB-I00/AEI
Abs ac
G een chemis y has been a g owing mul idisciplina y ield in ecen yea s showing
g ea p omise in biomedical applica ions, especially o cance he apy. Chi osan (CS) is
an abundan biopolyme de i ed om chi in and is p esen in insec s and ungi. This
polysaccha ide has a o able cha ac e is ics, including biocompa ibili y, biodeg adabil-
i y, and ease o modi ica ion by enzymes and chemicals. CS-based nanopa icles
(CS-NPs) ha e shown po en ial in he ea men o cance and o he diseases, a o ding
a ge ed deli e y and o e coming d ug esis ance. The cu en e iew emphasizes on
he applica ion o CS-NPs o he deli e y o a chemo he apeu ic agen , doxo ubicin
(DOX), in cance he apy as hey p omo e in e naliza ion o DOX in cance cells and
p e en he ac i i y o P-glycop o ein (P-gp) o e e se d ug esis ance. These
nanoa chi ec u es can p o ide co-deli e y o DOX wi h an i umo agen s such as cu -
cumin and cispla in o induce syne gis ic cance he apy. Fu he mo e, co-loading o
DOX wi h siRNA, shRNA, and miRNA can supp ess umo p og ession and p o ide
chemosensi i i y. Va ious nanos uc u es, including lipid-, ca bon-, polyme ic- and
me al-based nanopa icles, a e modi iable wi h CS o DOX deli e y, while unc-
ionaliza ion o CS-NPs wi h ligands such as hyalu onic acid p omo es selec i i y
owa d umo cells and p e en s DOX esis ance. The CS-NPs demons a e high
encapsula ion e iciency and due o p o ona ion o amine g oups o CS, pH-sensi i e
elease o DOX can occu . Fu he mo e, edox- and ligh - esponsi e CS-NPs ha e been
p epa ed o DOX deli e y in cance ea men . Le e aging hese cha ac e is ics and in
iew o he biocompa ibili y o CS-NPs, we expec o soon see signi ican p og ess
owa ds clinical ansla ion.
KEYWORDS
chi osan, d ug esis ance, gene he apy, s imuli- esponsi e nanoca ie s, syne gis ic he apy
1|INTRODUCTION
Cance ea men equi es de elopmen o he apeu ic s a egies o
minimizing g ow h and mig a ion o umo cells o imp o e o e all
su i al o pa ien s. Fo exe ing such ac i i ies, an i umo compounds
should be e ec i ely in e nalized by cance cells and induce a he a-
peu ic e ec a he cellula le el by a ec ing he molecula pa hways
and mechanisms esponsible o o ganelle o ganiza ion and unc ion,
such as mi ochond ia and endoplasmic e iculum.
1–8
Due o ad ance-
men in he ields o medicinal chemis y, a ious an i umo com-
pounds, namely cispla in, pacli axel, doce axel, and doxo ubicin (DOX)
among o he s, ha e been de eloped in cance he apy.
9,10
Chemo-
he apy is cu en ly a i s -line op ion o he ea men o cance
pa ien s o e adica e umo p og ession and imp o e p ognosis. Fu -
he mo e, chemo he apy is p e e ed o su ge y, as i is a nonin asi e
s a egy in cance ea men . Howe e , some o he cance s a e inhe -
en ly esis an o chemo he apy, o a ained d ug esis ance du ing
he ea men a ec ing an i umo agen o i s a ge . As
chemo esis ance h ea ens he li e o many people a ound he wo ld,
he e ha e been incessan e o s in unde s anding unde lying ac o s
in his p ocess. The d ug esis ance is a mul i ac o ial condi ion and
each ac o can independen ly pa icipa e in dec easing cy o oxici y
o an i umo agen . The enhanced d ug e lux, diminu ion in d ug
up ake, mu a ion, d ug inac i a ion, apop osis machine y impai men ,
signaling ne wo ks (up egula ion o umo -p omo ing ac o s and
down egula ion o umo -supp esso ), and pheno ype swi ching a e
he mechanisms ha can lead o cance d ug esis ance.
11–14
Gi en
he impo ance o d ug esis ance in chemo he apy ailu e, scien is s
ha e ollowed some s a egies o o e coming his condi ion by apply-
ing nanos uc u es ha imp o e d ug deli e y po en ial, enhance
2o 29 ASHRAFIZADEH ET AL.
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in acellula accumula ion, and p o ide a ge ed deli e y and co-
deli e y wi h o he an i umo agen s o nucleic acid he apeu ics.
15,16
The aim o p esen e iew is o discuss he ole o chi osan (CS) o
he deli e y o DOX as one o he mos well-known chemo he apeu ic
agen s in cance he apy and in oducing CS chemis y, s uc u e, and
po en ial applica ions in medicine. The unc ion o DOX in cance sup-
p ession, ac o s esponsible o i s esis ance and ole o nanopa icles
in e e sing DOX esis ance a e discussed wi h emphasis on CS-based
nanos uc u es o i s deli e y; pH- and edox-sensi i e asso ed CS
nanopa icles a e highligh ed including hei use o co-deli e yo DOX
wi h an i umo agen s and nucleic acid he apeu ics. Finally, he modi i-
ca ion o a ious nanopa icles and app op ia e solu ions o hei clinical
applica ions a e desc ibed o shed a ligh on he deploymen o hese
nanos uc u es o cance chemo he apy.
2|CHITOSAN: CHEMISTRY AND
BIOMEDICAL APPLICATION
The g een echnology is one o he newes and mos ecen app oaches
o he de elopmen o nanopha maceu icals in ea men o diseases.
The g een chemis y app oach u ilizes compounds and agen s de i ed
om na u e o syn hesis and modi ica ion o nanoca ie s o imp o e
hei cha ac e is ics and make hem be e op ions o disease ea -
men . In his s a egy, he haza dous ma e ial applica ion is a oided and
in u n, sa e, bio enewable and biocompa ible agen s isola ed om
na u e a e u ilized o de elop nanopa icles. Since g een-based
nanoca ie s demons a e good sa e y p o ile and biocompa ibili y, he
way o hei clinical applica ion is pa ed. The deli e y o d ugs and
nucleic acid he apeu ics is essen ial in cance he apy due o hei low
accumula ion a umo si e and eme gence o d ug esis ance; hence,
g een syn hesis o g een modi ica ion o nanopa icles can be bene icial
in his case o imp o ing e icacy in cance he apy.
17–19
In he p esen
e iew, ou aim is o highligh g eene modi ica ions o nanopa icles
wi h CS as a na u al compound o show i s po en ial o cance chemo-
he apy and possible clinical applica ions in he nea u u e.
A e cellulose, chi in is he mos abundan na u al polyme
20
and
CS is de i ed om chi in (Figu e 1),
22
an essen ial componen com-
p ising shells o insec s, c us aceans, and cell walls o ungi.
23–25
The
annual p oduc ion o chi in is es ima ed o be 10–100 G and he
comme cialized chi in/CS can esul om sea ood was e in which α-
and β-chi ins a e de i ed om shells o c ab and sh imp, while CS is
p epa ed by deace yla ion o chi in.
23,24,26–28
The amoun o
deace yla ion seems o be mo e han 60% in comme cialized CS
whe e Japan is conside ed as he majo p oduce o CS. Based on he
es ima es, he alue o CS ma ke has been 6.8 B$ in 2019.
20
The
unique chemical s uc u e o CS has made i a sui able op ion o bio-
medical and enginee ing applica ions. The mos impo an ea u e o
CS is i s g ea solubili y in aqueous solu ion due o he p esence o
amino g oups a C2 posi ion. In aqueous acidic sol en s, CS unde goes
p o ona ion o gene a e NH
3+
ha is bene icial in he design o
nanoa chi ec u es and hei syn hesis ia bo om-up app oach. Impo -
an ly, amino and ace ylamino g oups in CS a e main sou ces o ni o-
gen o gene a ing e ilize s and N-doped ca bon ma e ials o
deploymen as ca alys .
20,29
The applica ion o CS in indus y has demons a ed po en ial in
educing en i onmen al pollu ion as a biodeg adable and enewable
abundan ma e ial ha should no be disca ded in o sca ce land ills.
The aim o g een chemis y is o limi indus ial p oduc ion o haza d-
ous compounds and p e en des uc i e impac s, bo h sho - e m and
long- e m, on ecosys em.
30–32
Besides, g een chemis y is bene icial
in dec easing ene gy consump ion and subs i u ing con en ional sol-
en s wi h newe op ions ha a e enewable and demons a e low
des uc i e impac on en i onmen .
33
The p ecu so o CS, chi in is
made o up o 3000 epea ing uni s comp ising N-ace yl-D-glucos-
amine
34
ha a e in e connec ed ia β(1 !4) glycosidic bonds. The
chi in exhibi s high simila i y o cellulose in e ms o chemical s uc-
u e wi h he di e ence ha hyd oxyl g oup a posi ion C2 is
subs i u ed by ace amido g oup.
35
The e a e a ious kinds o chi in
including α,β, and γ, which show a ia ion in hyd a ion, size, and num-
be o chains
36
and a e p esen in a ious s uc u es and sou ces. Fo
ins ance, α-chi in is ound in shells and cell walls, β-chi in is p esen in
endocycle on o squid pens
36,37
and γ-chi in is obse ed in s omach
lining o squid and cu le ish.
36
The e a e wo saccha ides, namely, N-ace yl-D-glucosamine and β
1–4D-glucosamine in he CS s uc u e and du ing he deace yla ion
o chi in, N-ace yl-D-glucosamine monome s a e ans o med in o D-
glucosamine o gene a e CS. The LD
50
o CS is 16 g/kg body weigh
and i shows a g ea sa e y p o ile. The a ious kinds o CS a e ca ego-
ized based on molecula weigh and deace yla ion deg ee
38
;CSisa
polyca ion and i s cha ge densi y is de e mined by pH and
deace yla ion deg ee including he solubili y aspec s. The CS oligo-
me s display solubili y in acidic and basic media bu wi h inc ease in
i s molecula weigh , i is only soluble in acidic media e en wi h a
highe deace yla ion deg ee. Consequen ly, signi ican e o s ha e
been made in syn hesizing CS de i a i es ha a e soluble unde neu-
al and basic pH condi ions by al e ing ace yla ion, polyme iza ion,
and qua e niza ion
39
; pKa alue is sugges ed o be 6.5 and p o on-
a ion o NH
2
g oups p o ides CS solubili y in acidic media
40
as has
been a i med ha p o ona ion o 50% o amine g oups leads o CS
solubili y.
41
The molecula weigh and deace yla ion deg ee de e mine
he iscosi y o CS and educ ion in molecula weigh signi ican ly
FIGURE 1 Chemical s uc u es o
chi in and CS ia deace yla ion.Sou ce:
Rep in ed wi h pe mission om Re 21
ASHRAFIZADEH ET AL.3o 29
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diminishes CS's iscosi y.
41–43
The biocompa ibili y and biodeg adabil-
i y a e o he bene icial cha ac e is ics o CS.
44–46
The biomedical applica ion o CS nanos uc u es
47
has ga ne ed
much a en ion in ecen yea s, especially in cance he apy, which has
been in es iga ed in de ail; CS nanopa icles (CS NPs) can media e d ug
and nucleic acid he apeu ic deli e y,
48
chemo he apy,
49
pho o he apy,
50
and imaging in cance ea men .
51
The edox-sensi i e micelles wi h ca -
boxyme hyl CS deco a ion can be u ilized o NIR imaging o li e cance
cells and simul aneously, pho o- and chemo- he apy.
49,52
Ano he s udy
e alua ed he po en ial o gold (Au)-embedded CS nanos uc u es o
deli e y o d ugs in a pH-sensi i e manne and p o iding luo escence
imaging.
53
No ably, he su ace modi ica ion o CS nanos uc u es is o
impo ance o nucleic acid he apeu ic deli e y and syn hesizing ec o s
ha can o m s able complexes wi h gene ic ools. In a ecen s udy, CS-
Au nanos uc u es ha e been applied in pho oacous ic imaging-guided
nucleic acid he apeu ic deli e y and pho o he mal he apy o exe a syn-
e gis ic impac o cance supp ession.
54
The CS can be u ilized o he
de elopmen o pulmona y d ug deli e y sys ems. No ably, CS-based
nano-scale deli e y sys ems o pulmona y deli e y a e o impo ance in
ea men o ela ed cance s such as lung umo . Fu he mo e, i can be
used in ea men o in ec ious diseases such as COVID-19 ha is
in lic ing nowadays.
55–60
The CS-based nanos uc u es ha e demon-
s a ed g ea e icacy in p olonged deli e y o d ugs
61,62
ha is o u mos
impo ance in cance he apy. Due o CS's posi i e cha ge, i can easily
o m complexes wi h nega i ely cha ged nucleic acids. A ecen s udy has
exploi ed CS-hyalu ona e-SPION nanopa icles o hedeli e yo siRNA
and EP4 an agonis in cance he apy; hese nanopa icles e ec i ely sup-
p ess HIF-1α/EP4 axis in impai ing g ow h and in asion o umo
cells.
63
Fu he mo e, CS NPs can media e pulmona y deli e y o
CRISPR/Cas9 sys em, as a new eme ging gene ic ool.
56
Besides
cance he apy, CS has a he apeu ic impac in alle ia ing os eoa -
h i is
64
and, ecen ly, a hyd ogel sys em based on lac a e-modi ied
CS has been p epa ed o os eoa h i is ea men due o i s an ioxi-
dan ac i i y, whe e i exhibi s high biocompa ibili y.
65
Fu he mo e,
CS-based complexes can amelio a e os eoa h i is by enhancing p o-
li e a ion a e o chond ocy es and p e en ing apop osis.
66,67
In
ano he s udy, CS NPs we e used o he deli e y o osu as a in o
dec ease choles e ol le els upon a he oscle osis ea men and o
p e en he de elopmen o ca dio ascula diseases.
68
Fu he , CS
NPs can be u ilized in an i-in lamma o y o mula ions by deli e y o
d ugs such as diclo enac sodium
69
and dexame hasone,
70
among
o he s. O e all, s udies highligh he ac ha CS-based NPs demon-
s a e good biomedical applica ions.
71–76
The ollowing sec ions
explo e he ole o CS NPs in he deli e y o an icance d ug—
doxo ubicin (DOX).
3|DOXORUBICIN: MECHANISM OF
ACTION AND RESISTANCE
The DOX is an an h acycline an ibio ic de i ed om S ep omyces
peuce ius caesius wi h high an i umo ac i i y
77–79
as i displays
e icacy e en a low doses in supp essing di e en neoplasms.
80
The animal expe imen s e alua ing an icance ac i i y o DOX ha e
a i med i s po en ial in minimizing umo p og ession and imp o -
ing su i al o animal models.
81
An isupp essi e ac i i y o DOX
has been success ully demons a ed in p eclinical models and clini-
cal ials on a ious cance s, including leukemia, lymphoma, sa -
coma, and u ogeni al cance s, among o he s.
80,82
DOX mainly
a ge s gene ic componen s in nucleus and mi ochond ia inhibi ing
he cell g ow h and di ision. Howe e , DOX alone is no cell-
selec i e and a ec s also he unc ion o heal hy cells. This an i-
umo agen is capable o in e cala ing wi h DNA o p e en DNA
eplica ion and p o ein syn hesis. Fu he mo e, DOX s imula es
DNA damage in umo cells by p e en ing he ac i i y o opoisom-
e ase II enzymes. Addi ional in es iga ions e ealed ha DOX
enhances he p oduc ion o eac i e oxygen species (ROS) o
induce DNA damage and des oy cell memb ane ia di ec
in e ac ion.
83–86
Howe e , DOX esis ance e olu ion in umo cells is consid-
e ed a majo challenge as a ious unde lying molecula pa hways
and mechanisms a e esponsible o he de elopmen o DOX
esis ance.
87–89
The b eas umo is a he e ogeneous cance wi h
di e en sub ypes and i s incidence a e is a ious based on geo-
g aphical di e ences. Al hough chemo he apy is used o b eas
cance ea men , i s he apy is s ill a challenge.
90
The lncRNA
H19 is in ol ed in igge ing DOX esis ance in b eas umo
(in i oandin i o) iaPARP1down egula ion.
91
The lncRNA
TUG1 dec eases miRNA-9 exp ession ia sponging o induce
DOX esis ance in b eas cance .
92
The ci cRNA-0002060 medi-
a es he DOX esis ance in os eosa coma ia miRNA-198 down-
egula ion and subsequen inc ease in he exp ession le el o
ABCB1.
93
The TCF4 and EIF5A2 a e o he molecula pa hways
ha a e a ec ed in cance cells o egula e DOX chemo he apy
esponse.
93,94
Howe e , an i umo agen s, such as abec edin
and es e a ol among o he s, ha e shown po en ial in e e sing
DOX esis ance.
95,96
Di e en s udies p o ide no el insigh s and pa hways o
de elopmen o DOX esis ance. The DOX esis ance in os eosa -
coma can be media ed by TCF4 o e exp ession. In his case, ci c-
0001721 p omo es TCF4 exp ession ia miRNA-758 down-
egula ion o induce DOX esis ance.
94
Ano he expe imen
e eals ha ci cATXN7 inc eases HOXA11 exp ession ia
miRNA-149-5p down egula ion o inc ease b eas cance p og es-
sion and o inhibi DOX esis ance.
97
Fu he mo e, EMT is
esponsible o cance me as asis
98
and i s induc ion can lead o
DOX esis ance in umo cells. The e o e, a ge ing hese pa h-
ways can e ec i ely supp ess DOX esis ance in cance . Fo
ins ance, silencing RNF8,
99
CIP2A,
100
and miRNA-21
101
can
inhibi DOX esis ance in a ious umo s and impai s hei p oli -
e a ion. A mo e ad anced s a egy in e e sing DOX esis ance is
he applica ion o nanopa icles o a ge ed deli e y o DOX a
he umo si e and co-deli e y o DOX wi h o he an i umo
agen s o nucleic acid he apeu ics.
88,102–104
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4|NANOSTRUCTURES OF CHITOSAN-
DOXORUBICIN
4.1 |S imuli- esponsi e nanoca ie s
4.1.1 | pH- esponsi e
The umo mic oen i onmen has a mild acidic pH (app oxima ely 6.5)
ha is lowe han physiological condi ion and such di e ence in pH
le el can be exploi ed o d ug elease a umo si e; unc ionaliza ion
o nanoma e ials and hei d ug conjuga es can lead o elease a his
mild acidic pH. Based on his sys em, he bond be ween he ma e ial
and he d ug deg ades unde acidic pH o umo si e o media e d ug
elease.
105
Va ious kinds o bonds including imine, hyd azone, oxime,
amide, ace als, and o hoes e can be deployed o syn hesizing pH-
sensi i e nanoca ie s and d ug elease a umo si e
106
as has been
discussed in his sec ion. Figu e 2p o ides a schema ic ep esen a ion
o s imuli- esponsi e CS-based nano-scale deli e y sys ems in cance
he apy.
Recen ly, a CS-based polyme ic p od ug, ha is pH sensi i e and
can p o ide a pla o m o co-deli e y o DOX and siRNA, has been
syn hesized. The DOX and Bcl-2-siRNA can be conjuga ed o CS-
modi ied polyme ic nanopa icles and hen, syne gis ic cance he apy
is p o ided. These nanos uc u es a e in e nalized by hepa oma cells
ia glycy he inic acid ecep o -media ed endocy osis. A e 10 h,
nanos uc u es can elease siRNA and DOX as much as 90.2% and
81.3%, espec i ely. This CS-based polyme ic p od ug e icien ly sup-
p esses umo p og ession (HepG2 cells) by 88% ia media ing bo h
chemo- and nucleic acid- he apy.
107
The CS is a pH-sensi i e agen due o he p esence o amine
g oups ( NH
2
) ha unde goes p o ona ion in acidic pH
108,109
; highe
pH signi ican ly dec eases he solubili y o CS.
109
On he o he hand,
poly inylpy olidone (PVP) is o en u ilized o he syn hesis o
nanopa icles, bu i signi ican ly dec eases he ini ial bu s elease.
110
Fo o e coming such issues, he combina ion o PVP and CS has been
sugges ed o imp o e he solubili y o CS a high pH le els and
mechanical cha ac e is ic o PVP, simul aneously.
109–111
A ecen
s udy demons a ed ha CS/PVP/α-Fe
2
O
3
nanocomposi es o he
deli e y o DOX, whe e nanopa icles had a sphe ical s uc u e, and
hey could load Fe
2
O
3
in CS/PVP. The nanos uc u es showed a pa i-
cle size o 247 nm and due o conjuga ion o α-Fe
2
O
3
, hey demon-
s a ed p olonged elease and inc eased e en ion o DOX a umo
FIGURE 2 Ac i e a ge ing and s imuli- esponsi e d ug elease o CS-doxo ubicin nanoca ie . The su ace modi ica ion o CS-based
nanos uc u es wi h ligands can inc ease hei in e naliza ion in umo cells. Besides, Ex e nal and in e nal s imuli can be u ilized o de eloping
sma nanoca ie s in cance he apy. CSC, cance s em cell
ASHRAFIZADEH ET AL.5o 29
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si e. The CS/PVP-based nanocomposi es elease DOX in a pH-
sensi i e manne , mimicking pH le el o umo mic oen i onmen and
hey induced apop osis o signi ican ly dec ease he iabili y o b eas
cance (MCF-7 cells).
112
The e a e se e al easons o using pH-sensi i e nanoca ie s o
cance he apy and also deli e y o chemo he apeu ic agen s. The
nonspeci ici y o sys emic chemo he apy can nega i ely a ec no mal
and heal hy cells a e in a enous injec ion.
113,114
Besides, epea ing
injec ions can lead o pain, in ec ion, and hospi aliza ion. The e o e,
he applica ion o nanopa icles o sus ained deli e y o chemo he a-
peu ic agen s elimina es he need o epea ed injec ions and can
imp o e he chance in he igh agains cance .
114–116
Due o glycoly-
sis phenomenon in he umo mic oen i onmen and con e sion o
glucose o lac a e, pH le el is signi ican ly diminished, which is bene i-
cial o cance p og ession.
117,118
A ecen expe imen has ad anced
g aphene-CS nanocomposi es o DOX deli e y, which we e s abilized
wi h bo ine se um albumin (BSA); he p esence o BSA is bene icial in
p e en ing bu s elease o d ug om CS nanocomposi es. They show
uni o m elease o e 24 h and can elease d ug o up o 28 days
(84% o d ug). Such p olonged elease o DOX om CS-deco a ed
nanocomposi es ha is pH-sensi i e can imp o e cy o oxici y agains
cance cells.
119
In ano he s udy, a composi e s uc u e consis s o
halloysi e nano ubes as a na u al aluminosilica e ce amic and CS was
designed o pH- esponsi e elease o DOX o b eas cance he apy.
The d ug-loaded ca ie showed a sus ained elease in cell lysa e and
he mechanism o ac ion was o pene a e in o mi ochond ia ollowed
by inducing damage. Mo eo e , he IC
50
o nanoca ie agains MCF-7
cells was ound 1.17 μgml
1
lowe han ha o ee DOX
(2.43 μgml
1
). The in i o s udies e ealed ha he umo inhibi ion
a io o he nanoca ie was 83.5%, whe eas he ee DOX showed
46.1%. No ably, he ea ed mice wi h he DOX-loaded ca ie su -
i ed o e 60 days wi hou a signi ican sys emic cy o oxici y
(Figu e 3).
120
The UV- igge ed injec able CS hyd ogels a e ex ensi ely applied
in biomedicine.
121–124
Di e en UV-c osslinkable CS de i a i es ha e
been designed ia co alen a achmen o UV- esponsi e
componen s
125–128
o imp o e hei solubili y. The “ hiol-ene”click
chemis y can be u ilized o he de elopmen o pH- esponsi e UV
c osslinkable CS hyd ogel. The UV c osslinking abili y and pH-
sensi i e capaci y o CS ensue om allyl g oups on C
6
si e and amine
FIGURE 3 A pH- esponsi e CS ca ie
in combina ion wi h halloysi e nano ubes
o b eas cance he apy. (a,b) The
syn hesis p ocedu e ollowed by loading
o DOX molecules on he chi osan (COS)-
halloysi e nano ubes (HNTs) and he
up ake p ocess by which he d ug-loaded
ca ie induce cy o oxici y owa d
cance ous cells. (c) Tumo olume changes
a e being ea ed wi h di e en samples
including con ol (CON), ee DOX,
unloaded ca ie , and DOX-loaded ca ie ;
signi ican di e ence wi h he con ol
g oup ***P< 0.001, unloaded ca ie a
###P< 0.001, and DOX a &P< 0.01.
(d) The d ug elease om he ca ie a
di e en pH. (e) The excised umo s
emo ed a he end o ea men a e
being ea ed wi h di e en samples. ( )
The his ology ha was accomplished
h ough H&E s aining on he 14 h day o
ea men . Sou ce: Rep in ed om Re
120 wi h pe mission om ACS
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g oups on C
2
si e. A a ious pH le els, CS-based hyd ogels show di -
e en beha io s, and hei swelling and sh inkage can lead o he
elease o DOX in a pH-sensi i e manne .
129
The pu pose o using CS
in he modi ica ion o nanopa icles is i s capaci y in unc ionalizing o
loading a ious an i umo d ugs (DOX), a ge ing ligands (ap ame ),
coa ing polyme s and imaging p obes.
130
Fo his pu pose, Au
nanopa icles we e modi ied wi h CS and DNA ap ame o media e
selec i e a ge ing o glioblas oma cells. Ob ained nanos uc u es
we e u ilized o deli e y o 5- lou ou acil (5-FU) and DOX in glioblas-
oma supp ession. The p epa ed CS-Au NPs had a pa icle size o
196.2 nm wi h ze a ζ-po en ial o 16.26 mV and hey signi ican ly
enhanced he cy o oxici y o DOX and 5-FU agains glioblas oma cells
and induced cell dea h and G0/G1 cell cycle a es .
131
Based on hese
esul s, i can be concluded ha CS is a p omising agen o he syn-
hesis o pH- esponsi e nanoca ie s o DOX deli e y and cance
supp ession
132
and can be easily unc ionalized by o he ligands o
imp o e he selec i i y o NPs owa d cance cells, while simul a-
neously p o iding co-deli e y o DOX and o he an i umo agen s
such as 5-FU. By p o iding pH-sensi i e ea u e, hese nanoca ie s
elease DOX a he umo si e and also media e sus ained deli e y,
which a e bo h bene icial in cance supp ession.
4.1.2 | Redox esponsi e
The p esence o edox imbalance is ano he unique ea u e o umo
mic oen i onmen ha is esponsible o enhancing umo p oli e a-
ion a e. The p oduc ion o ROS, ini ia ed by in lamma o y cells,
endo helial cells, and cance -associa ed ib oblas s, induces an ae obic
glycolysis and signi ican ly inc eases umo p og ession. On he o he
hand, glu a hione (GSH) is an enzyme ha egula es oxida i e s ess
and diminishes ROS le els. In he pha maceu ical indus y, he e ha e
been e o s in syn hesizing edox-sensi i e nanoma e ials. P epa a-
ion o such nanos uc u es usually in ol es inco po a ion o disul ide
as i unde goes deg ada ion by GSH.
133,134
This sec ion ocuses on
edox-sensi i e CS-NPs and disul ide bond decomposi ion by GSH a
he umo si e o DOX elease.
As has been discussed in he p e ious sec ions, a combina ion o
CS wi h o he agen s is applied o syn hesize NPs and imp o e ea-
u es ha a e impo an o ca go deli e y. The CS oligosaccha ide
(CSO) and s ea ic acid (SA) can be u ilized o he p epa a ion o
glycolipid-like copolyme
135
and ensued CSO-SA copolyme has high
s abili y ha can be u he exploi ed o d ug deli e y
applica ions
136–139
as i exhibi s high in e naliza ion and cellula
up ake.
136
Howe e , micelles p epa ed om CSO-SA ha e a majo
challenge o e icien ly elease he d ug in i o due o slow deg ada-
ion kine ics o amide bond. To imp o e d ug elease p o ile om
CSO-SA-based NPs, DOX can be conjuga ed wi h CSO-SA ia disul-
ide bond. This app oach is ad an ageous in syn hesizing CSO-SA-
based nanopa icles ha a e edox sensi i e and due o highe GSH
le els in cells, hey elease DOX o supp ess b eas cance p og ession
(MCF-7 cells).
140
In ano he s udy, ca boxyme hyl CS (CMC)-based
micelles o deli e y o DOX in cance he apy we e p epa ed. The
poly-ε-cap olac one (PCL)-SS-CMC sel -assembled in o micelles o
imp o emen o hei selec i i y agains cance cells (li e and ce ical
cance s) and we e modi ied wi h glycy he inic acid (GA). Then, DOX
and ano he an i umo agen known as pheopho bide A (PHA) we e
loaded on hese NPs, which showed a elease p o ile up o 86.3% and
92.1% o DOX and PHA, espec i ely, a e 48 h. This app oach is
bene icial in enhancing in acellula accumula ion o DOX and PHA by
p o iding GA ecep o -media ed endocy osis and edox-sensi i e sys-
em.
49
Al hough a ew expe imen s ha e e alua ed he po en ial o
edox-sensi i e CS-based NPs o deli e y o DOX,
140
hey highligh
he ac ha disul ide bond be ween CS and DOX can be easily
deg aded in he p esence o GSH. This sys em is biocompa ible and
i s modi ica ion wi h ligands can be pe o med o p omo e i s po en-
ial in DOX deli e y.
4.1.3 | Ligh esponsi e
A ew expe imen s ha e exploi ed he ole o CS-based
nanos uc u es o ligh -media ed elease o DOX, which deployed
nanobubbles.
141
The nanobubbles ha e sphe ical co e–shell s uc u e
and hei su ace can be conjuga ed wi h unc ional g oups. The
nanobubbles possess enhanced pe meabili y and e en ion (EPR)
e ec ha is o impo ance o c ossing o e endo helial ba ie . The
nanobubbles can be adminis e ed ia in a enous ou e and in o de
o imp o e hei biocompa ibili y and biodeg adabili y, su ace modi i-
ca ion o nanopa icles wi h PLGA and PCL can be pe o med.
142
In
an expe imen , modi ica ion o nanobubbles wi h CS has been con-
duc ed. The CS nanobubbles can elease DOX in i o upon i adia ion
and signi ican ly enhance up ake o DOX in mammalian cells. These
biocompa ible nanobubbles can be used o inhibi ing b eas umo
supp ession (MCF-7) ia ligh -media ed DOX deli e y.
141
A ligh -
esponsi e he anos ic pla o m composed o DOX-loaded gold
nanopa icles and CS was epo ed o b eas cance he apy. Apply-
ing NIR i adia ion no only acili a ed he payload elease in he can-
ce cells bu also caused he gold nanopa icles o ele a e he inne
empe a u e up o le el, which leads apop osis. Besides pho o he mal
he apy, i was obse ed ha he libe a ed DOX caused an oxida i e
s ess h ough gene a ion o ROS.
143
Th ough Figu e 4, he p epa a-
ion and he mechanism o ac ion o he ligh - esponsi e pla o m a e
indica ed.
4.1.4 | The mosensi i e
The he mosensi i e hyd ogels ha e ga ne ed much a en ion in
ecen yea s as an implan able deli e y sys em. The mosensi i e
hyd ogels a e injec ed in o umo si e in a liquid s a e and unde go
con e sion in o a solid gel a body empe a u e. Besides, hyd ogels
can p o ide he p olonged elease o an i umo d ugs a he umo
si e.
144–146
A s udy desc ibes he syn hesis o he mosensi i e CS
hyd ogel o encapsula e liposomal DOX wi h a pa icle size o
94.2 nm and encapsula ion e iciency as much as 98%. This
ASHRAFIZADEH ET AL.7o 29
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he mosensi i e hyd ogel changes o a solid gel a body empe a u e
and p o ides sus ained elease o DOX. These hyd ogels demon-
s a ed a high sa e y p o ile and biocompa ibili y, and simul aneously,
hey showed capaci y in supp essing umo p og ession (H22 hepa-
oma cells and umo -bea ing mice).
147
The applica ion o CS p e en s
he bu s elease o DOX om hyd ogels. No ably, CS-DOX conjuga e
in hyd ogels does no a ec he an i umo ac i i y o DOX and i is
compa able o ee DOX. Bo h in i o and in i o expe imen s ha e
shown he po en ial o hyd ogels con aining CS-DOX conjuga e o
cance supp ession (A549 lung cance cells and nude mice).
148
Fu -
he mo e, loading liposomal DOX in hyd ogel does no nega i ely
a ec he en apmen e iciency o liposomes. Fo ins ance, an
expe imen syn hesized CS-based he mosensi i e hyd ogel con-
aining liposomal DOX o opical cance ea men (hepa oma).
The en apmen e iciency was 90% and a e loading liposomal
DOX in he hyd ogel, i s en apmen e iciency did no change.
149
No ably, ca bon nano ube (CNT)-CS can be loaded in
he mosensi i e hyd ogels o con olling DOX elease. Thei expo-
su e o i adia ion p o ides a pho o he mal e ec o CNTs ha is
bene icial in des oying hyd ogel s uc u e and media ing DOX
deli e y.
150
The e o e, a he mosensi i e hyd ogel can be syn he-
sized i s o con e sion o solid gel a body empe a u e and in
he nex s ep, CS-ca bon nano ubes a e loaded in o he hyd ogel
o egula ing DOX elease upon i adia ion.
150
The succeeding
sec ion ocuses on mul isensi i e CS-based nanoca ie s o DOX
deli e y.
4.1.5 | Mul i esponsi e
The e ha e been many e o s in de eloping mul i unc ional CS-based
NPs o DOX deli e y in cance ea men including nanocomposi es
ha a e iple sensi i e. Fo p epa ing such sys ems, CS is u ilized as a
pH-sensi i e agen , g-poly(N- inylcap olac am) (PNVCL) as a
he mosensi i e agen and H6R6 as a cell-pene a ing pep ide. Then,
DOX and oleanolic acid (OA) a e loaded on nanocomposi es wi h a
pa icle size o 190 nm, he loading e iciency being 13.2% and 7.3%
o DOX and OA, espec i ely. These nanocomposi es a e accumu-
la ed in he umo mic oen i onmen and he d ug is eleased a he
umo si e. The in i o and in i o expe imen s demons a ed he
po en ial o DOX and OA-loaded CS/PNVCL/H6R6 nanocomposi es
in supp essing cance p og ession and apop osis induc ion (SKOV3
o a ian cance cells and nude mice).
151
Ano he s a egy o imp o -
ing he physicochemical p ope ies o CS exploi ed i s conjuga ion
wi h PEG, which signi ican ly enhances solubili y and biocompa ibili y.
The hollow mesopo ous silica NPs ha e been modi ied wi h CS and
PEG wi h loading e iciency o 32.8%. The DOX is loaded in PEF-CS-
silica nanopa icles and he e is no elease o DOX a low le els o
GSH and pH 7.4. Howe e , a mild acidic pH o highe le els o GSH
can induce DOX elease in b eas cance supp ession.
152
Ano he
s udy p epa ed algina e/CS-based NPs o deli e y o DOX ha a e
pH- and ligh - esponsi e whe e algina e imp o ed s abili y o CS-
based NPs and could elease DOX in pH- and ligh -sensi i e manne
a e i adia ion and in mildly acidic pH (Figu e 5).
153
Based on hese
FIGURE 4 The ligh - esponsi e DOX-loaded gold-chi osan nanocomposi e. (a) The p epa a ion o CS-gold nano a les (AuNRT), DOX
loading and he e ec o NIR i adia ion on he payload elease. (b) The he mal images ela ed o he nanocomposi e a e being i adia ed
wi h 785 nm lase o 15 min wi h a ious concen a ions including (i) wa e as he con ol, (ii) 75, (iii) 150, (i ) 200, ( ) 500, and ( i) 800 μgml
1
.
(c) Measu emen s o empe a u e inc ease a e applying on/o cycles a a powe densi y o 5 W/cm
2
.Sou ce: Rep in ed om Re 143 wi h
pe mission om ACS
8o 29 ASHRAFIZADEH ET AL.
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s udies, CS and i s combina ion wi h o he agen s can be bene icial in
he de elopmen o mul i unc ional nanos uc u es o DOX deli e y
(Table 1).
159–161
Besides in e nal- esponsi e CS-NPs o DOX deli e y, he e is
ano he ca ego y e med hype he mia-based ex e nal-s imuli d ug
deli e y sys ems. These sys ems a e esponsi e o an ex e nal s imu-
lus, like magne ic ield and ligh capable o inc easing he empe a u e
o he umo mic oen i onmen ollowed by killing he cance ous
cells.
162
Mo eo e , a e being igge ed by he men ioned s imuli
agen s, he an icance d ug elease a e unde goes a signi ican
inc ease hus imp o ing he e iciency o he deli e y sys em.
163
This
s a egy has been exempli ied by a mul i unc ional chemo-
pho o he apeu ic deli e y sys em whe e black phospho us
nanoshee s ha e been adop ed as an ino ganic ligh - esponsi e ma e-
ial; he DOX has been i s loaded on o he nanoshee s ollowed by
being su ace modi ied wi h CS-PEG and olic acid o o m he inal
pla o m (BP-DcF). Nex , small in e e ing RNA and p og ammed
dea h-ligand 1 (PL) a e encapsula ed in o he deli e y sys em. Upon
i adia ion o nea -in a ed, a hype he mia e ec and bu s elease o
DOX could be obse ed and he combina ion o bo h chemo and
pho o he apies culmina ed in an e ec i e umo cells apop osis
(Figu e 6).
164
O e all, some echnical conclusions abou CS-based nanoca ie s
o DOX deli e y can be p o ided. Due o p o ona ion o amine
g oups o CS a acidic pH ha is simila o umo mic oen i onmen
pH, he pH-sensi i e elease o DOX occu s upon CS modi ica ion o
nanoca ie s. No ably, by loading some kinds o nanopa icles such as
Fe
3
O
4
in CS-based nanoca ie s, mul i unc ional nanoa chi ec u es
a e designed ha can p o ide s imulus- esponsi e elease o DOX
and simul aneous imaging.
4.2 |Re e sing d ug esis ance
The e a e se e al easons esponsible o ole o NPs in e e sing
chemo esis ance. F equen applica ion and high doses o chemo he a-
peu ic agen s can esul in d ug esis ance de elopmen and in
a ge ed deli e y, a low amoun o an icance agen is loaded ha
educes chance o d ug esis ance, while i main ains umo -
supp esso ac i i y.
165–167
Addi ionally, inc easing accumula ion o
FIGURE 5 Mul i esponsi e CS-NPs o DOX deli e y. (a) (i) S ep-by-s ep syn hesis o mul i esponsi e (pH, he mo, and edox esponsi e)
DOX/(oleanolic acid [OA[)@ unc ionalized cell-pene a ing pep ide (H6R6)-chi osan (CS)-g-poly(N- inylcap olac am) (PNVCL) NPs. (ii) The
applicabili y o nanopa icles o an icance he apy; he imp o ed pe mea ion and e en ion leads he NPs o emain in he umo en i onmen
ollowed by igge ing iple sensi i i y o elease doxo ubicin (DOX) and OA. Sou ce: Rep in ed om Re 151 wi h pe mission om Else ie .
(b) (i) Syn hesis o DOX-loaded algina e (ALG)/chi osan (CS) s abilized pe luo ohexane (PFH) NPs h ough nano-emulsion echnique. (ii) Double
sensi i i y (ul asound and pH) o he DOX-loaded nanod ople s agains cance cells. Sou ce: Rep in ed om Re 153 wi h pe mission om
Else ie
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micelles and ca bon nanoma e ials should be e alua ed in e ms o
co-deli e y o DOX and o he d ugs.
4.5 |Lipid nanopa icle modi ica ion
Liposomes a e syn he ic lipid NPs ha ha e been i s disco e ed in
he 1960s and comp ise a lipid bilaye wi h an aqueous co e.
230
The
liposomal nanoca ie s can be exploi ed o he deli e y o bo h
hyd ophilic and hyd ophobic d ugs. The hyd ophilic d ugs can be
loaded in he co e, while hyd ophobic d ugs can be loaded in lipid
bilaye . The d ugs loaded in liposomes a e p o ec ed agains inac i a-
ion in blood ci cula ion, dilu ion, and deg ada ion. The clinical applica-
ion o liposomes has some impedimen s such as hei apid clea ance,
immune sys em ac i a ion, and accumula ion in o he o gans.
231
Recen expe imen s ha e exploi ed liposomes o deli e y o DOX o
i s co-deli e y wi h o he agen s such as hispolon, cu cumin, and linal-
ool in combina ion cance he apy.
232–235
The e o e, liposomal
nanoca ie s can p o ide deli e y o DOX a he umo si e and his
sec ion ocuses on CS-modi ied liposomes in DOX deli e y.
An expe imen has conjuga ed DOX o amphiphilic
s ea olylspe mine ancho o p oduce a p od ug. Then, his p od ug
has been loaded in o liposomal nanoca ie s o colo ec al cance
he apy. Fo imp o ing he s abili y o DOX-loaded liposomes, hei
modi ica ion wi h CS and PEG has been made. Fu he mo e,
s ea oyl chains p omo e local mic o luidi y o liposomes and spe-
mine ia amine g oups in e ac s wi h phospha e g oups o lipids in
imp o ing liposome s abili y. In addi ion o s abili y, CS-PEG modi-
ica ion o liposomes p e en s agg ega ion and his coa ing medi-
a es cha ge neu aliza ion. These neu al liposomal nanoca ie s
demons a ed cy o oxici y agains A549 (lung cance ) and Caco-2
cells (colo ec al umo ) and hey showed high s abili y.
236
Ano he
s udy desc ibed he p epa a ion o liposomes using hyd ogena ed
soy phospha idylcholine (HSPC) and choles e ol (CHOL) and glycol
CS conjuga ion has been pe o med du ing ilm p epa a ion. Then,
DOX was embedded in p e o med liposomes ia ansmemb ane
pH g adien loading s a egy. These CS-based liposomes enhance
in e naliza ion o DOX in umo cells (HT1080 cells) and we e suc-
cess ul in enhancing he he apeu ic e icacy o DOX in i o and
in i o. This sys em was pH-sensi i e and could be exploi ed o
he ea men o o he cance ypes.
237
Ano he kind o lipid-based nanopa icles ha can be u ilized o
cance he apy a e micelles as hey a e conside ed as p omising ec-
o s in d ug deli e y and cance ea men due o hei ease o syn he-
sis and chemical modi ica ion. Fu he mo e, he size o micella NPs is
unable and hey can enhance d ug solubili y in wa e and signi ican ly
p omo e blood ci cula ion o d ugs. The inc eased bioa ailabili y o
he d ug, lowe ing ad e se impac s and high accumula ion a umo
si e a e o he bene i s o using micelles o d ug deli e y. The micelles
can p o ide pH- esponsi e elease o DOX a he umo si e and p o-
ide co-deli e y o DOX wi h o he an i umo agen s such as cispla in
o syne gis ic cance he apy. Fu he mo e, su ace modi ica ion o
micelles, o ins ance, wi h phenybo onic acid p omo es selec i i y
owa d umo cells and enhances he umo -supp esso ac i i y o
DOX.
238–242
The DOX-loaded micelles can be p epa ed using algina e and CS
in a wa e -in-oil emulsion me hod wi h a sphe ical pa icle size o
80 nm. This is an in e es ing me hod o loading DOX in nanoca ie s
and uses an aqueous phase dispe sed in a cyclohexane/dodecylamine
o ganic phase. These nanoca ie s showed high cellula up ake by
b eas cance cells and can supp ess p oli e a ion o 4 T1 cells.
243
The
CS-modi ied micelles can also p o ide co-deli e y o DOX and cu -
cumin in li e cance he apy. The CS-cys amine-poly(ε-cap olac one)
copolyme micelles ha e been p epa ed o cu cumin and DOX co-
deli e y and hen, modi ica ion wi h GA has been pe o med in
enhancing hei cellula up ake. They showed d ug loading e iciency
o 19.8% and 8.9% o DOX and cu cumin, espec i ely. They had a
sphe ical shape wi h a pa icle size o 110 nm. The GA modi ica ion
enhanced i s in e naliza ion in cells ia endocy osis and exposu e o
he umo mic oen i onmen induced changes in cha ge o
nanoca ie s om nega i e o posi i e. These CS-modi ied micelles
a e pH- and edox sensi i e and 10 mM o GSH induces he elease o
DOX (80.6%) and cu cumin (67.2%). This combina ion he apy exe s
a syne gis ic impac and is bene icial in supp essing he p og ession o
hepa oma cells.
244
O e all, CS de i a i es ha can sel -assemble in o
micelles, a e able o p o ide nanoca ie s ha a e biocompa ible, ha e
low immunogenici y, and p o ide nanopla o ms o d ug
deli e y.
245–247
An expe imen has p epa ed N-succinyl-N0-oc yl
chi osan (SOC)-based micelles o DOX deli e y and inc easing he
oce yl chain amoun , p omo es capaci y o hese micelles in DOX
loading. D ug loading and oce yl chain numbe de e mine he size o
micelles and hey ha e a pa icle size o 100–200 nm. They showed
high an i umo ac i i y agains a ious cance ypes including HepG2,
A549, BGC, and K562 cells.
248
Hence, simila o liposomes, micella
nanopa icles a e po en ial ec o s o DOX deli e y and cance sup-
p ession as well as p e en ing d ug esis ance de elopmen .
249,250
4.6 |Me al nanopa icle modi ica ion
Me al–o ganic amewo ks (MOFs) can be conside ed as ideal op ions
o d ug deli e y due o hei nanoscale size, high su ace a ea, and
po osi y as well as adjus able size.
251,252
To imp o e he p ope y o
MOFs in d ug elease, hei modi ica ion wi h polyme s has been pe -
o med; CS modi ica ion o MOFs ende s hem pH-sensi i e ea u e
and p o ides a condi ion o sus ained elease o DOX in cance che-
mo he apy. Fu he mo e, CS can be unc ionalized by olic acid
(FA) o selec i e a ge ing o umo cells o e exp essing ola e ecep-
o . Then, DOX can be loaded in CS-modi ied MOFs wi h a high d ug
loading capaci y (1.63 g). No ably, MOFs can encapsula e ca bon do s
o p o iding imaging. These CS-based me al NPs p o ide simul a-
neous chemo he apy and bioimaging ha a e bene icial in ce ical
cance ea men .
253
When exposed o mild acidic pH o he umo
mic oen i onmen , CS laye s loca ed on he su ace o MOFs would
collapse and swell, leading o he elease o DOX a he umo si e
and subsequen b eas cance supp ession.
254
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TABLE 3 A summa y o CS-based nanos uc u es o DOX deli e y in cance supp ession
Nanos uc u e
Pa icle size (nm); ze a po en ial (mV);
encapsula ion e iciency o d ug
loading (%) Cance ype
In i o/
in i o
Cell line/animal
model Rema ks Re e encs
Es ogen- unc ionalized CS
nanopa icles
198.2 and 206.4 nm; 28.3 and 30.6 mV;
up o 66.33%
B eas cance In i o MCF-7 cells High biocompa ibili y and an ineoplas ic
ac i i y
278
CS- aloxi ene nanopa icles 26.85 and 34.75 nm; 0.17 and 0.49 mV;
up o 98%
B eas cance In i o MCF-7 cells Dec easing p oli e a ion a e by 60%
Nanopa icles inhibi cance p og ession
ia supp essing es ogen ecep o
279
DOX-loaded LGCC NPs 200 nm; 20–35 mV; up o 86.4% B eas and li e
cance s
In i o;
in i o
QGY-7703 and 4 T1
cells
H22
hepa oca cinoma
model
Pene a ing di ec ly ia cell memb ane
and ci cum en ing endocy ic esicles
Ca go elease unde high GSH le els
Endosomal and lysosomal escape
High nuclea dis ibu ion
262
Ca echol-modi ied CS-hyalu onic acid
nanopa icles
160 nm; 19.8 mV O al cance In i o HN22 cells Nega i e cha ge and sphe ical shape
High mucoadhesi e abili y
P olonged elease o DOX
Reducing cance p oli e a ion
280
E hyl cellulose/CS/g-C
3
N
4
/MoS
2
co e–
shell nano ibe s
285–370 nm B eas and ce ical
cance s
In i o MCF-7 and HeLa
cells
Sus ained deli e y o DOX
Inducing cell dea h up o 89% and 85%
in MCF-7 and HeLa cells, espec i ely
in 7 days
281
Ap ame - unc ionalized CS-bases silica
nanos uc u es
87 nm; 35.9 o 32.3 mV B eas cance In i o;
in i o
MCF-7 and 4 T1
cells
C26 umo -bea ing
mice
Enhanced cellula up ake
Ta ge ed deli e y o DOX and an i-
miRNA-21 in cance supp ession
282
PEGyla ed CS nanopa icles 169–192 nm; up o 43 mV B eas cance In i o MCF-7 cells Func ionaliza ion o CS nanopa icles
wi h an i-hMAM and an i-HER2
p omo es selec i i y owa d cance
cells
Exe ing dose-dependen oxici y
agains cance cells
283
CMC/PCL nano ibe s 300 nm; highe han 30 mV; 90% B eas cance In i o MCF-7 cells Lack o ini ial bu s elease
Sus ained elease o 7 and 25 days
Cy o oxici y agains umo cells up o
85%
284
HMSN g a ed wi h CS-coppe sul ide
composi es
150 nm; 19.6 mV; 46.1% B eas cance In i o;
in i o
MDA-MB-231 cells
Mouse model o
b eas cance
High biocompa ibili y
Inc eased cellula up ake by cance cells
Apop osis induc ion
Inc easing su i al o mice
285
(Con inues)
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The in e es ing no e is he modi ica ion o Fe
3
O
4
nanopa icles
wi h CS ha p o ides a d ug deli e y sys em ha can media e bio-
imaging. The su ace modi ica ion o Fe
3
O
4
wi h CS is o impo ance
o loading DOX. The CS can o m a s able complex wi h DOX and
p oduces NH
2
-Zn(II)-DOX s uc u e. Exposing o ce ain pH des oys
he bond be ween DOX and CS and leads o he pH-sensi i e elease
o DOX and Fe
3
O
4
nanopa icles can p o ide magne ic esonance
imaging.
255
As has been men ioned in he In oduc ion sec ion, CS
can unde go changes by chemicals and enzymes. The e ha e been
e o s in he chemical modi ica ion o CS and imp o ing i s p ope -
ies. I has been epo ed ha CS modi ica ion wi h guanidine moie-
ies signi ican ly ele a es i s in acellula accumula ion; guadinyla ed
CS can o m chela es wi h coppe ia coppe -ni ogen coo dina ion.
The CS-coppe complexes enhance he p oduc ion o ROS in
impai ing lung cance p og ession and exe syne gis ic cance he apy
wi h DOX.
256
Based on hese expe imen s, modi ica ion o me al-
based nanos uc u es wi h CS imp o es hei biocompa ibili y and
loading o DOX. No ably, u he p og ess can be made by he modi i-
ca ion o CS-me al NPs. A ecen expe imen has syn hesized CS-Au
nanos uc u es and o enhancing hei selec i i y owa d lung (A549)
and b eas (4 T1) cance cells, hei modi ica ion wi h nucleolin
ap ame (AS1411) was conduc ed. These nanocomplexes a ge ed he
umo cells and e ec i ely pene a ed in o hem, leading o DOX
accumula ion and subsequen cance p og ession supp ession.
257
The e o e, CS is used as a educing and s abilizing agen o loading
DOX on Au NPs and u he modi ica ion o CS-Au NPs wi h polye h-
ylene glycol p omo e s hei blood ci cula ion ha is o impo ance o
ele a ing cy o oxici y o DOX agains lung cance cells.
258
Taking
e e y hing oge he , e icacy o me al-based NPs o DOX deli e y
and cance supp ession can signi ican ly enhance by CS
modi ica ion.
259–261
4.7 |Ca bon-based nanopa icle modi ica ion
A ecen expe imen has p o ided no el insigh s abou he su ace
modi ica ion o g aphene composi es by CS and i s impac on DOX
conjuga ion and elease. The concen a ion o pH o he solu ion
(le el o CS p o ona ion) a ec s he agg ega ion and dispe sion o CS
on he su ace o g aphene composi es. A low concen a ion le els o
CS and DOX, he ba e su ace o g aphene composi es enhances.
Inc easing he numbe s o NH
2
CS and DOX molecules p omo es
he adso p ion o DOX on ba e su ace a eas o g aphene and medi-
a es encapsula ion o DOX by CS clus e s on he su ace o esul s in
conjuga ion wi h CS chains. On he o he hand, when le els o NH
3
CS and DOX inc ease, he e will be highe posi i e cha ges and lowe
ba e su ace a ea o g aphene ha can p o ide condi ions o he
elease o DOX. The e o e, a mild acidic pH o he umo mic oen i-
onmen , p o ona ion o CS occu s and leads o he elease o DOX
om nanoca ie s.
262
G aphene oxide (GO) is a de i a i e o g aphi e
o g aphene and has a wo-dimensional pla e-like s uc u e. The GO
shee s ha e bo h sides and due o hei la ge su ace a ea, hey a e
conside ed as p omising s uc u es o he deli e y o an i umo
TABLE 3 (Con inued)
Nanos uc u e
Pa icle size (nm); ze a po en ial (mV);
encapsula ion e iciency o d ug
loading (%) Cance ype
In i o/
in i o
Cell line/animal
model Rema ks Re e encs
CS-, PEG- and PVA-modi ied MgFe
2
O
4
e i e magne ic nanopa icles
78–140 nm; below 21 mV B eas and
colo ec al
cance s
In i o Caco-2 and SKBR-3
cells
Dec easing cance cell iabili y in a
concen a ion-dependen manne
pH-sensi i e elease o DOX
85.86% elease o DOX a e 72 h
286
CS hyd ogel beads 13.5 mV B eas cance In i o MCF-7 cells High swelling a e (426%) and d ug
elease (81.33% in 144 h) a pH o 5.8
High biocompa ibili y
Dec easing p oli e a ion a e o MCF-7
cells
287
CMCS/MAGG hyd ogel - B eas cance In i o MCF-7 cells pH- esponsi e swelling o hyd ogels
67.06% elease o DOX a e 5 days in
pH o 5.5
32.13% elease o DOX a pH o 7.4
High biocompa ibili y
Cy o oxici y agains MCF-7 cells
287
Abb e ia ions: CMC, N-ca boxyme hyl chi osan; CS, chi osan; DOX, doxo ubicin; GSH, glu a hione; HMSN, hollow mesopo ous silica nanopa icle; NPs, nanopa icles; PCL, poly(ε-cap olac one); PVA, poly inyl
alcohol, PEG, polye hylene glycol.
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d ugs. Fu he mo e, a oma ic molecules and nucleobases can be
loaded on GO composi es ia π–πs acking and hyd ogen bonding in e -
ac ions.
263,264
Fo imp o ing he biodeg adabili y o CS and i s solubil-
i y, conjuga ion o CS wi h o he agen s such as ac ylic acid (AA) and
i aconic acid (IA) monome s has been pe o med o imp o e i s unc-
ionali y ia COOH g oup. Fu he mo e, modi ica ion by olic acid
(FA) selec i ely a ge s umo cells o e exp essing ola e ecep o . A
ecen expe imen has i s con e ed GO shee s o amine-
unc ionalized GO (AGO) o p o ide a unc ion o a ca ionic polyelec-
oly e. Nex , CS and FA conjuga ion ia N,N0-dicyclohexylca bodiimide
was pe o med. Then, CS was chemically modi ied by AA and IA mono-
me s by binding o COOH g oup ia e hyleneglycol dime hac yla e as
c oss-linke and po assium pe oxydisul a e as an ini ia o . Subse-
quen ly, DOX was embedded in o FA-chemically modi ied chi osan
(CMCS)/AGO nanocomposi es ia π–πs acking in e ac ions. The p e-
pa ed nanocomposi es demons a ed d ug loading capaci y as much as
95% and hey eleased DOX a a pH-sensi i e manne ( elease o DOX
a pH 5.3 compa ed o pH 7.4). These DOX-loaded nanopa icles we e
able o signi ican ly educe he iabili y o umo cells including HeLa
and MCF-7 cells.
265
Ano he expe imen has p epa ed injec able hyd ogels o he
con olled elease o DOX. This hyd ogel is based on c oss-linking o
g aphene, CS, and cellulose nanowhiske s whe e Schi base eac ion
by a syn he ic dialdehyde has been used. This hyd ogel is esponsi e
o pH and o he s imuli by adding benzaldehyde and amino acid cys e-
ine and can be adminis e ed subcu aneously o deli e bo h DOX and
cu cumin in syne gis ic cance he apy.
266
In addi ion, CNTs can be
modi ied wi h CS o p o ide pH-sensi i e elease o DOX in cance
he apy; CNTs can be nonco alen ly w apped wi h CS and hen
loaded wi h DOX. Due o he dep o ona ion o m o CS, DOX elease
does no occu a physiological pH, whe eas p o ona ion o CS a
pH 5–6.5 leads o DOX elease due o cha ge–cha ge epulsion
be ween CS and DOX, esul ing in con olled d ug elease
267
ha is
bene icial o cance he apy. Ano he expe imen p epa ed g aphene
FIGURE 8 Modi ica ion o a ious kinds o ca bon-based nanos uc u es wi h CS o DOX deli e y and cance supp ession. (a) Su ace
modi ica ion o single-walled ca bon nano ubes (SWCNs) wi h CS ollowed by loading doxo ubicin (DOX) and pacli axel (PTX); (i and ii) DOX and
PTX loading on he ba e SWCNs om on and side iews; a close iew o DOX (iii) and PTX (i ) o ien a ion on he side o SWCNs; CS
modi ica ion on he su ace o SWCNs ( and i); he inal d ug-loaded CS-coa ed SWCNs om on and side iews ( ii and iii). Sou ce:
Rep in ed om Re 277 wi h pe mission om RSC. (b) A schema ic on he syn hesis and applicabili y o e na y DOX-loaded g aphene oxide
nanopa icles (GON)-CS-dime hylmaleic anhyd ide (DMMA) o cance he apy. Sou ce: Rep in ed om Re 276 wi h pe mission om ACS
publica ion. (c) A schema ic on he syn hesis o olic acid (FA)-ancho ed O-ca boxyme hyl CS (OCMC)-Fe
3
O
4
modi ied wi h ca bon do s (CDs) o
DOX deli e y o he cance cells. Sou ce: Rep in ed om Re 253 wi h pe mission om ACS publica ion. NH
2
-H
2
BDC, 2-amino e ep halic acid;
IRMOF-3, me al o ganic amewo k
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and CNTs o co-deli e y o DOX and pacli axel (PTX). Fo imp o ing
loading e iciency and elease ea u es, u he unc ionaliza ion by CS
has been pe o med. Fu he mo e, CS p o ides pH-sensi i e manne
elease o DOX and PTX and slow elease o hese an i umo d ugs
p omo es umo -supp esso ac i i y.
268
Based on hese expe imen s,
ca bon-based NPs can p o ide deli e y o DOX in cance he apy and
CS modi ica ion imp o es hei bene icial ea u es.
99,269–275
Figu e 7
demons a es modi ica ion o ca bon-based nanoma e ials wi h CS
and hen, conjuga ion o olic acid as ligand on nanoca ie s o medi-
a e hei in e naliza ion in ce ical cance cells ia endocy osis,
esul ing in a signi ican inc ease in accumula ion o DOX in umo
cells.
253,276,277
Table 3p o ides a summa y o a ious nanopa icles
modi ied by CS o pu pose o DOX deli e y in cance supp ession.
Taking e e y hing oge he , hese s udies highligh he ac ha a i-
ous kinds o lipid-, ca bon- and me al-based nanos uc u es can be modi-
ied wi h CS in imp o ing hei cha ac e is ics. The nanopa icles
demons a e low pa icle size, sus ained d ug elease, and high encapsula-
ion e iciency. Fu he mo e, CS modi ica ion may signi ican ly enhance
biocompa ibili y and s abili y o nanoca ie s. Modi ica ion o CS-based
nano-scale deli e y sys ems wi h ligands such as HA and olic acid
inc eases hei selec i i y owa d umo cells o speci ic accumula ion o
DOX. The CS modi ica ion appea s o be i al o me al- and ca bon-
based nanoca ie s, as hey may show oxici y owa d no mal cells and
such modi ica ion imp o es hei biocompa ibili y(Figu e 8).
278–287
4.8 |Di ec ions o clinical applica ion
The cu en e iew a icle demons a ed ha a ional in eg a ion o
enginee ing and biology appea s o be p omising in ea men o can-
ce . The gold s anda d o imp o ing p ognosis and su i al o cance
pa ien s is chemo he apy. Howe e , chemo he apy ailu e is a com-
mon ou come in cance pa ien s due o d ug esis ance. The e o e,
he e is an u gen need owa d de elopmen o a ge ed deli e y sys-
ems o chemo he apeu ic agen s. Since DOX is equen ly used in
clinic o ea men o cance pa ien s, esis ance o i s an icance
ac i i ies is common. Al hough p oblem (d ug esis ance) is ob ious
and one o solu ions is applica ion o nanoca ie s, he e a e s ill a
numbe o challenges o use o DOX-loaded nanos uc u es in clinical
cou se. The i s p oblem is ela ed o biocompa ibili y o
nanopa icles o DOX deli e y in cance pa ien s. The second p ob-
lem is a o dabili y and inal di icul y is ela ed o la ge-scale p oduc-
ion o nanoca ie s. All o hese p oblems can be sol ed using
g eene modi ica ion o nanopa icles. Th oughou his e iew a icle,
i was shown ha su ace modi ica ion o a ious nanoca ie s by CS
p omo es hei biocompa ibili y, sa e y p o ile and inc eases hei s a-
bili y. Fu he mo e, CS is a na u al p oduc ha is a o dable and can
be used o syn hesis on la ge scale. A numbe o clinical s udies
(clinical ials.go ) ha e been conduc ed on CS applica ion in pa ien s;
howe e , he e is no expe imen pe aining o he use o CS-based
nanoca ie s o DOX deli e y in ea men o cance pa ien s ha
exploi s he a o e men ioned bene i s o CS. Hope ully, i will occu in
he nea u u e.
5|CONCLUSION AND REMARKS
The CS is among he mos abundan polysaccha ides ha ha e
ecei ed much a en ion in ecen yea s and a la ge numbe o expe i-
men s ha e been pe o med in e ealing he apeu ic po en ials o CS
and i s e icacy in NPs syn hesis and hei modi ica ion. Fu he mo e,
as CS is a na u e-de i ed agen , i is a o dable and can be u ilized in
bo h p eclinical and clinical s udies. Rega dless o he p o ec i e
impac s o CS in diabe es, an i-in lamma o y diseases and ca dio as-
cula diseases among o he s, CS appliance in cance has unde gone a
su ge due o i s cy o oxici y agains umo cells and abili y in nano-
s uc u e p epa a ion wi h high biocompa ibili y. On he o he hand,
cance ea men depends on o e coming d ug esis ance o imp o e
chemo he apy e icacy in umo cell supp ession. Among a ious che-
mo he apeu ic agen s, DOX is a well-known compound and ha is
why DOX i has been discussed in his e iew a icle. F equen appli-
ca ion o DOX leads o d ug esis ance and as DOX is an FDA-
app o ed agen and is u ilized in he clinic o he ea men o cance
pa ien s, e o s should be made in e e sing his esis ance. The p e-
sen e iew ocused on CS-NPs o DOX deli e y in cance ea men .
Di e en kinds o s imuli- esponsi e CS-based nanos uc u es ha e
been de eloped o DOX deli e y including pH-, edox-, he mo- and
mul i-sensi i e nanoca ie s. The pH o he umo mic oen i onmen
ends o be acidic and is lowe han physiological pH. The e o e, pH-
sensi i e CS-based NPs can deli e DOX a umo si e. Due o glycol-
ysis and high p oli e a ion a e o umo cells, edox-sensi i e NPs a e
also o impo ance and GSH le els can induce DOX elease om CS
nanos uc u es. The he mosensi i e CS-based hyd ogels ha e been
also de eloped ha can be ans o med o solid gel a body empe a-
u e and p o ide sus ained elease o DOX ha is o impo ance o
enhancing cy o oxici y agains cance cells and p e en ing he d ug
esis ance de elopmen .
Based on he documen ed expe imen s, CS has an i umo ac i i y
and i can exe a syne gis ic impac wi h DOX. Fu he mo e, CS-
based NPs p omo e DOX in e naliza ion in cance cells. The enhanced
cellula up ake is i al o p omo ing he sensi i i y o cance cells o
DOX chemo he apy. Fu he mo e, using o he agen s such as TPGS
wi h CS can p e en P-gp ac i i y in inhibi ing DOX e lux om umo
cells. Hence, CS-based NPs can p e en he de elopmen o DOX
esis ance. No ably, CS-based NPs can p o ide co-deli e y o DOX
wi h an i umo d ugs and nucleic acid he apeu ics. This s a egy can
induce apop osis in umo cells in p o iding DOX sensi i i y. Fu he -
mo e, he p oli e a ion a e and he in asion o umo cells unde go a
dec ease, and he pa hway is pa ed o DOX o induce i s umo -
supp esso ac i i y. Besides, a ious kinds o NPs including ca bon-,
lipid-, polyme - and me al-based nanos uc u es can be modi ied wi h
CS o imp o e hei s abili y and biocompa ibili y and p o ide condi-
ions o DOX complex o ma ion. A sea ch a clinical ials.go shows
ha CS is cu en ly applied in he clinical cou se o he ea men o
a ious cance such as p os a e and b eas cance s (NCT03202446;
NCT03712371). The e o e, u u e expe imen s can be di ec ed
owa d using DOX-loaded CS-based nanoa chi ec u es in he clinic.
The applica ion o some o he CS-modi ied nanopa icles in clinical
20 o 29 ASHRAFIZADEH ET AL.
23806761, 2023, 1, Downloaded om h ps://aiche.onlinelib a y.wiley.com/doi/10.1002/b m2.10325 by Uni e sidad Del Pais Vasco, Wiley Online Lib a y on [06/03/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
cou se s ill needs ex ensi e in es iga ion. Fo ins ance, CS-modi ied
me al nanos uc u es s ill equi e examina ion in e ms o biocompa i-
bili y, as me al nanopa icles a e oxic owa d no mal cells. The same
explana ion can be p o ided o ca bon-based nanoma e ials. How-
e e , lipid-based nanopa icles ha e demons a ed long- e m biocom-
pa ibili y, especially liposomes and hei modi ica ion wi h CS no only
inc eases hei biocompa ibili y bu also imp o es d ug elease p o ile
and hei s abili y, pa ing he way o clinical applica ion.
ACKNOWLEDGMENT
Go ka O i e wishes o hank he Spanish Minis y o
Economy, Indus y, and Compe i i eness (PID2019-106094RB-I00/
AEI/10.13039/501100011033) and echnical assis ance om he
ICTS NANBIOSIS (D ug Fo mula ion Uni , U10) a he Uni e si y o
he Basque Coun y. The au ho s also app ecia e he suppo om
he Basque Coun y Go e nmen (G upos Consolidados, No e :
IT907-16). Eb ahim Mos a a i would like o acknowledge he sup-
po om he Na ional Ins i u e o Biomedical Imaging and Bioengi-
nee ing (5T32EB009035). Alan P em Kuma was suppo ed by a
g an om he Singapo e Minis y o Educa ion (MOE-
T2EP30120-0016).
CONFLICT OF INTERESTS
The au ho s decla e no con lic o in e es .
PEER REVIEW
The pee e iew his o y o his a icle is a ailable a h ps://publons.
com/publon/10.1002/b m2.10325.
DATA AVAILABILITY STATEMENT
Da a sha ing is no applicable o his a icle as no new da a we e c e-
a ed o analyzed.
ORCID
Pooyan Mak andi h ps://o cid.o g/0000-0003-2456-0961
Esmaeel Sha i i h ps://o cid.o g/0000-0003-3400-3106
Ma cin Wojnilowicz h ps://o cid.o g/0000-0002-6480-6615
Ali Za abi h ps://o cid.o g/0000-0003-0391-1769
Eb ahim Mos a a i h ps://o cid.o g/0000-0003-3958-5002
Go ka O i e h ps://o cid.o g/0000-0002-0773-300X
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