This jou nal is © The Royal Socie y o Chemis y 2023 J. Ma e . Chem. B, 2023, 11, 10189–10205 | 10189
Ci e his: J. Ma e . Chem. B, 2023,
11, 10189
Di e gen app oach o nanoscale glycomicelles
and pho o- esponsi e sup amolecula glycogels.
Implica ions o d ug deli e y and pho oswi ching
lec in affini y†
Elena Rome o-Ben, ‡
a
M Ca men Cas illejos, ‡
a
C is ian Rosales-Ba ios,
a
Ma ı
´a Expo
´si o,
a
Pila Ruda,
a
Paula M. Cas illo,
a
S e ania Na decchia,
b
Juan de Vicen e
b
and Nou eddine Khia *
a
The ield o s imuli- esponsi e sup amolecula bioma e ials has apidly ad anced in ecen yea s, wi h
po en ial applica ions in di e se a eas such as cance he anos ics, issue enginee ing, and ca alysis.
Howe e , designing molecula ma e ials ha exhibi p ede e mined hie a chical sel -assembly o con ol
he size, mo phology, su ace chemis y, and esponsi eness o he inal nanos uc u es emains a
signi ican challenge. In his s udy, we p esen a di e gen syn he ic app oach o he ab ica ion o
sphe ical micelles and unc ional 1D-glyconano ube-based pho o esponsi e gels om s uc u ally
ela ed diazobenzene/diace ylene glycolipids. The esul ing nanos uc u es we e cha ac e ized using
NMR, TEM, and SEM, con i ming he o ma ion o sphe ical and ubula nanos uc u es in bo h he gel
and solu ion s a es. Upon UV i adia ion, a e e sible gel–sol ansi ion was obse ed, esul ing om he
pho oswi ching o he azobenzene uni om he s e ched ans o m o he compac , me as able cis
o m. Ou gels we e shown o enable spa io- empo al con ol o he adhesion and elease o he lec in
Concana alin A, demons a ing po en ial use as egene able bioma e ials o igh agains in ec ions wi h
oxins and pa hogens. Addi ionally, ou micelles and gels we e e alua ed as nanocon aine s o loading
and con olled elease o hyd ophobic dyes and an i umou al agen s, sugges ing hei possible use as
sma he anos ic d ug deli e y sys ems.
In oduc ion
The de elopmen o complex nanoscale sys ems able o ecei e
and execu e commands om ex e nal s imuli has ecei ed
inc eased a en ion in ecen yea s due o hei po en ial use in
d ug deli e y, issue enginee ing,biomine aliza ion,molecula
elec onics, and ca alysis.
1–7
O ele ance o he design o hese
sys ems as cance he anos ics, s uc u e–ac i i y ela ionship
s udies ha e shown ha opology and size a e key ac o s o
hei cellula up ake, ci cula ion ime and in e ac ion wi h speci ic
ecep o s.
8–12
Indeed, while sphe ical nanoma e ials a e well
sui ed o p ocesses in ol ing apid cellula up ake,
13
1D- od
s uc u esa emo eapp op ia e o hose equi ingalonge
ci cula ion ime.
14
On he o he hand, i has been shown ha
sphe ical micelles a e po en inhibi o s o globula ecep o s,
while 1D-nano ibe s as well as 3D-gels a e mo e sui able o
adhesion and inhibi ion o bac e ial mo ili y.
15–18
The e o e,
de eloping di e gen and cos -e ec i e syn he ic app oaches
allowing he syn hesis o sma unc ionalized o ganic ma e ials
and modula ing hei sizes, opology and unc ionali y om well-
designed molecula monome s is highly desi able, al hough i
emains an ou s anding challenge.
19
One amily o molecules
sui able o he c ea ion o sup amolecula di e si y a e he
amphiphiles, whose sel -o ganiza ion can lead o he o ma ion
o species wi h a wide ange o sizes and whose unc ionali y can
ange om o dina y soap o ex acellula ma ix mimics.,
20,21
A pa adigma ic example a e sup amolecula gels,
22,23
ob ained
om low molecula weigh o ganogela o s (LMOGS),
24–26
whose
hie a chical sel -o ganiza ion lead o lexible 1D-nano ibe s wi h a
high aspec a io ha ing sizes anging om submic on o hund eds
o mic ome e s which by en anglemen , o m he mac oscopic
sup amolecula gels o millime e size.
27,28
This hie a chy p o ides
an excellen oppo uni y o design in elligen sup amolecula
a
Asymme ic Syn hesis and Func ional Nanosys ems G oup, Ins i u o de
In es igaciones Quı
´micas (IIQ), CSIC-Uni e sidad de Se illa, A da. Ame
´ ico
Vespucio 49, 41092, Se ille, Spain. E-mail: [email p o ec ed]
b
Depa men o Applied Physics and Excellence Resea ch Uni ‘Modeling Na u e’
(MNa ), Facul y o Sciences, Uni e si y o G anada, C/Fuen enue a s/n, 18071 –
G anada, Spain
†Elec onic supplemen a y in o ma ion (ESI) a ailable. See DOI: h ps://doi.o g/
10.1039/d3 b01713c
‡These au ho s con ibu ed equally.
Recei ed 28 h July 2023,
Accep ed 7 h Oc obe 2023
DOI: 10.1039/d3 b01713c
sc.li/ma e ials-b
Jou nal o
Ma e ials Chemis y B
PAPER
Open Access A icle. Published on 09 Oc obe 2023. Downloaded on 6/11/2024 11:45:18 AM.
This a icle is licensed unde a
C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence.
View A icle Online
View Jou nal
| View Issue
10190 | J. Ma e . Chem. B, 2023, 11, 10189–10205 This jou nal is © The Royal Socie y o Chemis y 2023
sys ems wi h unc ional esponses by inco po a ing mo i s
esponsi e o ex e nal s imuli in o he molecula s uc u es o
amphiphiles.
29–31
Among he diffe en s imuli, using ligh offe s he ad an age
o being easily u ned on and off, employing adjus able wa e-
leng h and in ensi y, and offe ing high spa ial and empo al
con ol.
29,30,32–36
Mo eo e , an in e es ing class o amphiphiles
a e glycolipids whose hie a chical sup amolecula o ganiza ion
leads o complex sys ems endowed wi h impo an biological
ac i i ies due o he in ol emen o ca bohyd a es in i al
p ocesses such as pa hogen adhesion, ansplan ejec ion,
e iliza ion, and cell p oli e a ion/di e en ia ion.
29,37–40
Based
on hese p emises and wi hin ou in e es in he de elopmen
o unc ional so glyconanoma e ials,
41–44
we epo , he ein, a
new modula syn he ic app oach o sel -associa i e mul i unc-
ional neoglycolipids 1–3 o he di e gen nano ab ica ion o
unc ional sphe ical micelles, 1D-lipid glyconano ubes, and
pho o esponsi e 3D-gels, Fig. 1.
Resul s and discussion
Syn he ic design
In he design o he sel -associa i e monome s, diazobenzene,
linked di ec ly o he bio ecogni ion elemen mannose, was
used as a ligh - esponsi e g oup.
29,34
The design also includes a
a iable oligoe hylene glycol o ine- une he hyd ophobic–
hyd ophilic balance o he neoglycolipid. Fu he mo e, as hyd o-
phobic ail a 25 ca bon chain bea ing a pho o-polyme izable
diace ylenic unc ion, known o i s abili y o o m nanoma e ials
wi h in e es ing ch oma ic p ope ies was used.
44–49
The design
was alida ed by syn hesizing unc ional sphe ical micelles
(Fig.1a),and1D-lipidglyconano ubes(Fig.1b), ha en angle o
o m ligh esponsi e 3D-gels (Fig. 1c).
Syn hesis o he monome s
The syn hesis o he h ee compounds (1,2and 3), use e a-O-
ace yl-a-D-mannopy anosyl ichlo oace imida e 4, ob ained in
wo s eps om mannose pen aace a e, as s a ing ma e ial,
Scheme 1. Monoglycosyla ion o 4,40-dihyd oxyazobenzene 5
accep o ,
50
using dono 4and bo on i luo ide as an ac i a o
gi es he desi es compound 6wi h 86% yield. Fo he modula ion
o he hyd ophilic–hyd ophobic balance, as well as o un a elling
he e ec o he connec ing g oup be ween he pola head g oup
and he apola ail, bi unc ional space s 7–9, de i ed om e a-
e hyleneglycol (7,8) o eicosae yleneglycol (9), we e used,
Scheme 1. The condensa ion o alcohol 6wi h osyla ed space
7in he p esence o K
2
CO
3
, LiCl in ace oni ile gi es he
co esponding de i a i e 10 in 60% yield, Scheme 1a. Nex , he
dep o ec ion o he NHBoc de i a i e 10 using i luo oace ic
acid in me hylene chlo ide gi es he ee amine 11. Amida ion
wi h pen acosadiinoic acid (PCDA) in he p esence o TBTU and
DIPEA in DMF gi es he co esponding amide 12 wi h 60% yield
and, inally, Zemplen deace yla ion gi es he desi ed neoglycoli-
pid 1, Scheme 1a. Fo he syn hesis o he neoglycolipids 2and 3,
Scheme 1b, condensa ion o po assium alcohola e o 6wi h he
osyla ed azido space s de i ed om e ae hyleneglycol 8o
Fig. 1 Di e gen syn hesis o mannose-coa ed micelles (a) and pho o esponsi e mannose-coa ed gel (b) h ough sup amolecula sel -o ganiza ion o
suga -coa ed diazobenzene/diace ylene amphiphiles. Amhiphile 3wi h a la ge PEG
20
chain sel -o ganize in o sphe ical micelle able o hos and
solubilize he hyd ophobic dye Nile ed (a), while amphiphile 1wi h a sho e ae hyleneglycol chain sel -o ganize in o 1D-nano ubes (b) which e ol e o
idimensional gels, able o es ablish selec i e in e ac ions wi h mannose-speci ic lec in Texas ed
s
concana alin A (d), and o pe o m a e e sible gel–
sol ansi ion in esponse o ligh i adia ion (c and e).
Pape Jou nal o Ma e ials Chemis y B
Open Access A icle. Published on 09 Oc obe 2023. Downloaded on 6/11/2024 11:45:18 AM.
This a icle is licensed unde a
C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence.
View A icle Online
This jou nal is © The Royal Socie y o Chemis y 2023 J. Ma e . Chem. B, 2023, 11, 10189–10205 | 10191
eicosae hyleneglycol space 9, in ace oni ile gi es he e he
de i a i es 13 and 14 in 67% and 70% yields espec i ely.
Cu(I)-ca alyzed azide alkyne 1,3-dipola cycloaddi ions (CuAAC)
be ween azides 13 o 14 and he N-(2-p opynyl)pen acosa-10,12-
diynamide alkyne 15, i sel ob ained in one s ep om PCDA
and p opa gylamine, in he p esence o sodium asco ba e and
in a me hylene chlo ide/wa e mix u e, a o ded egioselec i ely
he 1,2,3- iazole de i a i es 16 and 17 wi h 60 and 80% yield
espec i ely. Finally, Zemplen deace yla ion gi es he desi ed
compounds 2and 3wi h 97 and 99% chemical yield. The
s uc u es o he 3 monome s we e con i med by monodimen-
sional and bidimensional NMR as well as by mass spec oscopy
(see expe imen al pa and ESI†).
Pho oisome iza ion s udy o he monome s
Azobenzene compounds a e well-known o hei e e sible pho o-
isome iza ion be ween he ans and cis o ms unde al e na ing
UV and isible ligh i adia ion.
51
The ligh - esponsi e beha io o
h ee neoglycolipids 1–3,Fig.1,wass udiedby
1
HNMR(Fig.2b
and c), UV-Vis (Fig. 2d and e), and HPLC-MS spec oscopies ( ide
in a). The mos signi ican p o ons o s udying he isome iza ion
kine ics o neoglycolipids 1–3 by
1
H NMR a e he diazobenzene
p o ons, hep o on5o he iazoleand heanome icp o ono
suga . In he s able ans (E) isome s he signals o p o ons 3, 5
and 30,5
0o hediazobenzenemoie yappea as wodouble sa
6.90 ppm and 7.10 ppm espec i ely, while p o ons 2.6 and 20.60
appea oge he a a lowe ield (abou 7.75 ppm). The iazole
p o on is obse ed as a single a 7.90 ppm, and he anome ic
p o on appea s ei he as a b oad single (in he case o 1- ans and
2- ans) o as a double wi h a small coupling cons an (1.34 Hz) in
he case o 3- ans, a app oxima ely 5.60 ppm. In he cis (Z)
isome s [1-cis,2-cis (see ESI†), and 3-cis], he signals o he 3, 5 and
30,5
0p o ons unde go a sligh shi a 7.00 and 6.90 ppm, while
he 2, 6 and 20,6
0p o ons alpha o he diazo unc ion unde go a
p onounced shielding e ec , om 8.00 ppm o 6.80 ppm.
Al hough he anome ic p o on unde goes a sligh chemical shi
change ( om 5.60 ppm o 5.50 ppm), i s loca ion in a posi ion
whe e he e a e no o he signals allows i o be used as an
addi ional con ol o moni o and quan i y he ans–cis isome s.
To gain u he s uc u al insigh s, we conduc ed selec i e
1D-NOESY and 1H/1H EASY ROESY 2D expe imen s (see ESI†).
In he case o he 2- ans de i a i e, ou NOESY 1D expe imen s
acili a ed mo e p ecise signal assignmen s o bo h a oma ic
ings (see Fig. S53–S56 in he ESI†). Addi ionally, 2D 1H/1H EASY-
ROESY expe imen s, ca ied ou on a p edominan ly 2-cis con igu-
a ion, e ealed con ac NOEs be ween he H3 and H5 p o ons o
he a oma ic ing linked o he suga and a me hylene p o ons o
hePEGchain(seeFig.S60in heESI†).
Ou s udy allowed us o quan i y he pho os a iona y (Z:E)
s a e o he h ee neoglycolipids in DMSO. Neoglycolipid 1
exhibi ed a pho os a iona y s a e o 75% cis (Z) and 25% ans
(E) isome s (Fig. 2b), while neoglycolipid 2displayed a pho o-
s a iona y s a e o 82% cis (Z) and 18% ans (E) isome s (see
ESI†). Rema kably, and con a y o mos epo ed diazobenzene
glycolipids, neoglycolipid 3showed a unique beha io as i s
pho oswi ching was independen o he sol en and comple e
e en in me hanol, wi h a pho os a iona y s a e o 100% cis (Z)
isome (Fig. 2c). The comple e isome ic con e sion o neogly-
colipid 3is o g ea in e es in s udying he in luence o
ca bohyd a e o ien a ion on lec in–ca bohyd a e in e ac ions.
The slow he mal e u n om pu e 3-cis o pu e 3- ans isome ,
occu ing o e a pe iod o 96 hou s in he da k, u he adds o
he signi icance o neoglycolipid 3. Mo eo e , unde blue ligh
i adia ion (460 nm), he e u n om he 3-cis o 3- ans isome
in neoglycolipid 3was signi ican ly accele a ed, aking only
2 hou s (Fig. 2c).
UV/Vis spec oscopic s udies we e conduc ed using DMSO as
he sol en and unde gela ion condi ions (see de ails below).
Glycolipids exhibi a b oad abso p ion peak a ound 320–350 nm,
p ima ily a ibu ed o he ans o m o he azobenzene g oup
(Fig. 2d and e). Upon i adia ion, he pho o-induced ans–cis
isome iza ion was obse ed o be e e sible, as he cis o m o
he azo-su ac an s elaxed back o he ans o m a e exposu e
o isible ligh o slowly in he absence o ligh (Fig. 2e).
Fu he mo e, a se ies o successi e ‘‘on–o ’’ swi ching expe i-
men s on he abso p ion bands o glycolipid 1was ca ied ou .
The esul s o hese expe imen s demons a ed ha he p ocess
was e e sible o a leas nine cycles, indica ing ha sample 1
exhibi s good s abili y (Fig. 2 ).
Sup amolecula sel -assembly o amphiphile 1 and
cha ac e iza ion o he pho o esponsi e-glycogel
In o de o de e mine he sup amolecula sel -associa ion capa-
ci ies o he monome s, we de e mined i s hei wa e and
o ganic sol en s solubili ies. Al hough monome s 1and 2a e
insolubleinmos sol en s, hemo ehyd ophilicmonome 3is
Scheme 1 Syn hesis o sel -associa i es neoglycolipid 1(a), 2and 3(b). (i)
BF
3
E
2
O, CH
3
CN, 0 1C; (ii) K
2
CO
3
, LiCl, CH
3
CN; (iii) TFA, CH
2
Cl
2
; (i ) TBTU,
DIPEA, DMF; ( ) MeONa, MeOH; ( i) CuSO
4
, AsCNa, CH
2
Cl
2
/H
2
O.
Jou nal o Ma e ials Chemis y B Pape
Open Access A icle. Published on 09 Oc obe 2023. Downloaded on 6/11/2024 11:45:18 AM.
This a icle is licensed unde a
C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence.
View A icle Online
10192 | J. Ma e . Chem. B, 2023, 11, 10189–10205 This jou nal is © The Royal Socie y o Chemis y 2023
soluble in a ious sol en s including wa e ( ide in a). The use o
mix u e o sol en s e eals wa e –e hanol as he bes mix u e.
Indeed, in 1 : 1 o 1 : 2 wa e –e hanol mix u e, monome 1showed
a g ea abili y o o m gels. In he same condi ions monome 2
was insoluble while monome 3ga e a clea yellowish solu ion.
In e es ingly, while in he 1 : 2 wa e e hanol mix u e, he
gela ion o 1 akes place a a concen a ion o 1% (w/ ), in 50%
aqueous e hanol solu ion i akes place a a concen a ion as low
as 0.1%. Addi ionally, in he la e case he compound geli ica e
ins an aneously, Fig. 3, a oom empe a u e wi h no need o
hea ing–cooling o sonica ion. The s uc u e o he as- o med gel
as well as he xe ogel o med om monome 1a 1% was
cha ac e ized by ansmission elec on mic oscopy (TEM) and
ield emission scanning elec on mic oscopy (FESEM) (Fig. 3).
In e locked agglome a ed ubules wi h a uni o m diame e o
31 nm, a hickness o 9 nm, and mic on-scale leng hs we e
egula ly ound in he glycogel-1 unde TEM analysis (Fig. 3a).
The obse a ion o xe ogel-1 unde SEM a he ens o mic ome e
scale showed in e es ing in e wined and wis ed s uc u es in a
bush- o m (see Fig. S32, ESI†). Mo eo e , FESEM analysis allowed
obse ing he de ailed ib illa agg ega es o ming he bundles
shown in he s anda d SEM images (Fig. 3b).
Small-angle X- ay sca e ing (SAXS) s udies allowed us o
ad ance in he exac s uc u al de e mina ion o he ib illa
glycogel-1 (Fig. 3c). Maximum peaks co esponding o a e aged
epea ing dis ances o abou 9.5 nm we e ob ained (Fig. 3c).
I should be no ed ha he s a ing monome is app oxima ely
5 nm in leng h when ex ended, as de e mined by Chem3D analysis
(Fig. 3 ). This sugges s ha a single bilaye would ex end o a
maximum o 10 nm, indica ing ha he ube walls a e likely o med
by a single amphiphilic bilaye wi h some in e pene a ion o he
lipid ail (as shown in Fig. 3d– ). A second peak in he SAXS
spec um a 2y=0.51, co esponding o a sepa a ion o 16.6 nm,
can be assigned o he inne diame e o he lipid nano ube, which
is likely in luenced by he packing o he amphiphilic bilaye .
Unde such sup amolecula sel -o ganiza ion, he ube in he gel
would expose he mannose esidue usually used o he adhesion o
pa hogens o he ex e nal phase, whose speci ic ecep o is in ol ed
in se e al biological p ocesses o in e es .
51,52
On he o he hand,
he in e nal ca i y o he ube, la ge han 10 nm, could accom-
moda e molecules o in e es such as cy o oxic compounds, dyes o
couldalsose easacon inedmedium o o ganic eac ions.
53
The mechanical p ope ies o gel-1 we e cha ac e ized
h ough heological s ain sweep and equency sweep
Fig. 2 Schema ic ep esen a ion o he pho oisome iza ion o neoglycolipids 1–3 (a).
1
HNMR s udies o ans–cis and cis– ans pho o and he mal isome iza ion
o he neoglycolipid 1in DMSOd
6
(b), and 3in MeOD (c). UV-Vis s udies o ans–cis (d) pho oisome iza ion and cis– ans eco e y unde blue ligh i adia ion (e)
o neoglycolipid 1(0,005 w / % in DMSO). Cycle o abso p ion a e al e na e i adia ion wi h UV (360 nm, g een ba ) and isible ligh (460 nm, yellow ba ) ( ).
Pape Jou nal o Ma e ials Chemis y B
Open Access A icle. Published on 09 Oc obe 2023. Downloaded on 6/11/2024 11:45:18 AM.
This a icle is licensed unde a
C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence.
View A icle Online
This jou nal is © The Royal Socie y o Chemis y 2023 J. Ma e . Chem. B, 2023, 11, 10189–10205 | 10193
expe imen s, e ealing i s high low-shea iscosi y and shea -
hinning beha io . The gel exhibi ed a hys e esis loop in he
low cu e, indica ing hixo opic beha io . Dynamic oscilla o y
shea es s showed ha he gel beha ed as a solid-like ma e ial
wi h a linea iscoelas ic ange, ollowed by non-linea beha io
and yielding a highe s ain ampli udes. The ull s udy wi h
de ailed esul s can be ound in he ESI.†
Diace ylenic amphiphiles (DA) possess pho o esponsi e
p ope ies as hey can unde go polyme iza ion h ough a 1,4-
addi ion eac ion o di adicals gene a ed by UV o gi adia ion.
This p ocess leads o he o ma ion o sma polydiace ylene
(PDA)-nanoma e ials, exhibi ing in iguing ch oma ic p ope ies.
P io o in es iga ing he unc ionali y o gel 1, we examined he
abili y o he sel -associa ed DA monome 1 o pho opolyme ize in
he gel s a e using Raman spec oscopy. The esul s o hese s udies
e ealed ha pho opolyme iza ionoccu sonlyin hed ys a eand
no in he gel s a e ( o de ailed in o ma ion, see he ESI†).
S udies on he UV-induced e e sible gel–sol ansi ion
To in es iga e he ligh - esponsi e beha io o glycogel 1, we,
i s , conduc ed UV/Vis spec oscopic s udies using dilu ion
solu ions in e hanol/wa e (Fig. 4). The esul s e ealed wo
dis inc abso p ion peaks a 365 nm and 445 nm, which
co espond o he p–p* and an n–p* ansi ions, espec i ely.
Fig. 3 Cha ac e iza ion o he glycogel o med by sup amolecula sel -o ganiza ion o neoglycolipid 1. La ge scale high (a) and enla ged (1) TEM images. (1).
La ge-scale heigh (b) and enla ge mic og aph o xe ogel. Small angle X- ay sca e ing (c). Model o he molecula bilaye nano ube de i ed om SAXS s udy (d).
Schema ic illus a ion o he molecula packing in he sel -assembled s a e (e). Chem 3D schema ic illus a ion o he size o sel -assembled amphiphile 1.
Jou nal o Ma e ials Chemis y B Pape
Open Access A icle. Published on 09 Oc obe 2023. Downloaded on 6/11/2024 11:45:18 AM.
This a icle is licensed unde a
C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence.
View A icle Online

10194 | J. Ma e . Chem. B, 2023, 11, 10189–10205 This jou nal is © The Royal Socie y o Chemis y 2023
Upon exposu e o UV ligh , a no iceable dec ease in he p–p*
ansi ion band was obse ed, accompanied by a sligh inc ease
in he n–p* ansi ion, indica ing he occu ence o ans–cis
pho oisome iza ion o monome 1upon UV i adia ion
(Fig. 4a). A e 20 minu es o exposu e, he abso p ion bands
s abilized, indica ing ha he pho os a iona y s a e had been
eached. Fu he mo e, we conduc ed High-Pe o mance Liquid
Ch oma og aphy (HPLC) o sepa a e he wo isome s, and he
esul s showed ha 1-cis elu ed a 11.3 minu es, while 1- ans
elu ed a 11.7 minu es (Fig. 4c and d). This sepa a ion allowed
us o quan i y he p opo ions o bo h isome s a di e en ime
poin s. The analysis e ealed ha neoglycolipid 1exhibi ed a
Fig. 4 Re e sible gel–sol ansi ion and hodamine elease s udies. UV-Vis s udies o ans–cis (a) pho oisome iza ion and cis– ans eco e y unde blue
ligh i adia ion (b) o 1(0,005% in E OH/H
2
O). HPLC ch oma og ams a e exposu e o 1 o UV ligh (c) and o whi e ligh om 0 o 20 minu es (d).
Pho og aphs o ials showing he gel–sol ansi ion and colo change unde UV i adia ion (e). La ge-scale heigh ( ) and enla ge phase (1) TEM imageso
sphe ical nano ubes in he solu ion. Rhodamine elease in he da k (g) and unde UV i adia ion (h).
Pape Jou nal o Ma e ials Chemis y B
Open Access A icle. Published on 09 Oc obe 2023. Downloaded on 6/11/2024 11:45:18 AM.
This a icle is licensed unde a
C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence.
View A icle Online
This jou nal is © The Royal Socie y o Chemis y 2023 J. Ma e . Chem. B, 2023, 11, 10189–10205 | 10195
pho os a iona y s a e wi h 88% in he cis (Z) isome and 12% in
he ans (E) isome (Fig. 4c). An impo an obse a ion o
p ac ical applica ions is ha his pho o-induced isome iza ion is
e e sible. When he glycolipid is in he cis o m, i elaxes back
o he ans o m a e exposu e o isible ligh (Fig. 4d) o
g adually in he da k (see ESI† o mo e de ails). Pho oexci a ion
o glycogel 1 wi h UV ligh a 365 nm causes a gel–sol ansi ion
accompanied by a colo change om yellow o o ange, (Fig. 4e).
Rema kably, he gel–sol ansi ion akes place as e (a e a ew
minu es, see ideo in ESI†), in he case o gel o med in a 33%
compa ed o ha o med in 50% aqueous e hanol mix u e (10–
12 h). The esul ing solu ion was analysed by ansmission
elec on mic oscopy, which e ealed hep esencedispe sedlipid
nano ubes (Fig. 4 ). In e es ingly, he diame e o he ubes (abou
39 nm) was ound o be sligh ly la ge han ha o he ube in he
gel s a e. I is belie ed ha he inc ease in diame e is mainly due
o he widening o he inne ca i y o he ube, as he walls
emained he same size. The p ecise cause o his change is
challenging o elucida e, bu i is likely a ibu ed o al e a ions in
he cu a u e o he lipid laye esul ing om he isome iza ion o
he glycogel-1 molecules. The analysis o cis-glycogel-1 h ough
SAXS s udies (see ESI†) indica es ha he size o he ube walls,
o med by a single amphiphilic bilaye , emained unchanged.
Howe e , he inne diame e o he lipid nano ubes exhibi ed an
inc easeandshowednon-uni o mi y. Speci ically, we obse ed
h ee dis inc peaks co esponding o a e aged epea ing dis-
ances o app oxima ely 9.17 nm, 17.86 nm, and 20.18 nm. These
indings sugges ha he diame e inc emen p ima ily a ises
om he widening o he inne ca i y o he ube, a he han he
widening o he ube walls. The gel is also capable o main ain
se e al cycles o o ma ion and disin eg a ion p omo ed by ligh
s imuli wi h no no iceable deg ada ion (da a no shown).
S udy o hodamine s o age and con olled elease om
glycogel-1
Nex , in o de o in es iga e he capabili y o glycogel-1 o small
molecules s o age, as well as passi e and ligh -con olled elease
we measu ed he diffusion o hodamine B (a common biological
dye) om gel-1 o med a 0.5% in he da k and upon UV ligh
i adia ion (Fig. 4g and h). Fo his, eshly p epa ed Rho/gel-1 was
co e ed wi h he same hyd oalcoholic solu ion used o i s p e-
pa a ion and, a diffe en ime in e als, he en i e supe na an
was emo ed, eplaced, and he abso p ions a 550 nm eco ded.
As deduced om sigmoid cu e o Fig. 5d and he each o a
pla eau, a o al hodamine elease om Rho/gel-1 was a ained a
50h(Fig.4g)in heda k.Incon as ,i adia iona 365nmled o
he elease o 100% o he d ug wi hin 15 h, Fig. 4h, indica ing
ha he diffusion o hodamine om he gel-1 in he da kness is
a leas 3- old slowe han i s elease unde UV ligh i adia ion.
Spa io empo al con ol o adhesion and elease o he lec in
concana alin A
Once demons a ed he abili y o he gel o en ap and elease
molecules o in e es in a con olled manne , we ocused on
he addi ional unc ionali y con e ed by spa ial o ien a ion o
he mannose esidue. I is pe inen o ecall a his poin ha
spec oscopic and mic oscopic s udies ( ide sup a), suppo he
p oposi ion o a model acco ding o which glycogel-1 de i es
om he in e connec ion o nano ubes whose walls a e o med
by a single bilaye o he amphiphile. I his model is co ec ,
he ex e nal ace o he nano ubes will expose mannose
esidues, p o iding an excellen oppo uni y o s udy he
p esen a ion and o ien a ion o ca bohyd a e moie ies in
hei mul i alen in e ac ions wi h speci ic ecep o s o
he i s ime in he gel s a e. The in e ac ion o he plan lec in
concana alin A (ConA), ob ained om jack bean (Conca alia
ensi o mis), wi h mul i alen mannosyla ed ma e ials is well
s udied and p o ides an excellen ool o alida e ou
model.
54–56
ConA is known o selec i ely ecognizes a-manno-
py anoside, a-glucopy anoside and o a lesse ex en a-N-
ace ylglucosamine.
57–59
As a lec in con ol we used he Peanu
agglu inin lec in (PNA) om A achis hypogaea, known o
selec i ely ecognize b-galac ose bu no a-mannose epi opes.
The s udies we e conduc ed by luo escence spec oscopy using
Texas Red
s
-labelled ConA and FITC-labelled PNA. Conside ing
ha PDA de i a i es can exhibi au o luo escence, we con-
duc ed a lec in- ee con ol assay (Fig. 5a and b), which showed
Fig. 5 Fluo escence s udy o he selec i e in e ac ion o mannose-
coa ed glycogel-1 wi h lec ins. The images o he de ec ion o he g een
luo escence we e acqui ed upon exci a ion a 480/40 nm wi h a band
pass il e a 527/30 nm. The images o he de ec ion ed luo escence
we e acqui ed a e exci a ion a 560/40 nm wi h a band il e 645/75.
Images o he glycogel-1 in he ans o m alone (a) and (b), a e
incuba ion wi h PNA-FITC (c), a e in e ac ion wi h ConA-Texas Red (d),
a e incuba ion wi h e e sely labelled lec ins ConA-FITC (e), and wi h
PNA-Alexa Fluo 594 ( ).
Jou nal o Ma e ials Chemis y B Pape
Open Access A icle. Published on 09 Oc obe 2023. Downloaded on 6/11/2024 11:45:18 AM.
This a icle is licensed unde a
C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence.
View A icle Online
10196 | J. Ma e . Chem. B, 2023, 11, 10189–10205 This jou nal is © The Royal Socie y o Chemis y 2023
ha glycogel-1 lacks bo h g een (Fig. 5a) and ed luo escence
(Fig. 5b).
Howe e , an image showing a gel ha ing a ed luo escence
was obse ed upon ea men o glycogel-1 wi h ConA-Texas
Red
s
(Fig. 5d), indica ing an effec i e in e ac ion be ween
lec in and mannose on he su ace o he ibe s. Con e sely,
no luo escence was obse ed when glycogel-1 was ea ed wi h
PNA-FITC (Fig. 5c), indica ing ha glycogel-1 is able o es ablish
selec i e in e ac ions and is esis an o non-speci ic in e ac ions.
As an addi ional con ol, he same assay was pe o med using
e e se labelled lec ins (ConA-FITC and PNA-AlexaFluo ). In his
case (Fig. 5e and ), and as expec ed, glycogel-1 exhibi ed luo es-
cence only in g een. I is also ema kable ha his speci ic
ecogni ion akes place in a e y sho ime (30 s), compa able
o he bes sys ems epo ed in he li e a u e.
60
This efficiency
can be explained by he so-called glycoside clus e effec ,
61–63
consequence o mannose mul i alen exposi ion on he 1D-glyco-
nano ubes in glycogel-1. In his sense we ecen ly epo ed ha
mannose-coa ed single-walled ca bon nano ubes a e among he
mos e icien binde o ConA.
31
Taking ad an age o he possibili y o isualizing suga -
lec in in e ac ions by luo escence mic oscopy, we conduc ed
a s udy on he effec o he spa io empo al a angemen o
mannose on hese in e ac ions (Fig. 6) in he gel s a e.
Fo his, we ca ied ou wo diffe en es s. The ini ial one
consis ed o isome izing he gel om he s able ans o m o
he cis o m, ollowed by incuba ion wi h lec in. A e ca ying
ou successi e washes, we analysed he luo escence o he
agg ega es ob ained (me hod 1, Fig. 6). No luo escence was
de ec ed in his case (Fig. 6a), highligh ing he absence o
ConA-mannose in e ac ion. This esul indica es o he i s ime,
ha a e isome iza ion, he mannose wi hin gel-1 in he cis o m
is no longe accessible and he e o e canno es ablish effec i e
in e ac ions wi h ConA. This obse a ion is in line wi h p e ious
esea ch conduc ed by he Jaya aman g oup,
64
he Ha mann
g oup,
65
and he Lindho s g oup.
66,67
These s udies ha e high-
ligh ed he c i ical ole o ca bohyd a e ligand o ien a ion in lec in
ecogni ion, mainly in solu ion. The Jaya aman g oup pionee ed
he de elopmen o pho oswi chable mul i alen ca bohyd a e
ligands, showcasing pho oinduced a ia ions in binding
affini ies.
64
Simila ly, he Ha mann g oup epo ed changes in
inhibi o y concen a ions upon pho oswi ching, unde sco ing he
impo ance o ligand s uc u e and o ien a ion.
65
Addi ionally, he
Lindho s g oup demons a ed ligh -dependen diffe ences in
bac e ial adhesion on immobilized glycosyla ed azo-benzene de i-
a i es, bo h on mic o i e pla es
66
and human cell memb anes.
67
In e es ingly, in he second es , once he glycogel-1-ConA
Texas Red agg ega e was ob ained (Fig. 6b), UV i adia ion
(360 nm, 30 min), ollowed by successi e washes, led o he
loss o he ini ial ed luo escence (me hod 2, Fig. 6c). This es
indica es ha glycogel-1 is able o elease he adhe en lec in by
changing om he ans o m o he cis o m. The abili y o
glycogel-1 o cap u e and elease soluble lec ins highligh s i s
po en ial o he de elopmen o egene able bioma e ials o
igh agains oxins and pa hogen in ec ions.
Sup amolecula sel -assembly o he mo e hyd ophilic
monome 3
Finally, we ocused on he sup amolecula sel -o ganiza ion o
monome 3, which unlike he o he wo neoglycolipids is wa e
soluble. We we e especially in e es ed in knowing i his
monome is capable o o ming micelles o liposomes due o
hei impo ance as sma d ug deli e y sys ems. The amphiphilic
neoglycolipid 3showed a c i ical micella concen a ion (CMC) in
wa e o 22 mM as de e mined by DLS echnique using a Ze asize
Nano ZS sys em. Fo ma ion o he nanomicella sys em ManMic-3
wasca iedou byasimpledispe sion o he neoglycolipid 3in
wa e a a concen a ion abo e he CMC. The pho o-polyme i-
za ion o he diace ylene unc ion upon ul a iole i adia ion
(254 nm) affo ded a pa ially conjuga ed polydiace ylene back-
bone o al e na ing enyne g oups (Fig.7a).Thecha ac e is ic size
and mo phology o he o med nanosys ems we e de e mined by
DLS and TEM. The TEM mic og aph shows he o ma ion o
se e al en i ies, being he sphe ical micelles ManMic-3 wi h sizes
o 15 nm he mos abundan (Fig. 7b). TEM analysis also shows
he p esence o liposome wi h app oxima ely 150 nm in size
(Fig. 7c). DLS analysis con i ms he p esence o esicle ha ing
an a e age diame e o 184 nm, uni o m in shape and mono-
dispe se as indica ed by he PDI o 0.05(Fig.7d).Howe e , he
micelles de ec ed by TEM, could no be de ec ed by DLS, since he
signal is domina ed by he powe ul sca e ing o he liposome
hus hiding he micelles p esen . Indeed, being micelles mo e
han one o de o magni ude smalle , sca e mo e han h ee
o de s o magni ude less o simila olume phase. As o he gel,
we s udied he pho opolyme iza ion o he s a ing DA monome s
in he micelle by Raman spec oscopy (Fig. 7g).
In his case he Raman spec um shows he p esence o he
peak a 2268 cm
1
co esponding o he iple bond in he
monome oge he wi h he peaks a 2084 cm
1
and 1454 cm
1
co esponding o he conjuga ed ene-yne sys em, indica ing an
incomple e pho opolyme iza ion o he DA monome s in he
micelles (Fig. 7g). The ob ained micelles ManMic-3 p esen a
shel e ed hyd ophobic inne ca i y o med by he hyd oca bon
ails, a hyd ophilic PEG chain su ounded by a diazobenzene and
mannose moie ies. In e es ingly, bo h he in e nal hyd ophobic
a ea and he diazobenzene co ona o hese micelles can, hos
hyd ophobic gues molecules such as cy o oxic o image enhan-
cing agen s.
30
As a p elimina y es o show he encapsula ion
Fig. 6 Fluo escence s udy o he effec o he spa io empo al a ange-
men o mannose on gel-1-lec in in e ac ions. Me hod 1: Image o he cis
gel-1 a e incuba ion wi h ConA-Texas Red (a). Me hod 2: Image o he
ans gel-1 a e incuba ion wi h ConA-Texas Red (b), image o he ans
gel-1-ConA Texas Red a e pho oisome iza ion (c)
Pape Jou nal o Ma e ials Chemis y B
Open Access A icle. Published on 09 Oc obe 2023. Downloaded on 6/11/2024 11:45:18 AM.
This a icle is licensed unde a
C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence.
View A icle Online
This jou nal is © The Royal Socie y o Chemis y 2023 J. Ma e . Chem. B, 2023, 11, 10189–10205 | 10197
pe o mance o ManMic-3 micelles, Nile Red was chosen as
a model o hyd ophobic d ug and dye. Nile Red is insoluble
in wa e (solubili y o1mgmL
1
), Fig. 7e(i), he luo escence o
which inc eases subs an ially in hyd ophobic en i onmen s.
The micelles o mula ed wi h Nile Red we e p epa ed simply
mixing he p e iously o med ManMic3 micelles wi h Nile Red
(Fig. 7e). A e s i ing and hea ing a 50 1C o 24 hou s,
il a ion o elimina ion o he non-encapsula ed dye, a pink
solu ion wi hou isible p ecipi a ion was ob ained (Fig. 7e(iii)).
In compa ison, applying he same p ocedu e in wa e wi hou
micelles esul ed in a clea colo less solu ion (Fig. 7e(i )), which
also did no show he cha ac e is ic band abso bance o Nile
Red (Fig. 7 ).
Subsequen ly, we in es iga ed he po en ial o MicMan3
as a nanoca ie o hyd ophobic d ugs, wi h he aim o
imp o ing hei wa e solubili y and p o ec ing hem wi hin
he hyd ophobic co e. Doce axel (DTX), a d ug widely used in
clinical p ac ice bu wi h e y low aqueous solubili y (solubili y
0.3 mgmL
1
a 37 1C), p esen ed a signi ican challenge. In
esponse o his challenge, we endea o ed o c ea e inclusion
complexes using a sol en - ee me hod in ol ing s i ing
and hea ing. This app oach elimina ed he need o o ganic
sol en s. The quan i y o inco po a ed DTX was de e mined
by measu ing he diffe ence in mass be ween he loaded and
emp y micelles, complemen ed by HPLC analysis. The d ug
loading con en (DLC) and encapsula ion efficiency (DLE) we e
calcula ed using eqn (1) and (2) as ollows:
DLC %ðÞ¼ Weigh o loaded DTX
W o MicMan3 þW o loaded DTX 100%
(1)
DLE %ðÞ¼
Weigh o loaded DTX
Weigh o inpu DTX 100%(2)
The d ug loading con en and encapsula ion efficiency o
MicMan3 o DTX we e 2.8% and 11.2%. These p elimina y
indings unde sco e he capabili y o MicMan3 o enhance he
wa e solubili y o highly insoluble o ganic molecules, which is o
u mos signi icance o hei po en ial u ili y as effec i e d ug
deli e y sys ems.
Conclusions
In conclusion, we ha e de eloped a e sa ile design o he
syn hesis o mul i unc ional diazobenzene/diace ylene glycoam-
phiphiles. By adjus ing he space leng h and he p esence o a
iazole ing, we can con ol he hie a chical sel -o ganiza ion o
hese molecules. Neoglycolipid 3 o ms sphe ical micelles
(MicMan-3) wi h a shel e ed inne co e, capable o solubilizing
hyd ophobic molecules like Nile Red and doce axel. On he
o he hand, monome 1 o ms a hyd o-alcoholic gel wi hou
he need o addi ional p ocessing, consis ingo en angled
Fig. 7 Syn hesis and use as nanocon aine o s a ic mannose-coa ed nanomicelles ManMic-3 h ough sonica ion-p omo ed sup amolecula sel -
assembly ollowed by in e molecula pho o-polyme iza ion o neoglycolipid 3in wa e (a). TEM images (b) and (c) o he o med micelles and liposomes.
CMC and DLS size de e mina ion o MicMan-3 (d). Nile Red encapsula ion s udy (e). Abso p ion spec a o Nile Red in wa e (black line) and in ManMic-3
solu ion (pu ple line) ( ). Raman spec um o he polyme ized ManMic-3 (g).
Jou nal o Ma e ials Chemis y B Pape
Open Access A icle. Published on 09 Oc obe 2023. Downloaded on 6/11/2024 11:45:18 AM.
This a icle is licensed unde a
C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence.
View A icle Online
10204 | J. Ma e . Chem. B, 2023, 11, 10189–10205 This jou nal is © The Royal Socie y o Chemis y 2023
26 J. Y. C. Lim, Q. Lin, K. Xue and X. J. Loh, Recen Ad ances in
Sup amolecula Hyd ogels o Biomedical Applica ions,
Ma e . Today Ad ., 2019, 3, 100021.
27 Q. Zhang, D. H. Qu, H. Tian and B. L. Fe inga, Bo om-Up:
Can Sup amolecula Tools Deli e Responsi eness om
Molecula Mo o s o Mac oscopic Ma e ials?, Ma e , 2020,
3(2), 355–370, DOI: 10.1016/j.ma .2020.05.014.
28 A. Ba na d and D. K. Smi h, Sel -Assembled Mul i alency:
Dynamic Ligand A ays o High-Affini y Binding, Angew.
Chem., In . Ed., 2012, 6572–6581, DOI: 10.1002/anie.201200076.
29 M. J. Clemen e, R. M. Tejedo , P. Rome o, J. Fi emann and
L. O iol, Pho o esponsi e Sup amolecula Gels Based on
Amphiphiles wi h Azobenzene and Mal ose o Polye hyle-
neglycol Pola Head, New J. Chem., 2015, 39(5), 4009–4019,
DOI: 10.1039/c4nj02012j.
30 I. N. Lee, O. Dob e, D. Richa ds, C. Balles em, J. M. Cu an,
J. A. Hun , S. M. Richa dson, J. Swi and L. S. Wong,
Pho o esponsi e Hyd ogels wi h Pho oswi chable Mechan-
ical P ope ies Allow Time-Resol ed Analysis o Cellula
Responses o Ma ix S iffening, ACS Appl. Ma e . In e aces,
2018, 10(9), 7765–7776, DOI: 10.1021/acsami.7b18302.
31 L. Li, J. M. Scheige and P. A. Le kin, Design and Applica-
ions o Pho o esponsi e Hyd ogels, Ad . Ma e ., 2019,
31(26), 1807333.
32 M. Ba oncini, J. G oppi, S. Co a, S. Sil i and A. C edi, Ligh -
Responsi e (Sup a)Molecula A chi ec u es: Recen
Ad ances, Ad . Op . Ma e ., 2019, 7(16), 1900392.
33 J. Zhang, Q. Zou and H. Tian, Pho och omic Ma e ials: Mo e
han Mee s he Eye, Ad . Ma e ., 2013, 25(3), 378–399, DOI:
10.1002/adma.201201521.
34 W. Feng, W. Luo and Y. Feng, Pho o-Responsi e Ca bon
Nanoma e ials Func ionalized by Azobenzene Moie ies:
S uc u es, P ope ies and Applica ion, Nanoscale, 2012,
4(20), 6118–6134, DOI: 10.1039/c2n 31505j.
35 D. Ble
´ge and S. Hech , Visible-Ligh -Ac i a ed Molecula
Swi ches, Angew. Chem., In . Ed., 2015, 54(39), 11338–11349,
DOI: 10.1002/anie.201500628.
36 E. Me ino, Syn hesis o Azobenzenes: The Colou ed Pieces
o Molecula Ma e ials, Chem. Soc. Re ., 2011, 40(7),
3835–3853, DOI: 10.1039/c0cs00183j.
37 V. Chand aseka an, E. Johannes, H. Koba g,
F. D. So
¨nnichsen and T. K. Lindho s , Syn hesis and Pho o-
ch omic P ope ies o Con igu a ionally Va ied Azobenzene
Glycosides, Chemis yOpen, 2014, 3(3), 99–108, DOI:
10.1002/open.201402010.
38 L. Mo
¨ckl, A. Mu
¨lle , C. B a
¨uchle and T. K. Lindho s , Swi ch-
ing Fi s Con ac : Pho ocon ol o E. Coli Adhesion o
Human Cells, Chem. Commun., 2016, 52(6), 1254–1257,
DOI: 10.1039/c5cc08884d.
39 M. J. Clemen e, P. Rome o, J. L. Se ano, J. Fi emann and
L. O iol, Sup amolecula Hyd ogels Based on Glycoamphi-
philes: Effec o he Disaccha ide Pola Head, Chem. Ma e .,
2012, 24(20), 3847–3858, DOI: 10.1021/cm301509 .
40 Y. Ogawa, C. Yoshiyama, T. Ki aoka, M. Bha acha ya, M. M.
Malinen,P.Lau en,Y.R.Lou,S.W.Kuisma,L.Kanninen,
M. Lille, A. Co lu, C. Guguen-Guillouzo, O. Ikkala, A. Laukkanen,
A. U i and M. Ylipe ula, Nano ib illa Cellulose Hyd ogel
P omo es Th ee-Dimensional Li e Cell Cul u e, Langmui ,
2012, 28(9), 291–298, DOI: 10.1016/j.jcon el.2012.06.039.
41 J. J. Cid, M. Assali, E. Fe na
´ndez-Ga cı
´a, V. Valdi ia,
E. M. Sa
´nchez-Fe na
´ndez, J. M. Ga cia Fe na
´ndez,
R. E. Wellinge , I. Fe na
´ndez and N. Khia , Tuning o
Glyconanoma e ial Shape and Size o Selec i e Bac e ial
Cell Agglu ina ion, J. Ma e . Chem. B, 2016, 4(11),
2028–2037, DOI: 10.1039/c5 b02488a.
42 M. Assali, J.-J. Cid, M. Pe nı
´a-Leal, M. Mun
˜oz-B a o,
I. Fe na
´ndez, R. E. Wellinge and N. Khia , Glyconano-
somes: Disk-Shaped Nanoma e ials o he Wa e Solubili-
za ion and Deli e y o Hyd ophobic Molecules, ACS Nano,
2013, 7(3), 2145–2153.
43 E. Rome o-Ben, T. Mena Ba aga
´n, E. Ga cı
´a De Dionisio,
E. M. Sa
´nchez-Fe na
´ndez, J. M. Ga cia Fe na
´ndez,
E. Guille
´n-Mancina, M. Lo
´pez-La
´za o and N. Khia ,
Mannose-Coa ed Polydiace ylene (PDA)-Based Nanomi-
celles: Syn hesis, In e ac ion wi h Concana alin A and
Applica ion in he Wa e Solubiliza ion and Deli e y o
Hyd ophobic Molecules, J. Ma e . Chem. B, 2019, 7(39),
5930–5946, DOI: 10.1039/c9 b01218d.
44 M. Assali, J. J. Cid, I. Fe na
´ndez and N. Khia , Sup amole-
cula Di e si y h ough Click Chemis y: Swi ching om
Nanomicelles o 1D-Nano ubes and T idimensional Hyd o-
gels, Chem. Ma e ., 2013, 25(21), 4250–4261, DOI: 10.1021/
cm4022613.
45 R. Jelinek and M. Ri enbe g, Polydiace ylenes-Recen Mole-
cula Ad ances and Applica ions, RSC Ad ., 2013, 3(44),
21192–21201, DOI: 10.1039/c3 a42639d.
46 X. Quian and B. S a
¨dle , Recen De elopmen s in Polydiace ylene-
Based Senso s, Chem. Ma e ., 2019, 31, 1196–1222.
47 M. Gou, X. Qu, W. Zhu, M. Xiang, J. Yang, K. Zhang, Y. Wei
and S. Chen, Bio-Inspi ed De oxi ica ion Using 3d-P in ed
Hyd ogel Nanocomposi es, Na . Commun., 2014, 5(May),
1–9, DOI: 10.1038/ncomms4774.
48 M. P. Leal, M. Assali, I. Fe na
´ndez and N. Khia , Coppe -
Ca alyzed Azide-Alkyne Cycloaddi ion in he Syn hesis o
Polydiace ylene: ‘‘Click Glycoliposome’’ as Biosenso s o
he Speci ic De ec ion o Lec ins, Chem. – Eu . J., 2011, 17(6),
1828–1836.
49 I. Theodo ou, P. Anilkuma , B. Lelandais, D. Cla isse,
A. Doe linge , E. G a el, F. Duconge
´and E. Do is, S able
and Compac Zwi e ionic Polydiace ylene Micelles wi h
Tumo -Ta ge ing P ope ies, Chem. Commun., 2015, 51(80),
14937–14940, DOI: 10.1039/c5cc05333a.
50 M. Z. Alam, A. Shibaha a, T. Oga a and S. Ku iha a, Syn h-
esis o Azobenzene-Func ionalized S a Polyme s ia RAFT
and Thei Pho o esponsi e P ope ies, Polyme , 2011,
52(17), 3696–3703, DOI: 10.1016/j.polyme .2011.06.035.
51 E. Dalle Vedo e, G. Cos abile and O. M. Me kel, Mannose and
Mannose-6-Phospha e Recep o –Ta ge ed D ug Deli e y Sys-
ems and Thei Applica ion in Cance The apy, Ad . Heal hca e
Ma e ., 2018, 7(14), 1–19, DOI: 10.1002/adhm.201701398.
52 T. S. Pa il and A. S. Deshpande, Mannosyla ed Nanoca ie s
Media ed Si e-Speci ic D ug Deli e y o he T ea men o
Pape Jou nal o Ma e ials Chemis y B
Open Access A icle. Published on 09 Oc obe 2023. Downloaded on 6/11/2024 11:45:18 AM.
This a icle is licensed unde a
C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence.
View A icle Online

This jou nal is © The Royal Socie y o Chemis y 2023 J. Ma e . Chem. B, 2023, 11, 10189–10205 | 10205
Cance and O he In ec ious Diseases: A S a e o he A
Re iew, J. Con olled Release, 2020, 320(Janua y), 239–252,
DOI: 10.1016/j.jcon el.2020.01.046.
53 T. Shimizu, W. Ding and N. Kame a, So -Ma e Nano ubes:
A Pla o m o Di e se Func ions and Applica ions, Chem.
Re ., 2020, 120(4), 2347–2407, DOI: 10.1021/
acs.chem e .9b00509.
54 N. Yu. Kos ina, D. So
¨de , T. Ha asz i, Q. Xiao, K. Rahimi,
B. E. Pa idge, M. L. Klein, V. Pe cec and C. Rod iguez-
Emmenegge , Enhanced Concana alin A Binding o P eo -
ganized Mannose Nanoa ays in Glycodend ime somes
Re ealed Mul i alen In e ac ions, Angew. Chem., In . Ed.,
2021, 60(15), 8352–8360, DOI: 10.1002/anie.202100400.
55 T. Kim, H. Lee, Y. Kim, J. M. Nam and M. Lee, P o ein-Coa ed
Nano ibe s o P omo ion o T Cell Ac i i y, Chem. Commun.,
2013, 49(38), 3949–3951, DOI: 10.1039/c3cc41215 .
56 J. E. Ges wicki, C. W. Cai o, L. E. S ong, K. A. Oe jen and
L. L. Kiessling, In luencing Recep o -Ligand Binding
Mechanisms wi h Mul i alen Ligand A chi ec u e, J. Am.
Chem. Soc., 2002, 124(50), 14922–14933, DOI: 10.1021/
ja027184x.
57 G. N. Pa el, R. R. Chance, E. A. Tu i and Y. P. Khanna,
Ene ge ics and Mechanism o he Solid-S a e Polyme iza-
ion o Diace ylenes, J. Am. Chem. Soc., 1978, 100(21),
6644–6649.
58 W. Neumann and H. Sixl, The Mechanism o he Low
Tempe a u e Polyme iza ion Reac ion in Diace ylene C ys-
als, Chem. Phys., 1981, 58(3), 303–312, DOI: 10.1016/0301-
0104(81)80066-3.
59 M. A. Je myn, Inc easing he Sensi i i y o he An h one
Me hod o Ca bohyd a e, Anal. Biochem., 1975, 68(1),
332–335, DOI: 10.1016/0003-2697(75)90713-7.
60 Y. Ogawa, C. Yoshiyama and T. Ki aoka, Helical Assembly o
Azobenzene-Conjuga ed Ca bohyd a e Hyd ogela o s wi h
Speci ic Affini y o Lec ins, Langmui , 2012, 28(9),
4404–4412, DOI: 10.1021/la300098q.
61 C. R. Bece , The Glycopolyme Code: Syn hesis o Glycopo-
lyme s and Mul i alen Ca bohyd a e-Lec in In e ac ions,
Mac omol. Rapid Commun., 2012, 33(9), 742–752, DOI:
10.1002/ma c.201200055.
62 D. Deniaud, K. Julienne and S. G. Gouin, Insigh s in he
Ra ional Design o Syn he ic Mul i alen Glycoconjuga es as
Lec in Ligands, O g. Biomol. Chem., 2011, 9(4), 966–979,
DOI: 10.1039/c0ob00389a.
63 J. J. Lundquis and E. J. Toone, The Clus e Glycoside Effec ,
Chem. Re ., 2002, 102(2), 555–578, DOI: 10.1021/c 000418 .
64 O. S ini as, N. Mi a, A. Su olia and N. Jaya aman, Pho o-
swi chable Mul i alen Suga Ligands: Syn hesis, Isome iza-
ion, and Lec in Binding S udies o Azobenzene-
Glycopy anoside De i a i es, J. Am. Chem. Soc., 2002,
124(10), 2124–2125, DOI: 10.1021/ja0173066.
65 U. Osswald, J. Bonebe g and V. Wi mann, Pho oswi ching
Affini y and Mechanism o Mul i alen Lec in Ligands,
Chem. – Eu . J., 2022, 28(27), e202200267.
66 T. Webe , V. Ch aseka an, I. S ame , M. B. Thygesen,
A. Te o and T. K. Lindho s , Swi ching o Bac e ial Adhe-
sion o a Glycosyla ed Su ace by Re e sible Reo ien a ion o
he Ca bohyd a e Ligand, Angew. Chem., In . Ed., 2014,
53(52), 14583–14586, DOI: 10.1002/anie.201409808.
67 G. Desp as, L. Mo
¨ckl, A. Hei mann, I. S ame , C. B a
¨uchle
and T. K. Lindho s , A Pho oswi chable T i alen Clus e
Mannoside o P obe he Effec s o Ligand O ien a ion in
Bac e ial Adhesion, ChemBioChem, 2019, 20(18), 2373–2382,
DOI: 10.1002/cbic.201900269.
Jou nal o Ma e ials Chemis y B Pape
Open Access A icle. Published on 09 Oc obe 2023. Downloaded on 6/11/2024 11:45:18 AM.
This a icle is licensed unde a
C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence.
View A icle Online