polyme s
Re iew
Sup amolecula Cyclodex in-Based Hyd ogels o
Con olled Gene Deli e y
Ana Rey-Rico 1,* and Magali Cucchia ini 2
1Cell The apy and Regene a i e Medicine Uni , Cen o de In es igacións Cien í icas A anzadas (CICA),
Uni e sidade da Co uña, Campus de A Co uña, 15071 A Co uña, Spain
2Cen e o Expe imen al O hopaedics, Saa land Uni e si y Medical Cen e , D-66421 Hombu g/Saa ,
Ge many; [email p o ec ed]
*Co espondence: ana. ey[email p o ec ed]; Tel. +34-881-01-5543
Recei ed: 6 Ma ch 2019; Accep ed: 17 Ma ch 2019; Published: 19 Ma ch 2019


Abs ac :
Con olled deli e y o gene ans e ec o s is a powe ul s a egy o enhance he empo al
and spa ial p esen a ion o he apeu ic agen s in a de ined a ge . Hyd ogels a e adap ed bioma e ials
o gene deli e y capable o ac ing as a localized depo o genes while main aining he long e m local
a ailabili y o DNA ec o s a a speci ic loca ion. Sup amolecula hyd ogels based on cyclodex ins
(CDs) ha e a ac ed conside able a en ion as po en ial bioma e ials in a b oad ange o d ug
deli e y applica ions. Thei unique cha ac e is ics o hixo opici y and low cy o oxici y due o hei
p oduc ion unde mild condi ions make hem po en ial candida es o o m injec able deli e y sys ems.
This wo k aims o p o ide an o e iew o he use o CD-based polypseudo o axane hyd ogels as
con olled gene deli e y sys ems o di e en applica ions in egene a i e medicine.
Keywo ds:
sup amolecula hyd ogels; cyclodex in-based polypseudo o axane hyd ogels; con olled
gene deli e y; non i al ec o s; i al ec o s; gene ans e
1. In oduc ion
1.1. Cyclodex ins
Cyclodex ins (CDs) ep esen a g oup o cyclic oligosaccha ides consis ing o a ela i ely
hyd ophobic ca i y and a hyd ophilic ex e nal ace ob ained om enzyma ic ans o ma ion o s a ch
wi h a o us-like molecula shape [
1
]. CDs a e classi ied as
α
-,
β
, o
γ
-CDs, depending on he numbe
o D(+)-glucose uni s linked by
α
-1,4-linkages, being o 6, 7, and 8, espec i ely [
2
] (Figu e 1). Mo eo e ,
he p esence o 2-, 3-, and 6-hyd oxyl g oups on he ing makes CDs e sa ile pla o ms o s uc u al
modi ica ions o imp o e hei na u al p ope ies in di e en applica ions [
3
]. In addi ion, CDs a e
gene ally conside ed as sa e (GRAS) subs ances by he Food and D ug Adminis a ion (FDA) [1].
CDs ha e he abili y o h ead along ce ain polyme egions (main-chain complexes) o la e al
chains (side-chain complexes), leading o he o ma ion o sup amolecula assembled s uc u es. These
sup amolecula s uc u es a e no mally e e ed o as polypseudo o axane when CDs can e e sibly
a el along he polyme backbone o la e al chains. Con e sely, when bo h ends o he polyme chains
in polypseudo o axanes a e co alen ly capped wi h bulky molecules, CDs a e en apped and canno
be de- h eaded om he assembly, gi ing so-called poly o axanes [4,5].
Polyme s 2019,11, 514; doi:10.3390/polym11030514 www.mdpi.com/jou nal/polyme s
Polyme s 2019,11, 514 2 o 9
Polyme s 2018, 10, x FOR PEER REVIEW 2 o 10
Figu e 1. S uc u e o cyclodex ins. Two-dimensional sequences o α-CDs (CID: 444913) (A), β-CDs
(CID: 444041) (B), and γ-CDs (CID: 5287407) (C) we e ob ained om PubChem Compound.
Th ee-dimensional (3D) s uc u es o he di e en compounds we e d awn wi h ChemBioO ice
2012 (Chem3D P o 13; Pe kinElme In o ma ics).
1.2. CD-based Polypseudo o axane Hyd ogels
Sup amolecula hyd ogels ep esen a ype o bioma e ial consis ing o a solid
h ee-dimensional ne wo k o med ia nonco alen bonds, such as a hyd ogen bond, hyd ophobic
in e ac ion, and ca ion–π and π–π in e ac ions [6].
CD-based polypseudo o axanes gene ally consis o polyme s, such as poly(e hylene oxide)
(PEO) o poly(e hylene glycol) (PEG) [7], poly(p opylene oxide) (PPO) [8], o copolyme s ha ing
blocks o PEO and/o PPO, alone as PEO-PPO-PEO (Plu onics) [9–11], o combined wi h o he
blocks, such as poly[(R)-3-hyd oxybu y a e] [12] o poly(cap olac one) (PCL) [13–15].
Sup amolecula hyd ogels based on polypseudo o axanes ha e al eady been epo ed as
po en ial candida es o di e en issue enginee ing applica ions due o hei hixo opic na u e and
excellen biocompa ibili y, showing as po en ial as injec able hyd ogel ca ie s ha may be
adminis e ed ia non-in asi e implan a ion [16]. Likewise, he mild condi ions in he absence o
o ganic sol en s unde which polypseudo o axane gels a e o med allow o he inco po a ion o a
a ie y o biomolecules, also encompassing hyd ophobic molecules ha bene i om he p esence o
ee CDs o micelle-like s uc u es o d ug hos ing [1,16,17].
2. Gene T ans e Vec o s: Basic Concep s
2.1. Non i al Vec o s
Gene ans e ia non i al ec o s ( ans ec ion) is based on he inco po a ion o DNA, ei he
naked bu mos ly complexed wi h ca ionic polyme s o wi h ca ionic lipids (in polyplexes and
lipoplexes) in o a a ge popula ion [18]. As a esul o his complexa ion, DNA ca go may be
p o ec ed agains deg ada ion by nucleases and se um componen s by c ea ing a less nega i e
su ace cha ge [19]. S ill, and unlike i al coun e pa s ha ha e e ol ed o o e come cellula and
immune de ense mechanisms, non i al ca ie s exhibi educed ans ec ion e iciencies as hey a e
p ecluded by nume ous ex a- and in acellula obs acles [18]. The e o e, he ob aining o an
e icien non i al-media ed ans e migh need epea ed adminis a ion o achie e sa is ac o y gene
he apeu ic e ec s, due o hei sho e en ion ime o low he apeu ic e icacy in a ge issues [15].
Howe e , he main ad an age o hese ypes o ec o s is hei biosa e y as hey a oid he isk o
acqui ing eplica ion compe ence and o inse ional mu agenesis commonly associa ed wi h i al
ec o s. Likewise, i s po en ial o la ge scale p oduc ion a ela i ely low expense makes hese
ec o s a ac i e ools o gene he apy [20].
2.2. Vi al Vec o s
Figu e 1.
S uc u e o cyclodex ins. Two-dimensional sequences o
α
-CDs (CID: 444913) (
A
),
β
-CDs (CID: 444041) (
B
), and
γ
-CDs (CID: 5287407) (
C
) we e ob ained om PubChem Compound.
Th ee-dimensional (3D) s uc u es o he di e en compounds we e d awn wi h ChemBioO ice 2012
(Chem3D P o 13; Pe kinElme In o ma ics).
1.2. CD-Based Polypseudo o axane Hyd ogels
Sup amolecula hyd ogels ep esen a ype o bioma e ial consis ing o a solid h ee-dimensional
ne wo k o med ia nonco alen bonds, such as a hyd ogen bond, hyd ophobic in e ac ion, and
ca ion–πand π–πin e ac ions [6].
CD-based polypseudo o axanes gene ally consis o polyme s, such as poly(e hylene oxide) (PEO)
o poly(e hylene glycol) (PEG) [
7
], poly(p opylene oxide) (PPO) [
8
], o copolyme s ha ing blocks o
PEO and/o PPO, alone as PEO-PPO-PEO (Plu onics) [
9
–
11
], o combined wi h o he blocks, such as
poly[(R)-3-hyd oxybu y a e] [12] o poly(cap olac one) (PCL) [13–15].
Sup amolecula hyd ogels based on polypseudo o axanes ha e al eady been epo ed as po en ial
candida es o di e en issue enginee ing applica ions due o hei hixo opic na u e and excellen
biocompa ibili y, showing as po en ial as injec able hyd ogel ca ie s ha may be adminis e ed ia
non-in asi e implan a ion [
16
]. Likewise, he mild condi ions in he absence o o ganic sol en s unde
which polypseudo o axane gels a e o med allow o he inco po a ion o a a ie y o biomolecules,
also encompassing hyd ophobic molecules ha bene i om he p esence o ee CDs o micelle-like
s uc u es o d ug hos ing [1,16,17].
2. Gene T ans e Vec o s: Basic Concep s
2.1. Non i al Vec o s
Gene ans e ia non i al ec o s ( ans ec ion) is based on he inco po a ion o DNA, ei he
naked bu mos ly complexed wi h ca ionic polyme s o wi h ca ionic lipids (in polyplexes and
lipoplexes) in o a a ge popula ion [
18
]. As a esul o his complexa ion, DNA ca go may be
p o ec ed agains deg ada ion by nucleases and se um componen s by c ea ing a less nega i e
su ace cha ge [
19
]. S ill, and unlike i al coun e pa s ha ha e e ol ed o o e come cellula and
immune de ense mechanisms, non i al ca ie s exhibi educed ans ec ion e iciencies as hey a e
p ecluded by nume ous ex a- and in acellula obs acles [
18
]. The e o e, he ob aining o an e icien
non i al-media ed ans e migh need epea ed adminis a ion o achie e sa is ac o y gene he apeu ic
e ec s, due o hei sho e en ion ime o low he apeu ic e icacy in a ge issues [
15
]. Howe e , he
main ad an age o hese ypes o ec o s is hei biosa e y as hey a oid he isk o acqui ing eplica ion
compe ence and o inse ional mu agenesis commonly associa ed wi h i al ec o s. Likewise, i s
po en ial o la ge scale p oduc ion a ela i ely low expense makes hese ec o s a ac i e ools o
gene he apy [20].
2.2. Vi al Vec o s
Vi al gene ans e ( ansduc ion) is based on he na u al cellula en y pa hways o i uses
om which hey a e de i ed [
20
]. The mos common i uses manipula ed o gene ans e pu poses
Polyme s 2019,11, 514 3 o 9
include he pes simplex i us (HSV) [
21
,
22
], adeno i uses [
23
,
24
], e o- and len i i uses [
25
–
27
], and
adeno-associa ed i us (AAV) [
28
–
30
]. While gene ans e ia i al ec o s is highly e icien , he
exis ence o pa ien -associa ed ac o s and physiological ba ie s (high immunogenici y, inhibi ion o
ansduc ion in he p esence o speci ic an icoagulan s) may hinde he e ec i e deli e y, p ocessing,
and exp ession o ansgenes in he a ge cells [31–33].
3. Con olled Deli e y o Gene T ans e Vec o s ia CD Hyd ogels
3.1. P inciples o Con olled Gene Deli e y
The con olled deli e y o gene ans e ec o s ep esen s a powe ul ool o add ess he issues
associa ed wi h he use o gene ans e ec o s in clinical se ings (i.e., educed e iciency, apid
deg ada ion, physiological ba ie s, and/o ec o - and pa ien -speci ic- immune esponses) [
33
].
In addi ion, sus ained gene exp ession has been epo ed o be mo e e ec i e compa ed wi h he
adminis a ion o ecombinan molecules [
34
], p o iding high le els o he apeu ic genes o a ge
a ious physiological mechanisms, such as angiogenesis [
35
] o chond ogenesis [
11
], o du ably
enhance he epai o inju ed issues and o gans [
36
]. He eo , he p olonged p esence o he gene
ans e ec o s in he cellula mic oen i onmen may imp o e he e icacy o he he apeu ic ca go
by p o iding a long e m, sus ained a a speci ic place ea men while minimizing he exposi ion o
non- a ge issues [15,34,37].
Among a a ie y o bioma e ials, hyd ogels ha e been epo ed as po en ial ools o gene deli e y,
a o ding bo h p o ec ion o he gene ans e ec o s agains ex acellula deg ada ion and p ema u e
agg ega ion and con olled supply o he he apeu ic molecules a he a ge place.
3.2. Con olled Deli e y o Gene T ans e Vec o s ia Sup amolecula -Based CD Hyd ogels
While polypseudo o axane hyd ogels ha e been ex ensi ely s udied o d ug deli e y
app oaches [
1
,
4
], hei applica ion in gene deli e y app oaches has been less explo ed. In his ega d,
mos applica ions using CDs o gene he apy pu poses ocused on he use o poly o axanes based on
CD-con aining ca ionic polyme s ac ing as ca ie s o plasmid DNA.
Gene deli e y om polypseudo o axanes hyd ogels has been chie ly associa ed wi h he shedding
o CDs om he linea polyme backbone, being he de- h eading a e p opo ional o he olume o
he dissolu ion medium [
38
]. The e o e, when injec ed in o he body, polypseudo o axane hyd ogels
migh g adually dilu e upon con ac wi h physiological luids leading o CD all-o and he eleased
genes being abso bed by su ounding cells h ough endocy osis [38].
He e, we will explo e he use o polypseudo o axane hyd ogels as con olled deli e y sys ems
o gene ans e ec o s and hei po en ial applica ion in issue enginee ing and egene a i e
medicine app oaches.
3.2.1. Con olled Deli e y o Non i al Vec o s
Sup amolecula hyd ogels based on block copolyme composed o poly(L-lysine) (PLL) segmen s
o complexa ion o plasmid DNA encoding o he g een luo escen p o ein (GFP) and Plu onic
®
F68
(PF68-PLL) o o m inclusion complexes
α
-CD we e p oduced [
9
] (Table 1). Bo h gela ion ime and
mechanical s eng h could be modula ed by uning he amoun s o F-68-PLL and
α
-CD. Likewise, he
sys ems eleased DNA complexes o 3 days allowing o sus ained ansgene exp ession in a ib oblas
cell line wi h educed cy o oxici y.
Polyme s 2019,11, 514 4 o 9
Table 1. Con olled deli e y o non i al ec o s ia sup amolecula -based CD hyd ogels.
Polyme s/CDs Vec o s Ou comes App oaches Ta ge s Re e ences
PF68-PLL/α-CD pDNA-GFP Sus ained pDNA deli e y o 80 h;
ans ec ion e iciency ~14% mouse ib oblas cells 3T3 n.s. [9]
MPEG-PCL-PDMAEMA/α-CD pDNA-luc
Sus ained elease o pDNA up o 6
days; ans ec ion e iciency
compa able o eshly p epa ed
PEI polyplexes
COS-7 cells n.s. [13]
PEG-α-CD-c oss-linked PVDT pDNA-luc E icien e e se gene ans ec ion o
cells cul u ed on he gel su ace COS-7 cells n.s. [39]
MPEG-PCL-PEI/α-CD
MPEG-PCL-PEIFA/α-CD
pDNA-GFP
pDNA-Nu 77
Sus ained elease o pDNA o 7 days;
ans ec ion e iciency o 63% a
op imal weigh a io o 1.5; signi ican
inhibi ion o he apeu ic esis an
umo g ow h wi h high exp ession
o Bcl-2 p o eins
Highe e iciency when combining he
chemo he apeu ic agen pacli axel and
he a ge ing abili y o FA
HEK293 cells, umo model
(BALB/c nude mice) umo [15,40]
MPEG-PLLD-A g/α-CD pMMP-9
Con olled elease o 6 days;
ans ec ion e iciency up o 72%;
sus ained umo g ow h inhibi ion
a e 21 days wi h good
biocompa ibili y
HNE-1 cells, nude mice
bea ing HNE-1 umo s umo [37]
Abb e ia ions: CD: cyclodex in; Plu onic
®
F68; PLL: poly(L-lysine);
α
-CD: alpha-CD; MPEG-PCL-PDMAEM:. me hoxy-poly(e hylene glycol)-b-poly(
ε
-cap olac one)-b-
poly[2-(dime hylamino)e hyl me hac yla e]; PEG: poly-e hylene glycol;
β
-CD: be a-CD; PVDT: poly-2- inyl-4,6-diamino-1,3,5- iazine; PEI: poly(e hylene imine);
PLLD-A ginine- unc ionalized PLL dend on; pDNA: plasmid DNA; GFP: g een luo escen p o ein; luc: luci e ase; Nu 77: Bcl-2 (B-cell lymphoma 2) con e sion Nu 77
gene; FA: olic acid; MMP-9: ma ix me allop o einase 9; HNE-1: human nasopha yngeal ca cinoma HNE-1 cells; n.s.: no speci ied.
Polyme s 2019,11, 514 5 o 9
Li e al. p epa ed iblock copolyme s o me hoxy-poly(e hylene glycol)-b-poly(
ε
-cap olac one)-b-
poly[2-(dime hylamino)e hyl me hac yla e] (MPEG-PCL-PDMAEMA) wi h well-de ined ca ionic
block leng hs o condense pDNA in polyplexes. O no e, MPEG impa ed s abili y o he pDNA
polyplexes and also se ed as an ancho ing segmen when he pDNA polyplexes we e encapsula ed in
α
-CD-based sup amolecula polypseudo o axane hyd ogels. In addi ion, he sys ems eleased pDNA
in a sus ained way o up o 6 days, leading o ans ec ion le els compa able o hose achie ed wi h
eshly p epa ed poly(e hylene imine) (PEI) polyplexes [13].
Sup amolecula based CD hyd ogels ha e also been manipula ed as sca olds o ma ix-media ed
gene ans ec ion. By hese lines, hyd ogen bonding s eng hened hyd ogels we e p epa ed by adical
copolyme iza ion o PEG me hac yla ed
β
-CD (PEG-
β
-CD) and 2- inyl-4,6- diamino-1,3,5- iazine
(VDT) monome [
39
]. Immobiliza ion o plasmid DNA on o he su ace o hyd ogels was achie ed by
hyd ogen bonding be ween he base pai s and diamino iazine, esul ing in an e icien e e se gene
ans ec ion o he luci e ase gene in a kidney cell line (COS-7) cul u ed on he gel su ace.
CD-based polypseudo o axane hyd ogels ha e also been desc ibed as po en ial candida es o
design injec able hyd ogels o cance he apy by p o iding a long e m, sus ained a umo si es
ea men while minimizing he exposi ion o non- a ge issues [15,37].
Injec able sup amolecula hyd ogel sys ems we e o med by complexa ions be ween
α
-CD and
ca ionic MPEG-PCL-PEI copolyme . The esul ing hyd ogels we e capable o o ming polyplexes wi h
epo e plasmid DNA and o p o iding a sus ained elease o pDNA in he o m o polyplexes o up
o 7 days. O no e, he inco po a ion o he an ipop o ic Bcl-2 con e sion gene in he sys ems esul ed
in an e ec i e inhibi ion o umo g ow h a e 7 days
in i o
when injec ing in o a solid umo o
nude mice [
15
]. Mo e ecen ly, he same au ho s in ol ed a simila sys em inco po a ing a olic acid
a ge ed g oup (MPEG-PCL-PEI-FA/
α
-CD) o co-deli e he chemo he apeu ic pacli axel and he
an ipop o ic Bcl-2 con e sion gene in a umo o mice [
40
]. Rapid solidi ica ion o he sys ems was
no ed a e adminis a ion ia pe i umo al injec ion. Likewise, a signi ican p e en ion o he
in i o
g ow h o he apeu ic- esis an H460/Bcl-2 umo was obse ed as a consequence o he sus ained
elease o sup amolecula hyd ogel and a ge ing abili y media ed by FA ligand.
A simila endency was obse ed upon encapsula ion o an MMP-9 shRNA plasmid (pMMP-9)
in o α-CD and PEGyla ed a ginine- unc ionalized PLL dend on hyd ogels [37].
3.2.2. Con olled Deli e y o Vi al Vec o s
While less explo ed han hei non i al ec o coun e pa s, mos o he a emp s o design
con olled deli e y sys ems o i al ec o s ocused on he design o mic ocapsules o biodeg adable
polyme s o he sus ained elease o he ec o a he a ge place, and polyme conjuga es ha p o ide
s eal h, cell- a ge ed shells o he i al ec o s [
41
–
43
]. In his ega d, al hough i al gene ans e is
highly e icien , i s ou come can s ill be p ecluded by some ba ie s, such as high immunogenici y and
inhibi ion o ansduc ion in he p esence o speci ic an icoagulan s [31–33].
While ecombinan adeno-associa ed i us ( AAV) ec o s a e conside ed he sa es ec o s o
i al gene ans e , hei ansla ional use in pa ien s migh be impeded by he p esence o neu alizing
an ibodies agains he AAV capsid p o eins in he hos [
32
], especially by hose p esen in he syno ial
luid o pa ien s wi h join diseases [
44
]. Con olled deli e y o AAV ec o s ia polyme ic bioma e ials
has al eady shown o be a po en way o o e come hese issues [
33
]. Addi ionally, sy ingeable
hyd ogels ha can be p ecisely placed in a speci ic si e o he body using minimally in asi e ways
and ha ans o m in o depo s o sus ained elease o ac i e subs ances a oiding hei di usion o
non- a ge places, ha e been la gely pu sued o di e en egene a i e medicine app oaches. The e o e,
we ecen ly gene a ed sy ingeable polypseudo o axane gels o p oduce ma e ials ha can du ably
deli e AAV ec o s o applica ions in ca ilage egene a ion [
11
] (Table 2). To achie e his goal,
dispe sions o Plu onic
®
F68 (PF68) o Te onic
®
908 (T908) con aining ei he hyalu onic acid (HA) o
chond oi in sul a e (CS) we e p epa ed in PBS.
α
-CD was nex added o o m polypseudo o axane gels.
Compa ed wi h ee ec o s, he gels allowed o p omo e highe le els o ansgene exp ession. CS (o

Polyme s 2019,11, 514 6 o 9
HA)/PF68/
α
-CD gels apidly eleased AAV ec o s while CS (o HA)/T908/
α
-CD gels p o ided
sus ained elease, p obably due o di e en in e ac ions wi h he i al ec o s. Inco po a ion o
α
-CD
in o CS (o HA)/PF68 gels esul ed in highe AAV concen a ions and sus ained le els o ansgene
exp ession in monolaye cul u es o p ima y human bone ma ow-de i ed mesenchymal s em cells
(hMSCs) o e ime. In addi ion, HA inc eased bo h bioac i i y and cy ocompa ibili y o he gels [11].
Table 2. Con olled deli e y o i al ec o s ia sup amolecula -based cyclodex ins (CD) hyd ogels.
Polyme s/CDs Vec o s Ou comes App oaches Ta ge s Re e ences
CS (o
HA)/PF68/
α
-CD
CS (o
HA)/T908/
α
-CD
AAV-lacZ
Sus ained elease o
21 days; CS (o
HA)/PF68/α-CD
gels esul ed in he
highes AAV
concen a ions and
sus ained le els o
ansgene exp ession
o e ime
hMSCs ca ilage
epai [11]
Abb e ia ions: CD: cyclodex in; CS: chond oi in sul a e; HA: hyalu onic acid; PF68: Plu onic
®
F68; T908: Te onic
®
908; α-CD: alpha-CD; hMSCs: human bone ma ow-de i ed mesenchymal s em cells.
Likewise, o s udy he po en ial o he sys ems o ca ilage egene a ion app oaches, hyd ogels
we e cul u ed o 21 days upon con ac wi h hMSCs in a 3D agg ega e cul u e model. O no e, no
dele e ious e ec s om he hyd ogels we e no ed on he chond ogenic po en ial o he cells exhibi ing
no di e ences wi h hose cells cul u ed in he absence o polyseudo o axane sys ems (Figu e 2A).
No ewo hy, con olled deli e y o a epo e gene ( AAV-lacZ) ia HA/PF68/
α
-CD hyd ogels esul ed
in he mos e ec i e gene ans e (Figu e 2A). Simila ly, supe io chond ogenic di e en ia ion was
no ed by deli e y o he chond ogenic ac o SOX9 ( AAV-FLAG-hsox9) ia hese hyd ogel sys ems
(Figu e 2B). These sys ems migh also be en isioned o he deli e y o o he mo phogens capable o
s imula ing MSC di e en ia ion o ano he lineages, such as os eoblas s.
Polyme s 2018, 10, x FOR PEER REVIEW 7 o 10
Figu e 2. Con olled deli e y o AAV-lacZ (A) o AAV-FLAG-hsox9 (B) ia polypseudo a axane
hyd ogels. Pelle s we e cul u ed in he absence (posi i e con ol; ee AAV o m) o p esence o
AAV-loaded hyd ogels sys ems (Plu onic® F68 (PF68)/ chond oi in sul a e (CS)/alpha-cyclodex ins
(α-CD) o PF68/ hyalu onic acid (HA)/α-CD) o 21 days and moni o ed o chond ogenic
di e en ia ion (A, B: Toluidine blue s aining: magni ica ion x4, all ep esen a i e da a) and
β-galac osidase ac i i y (A: β-gal immunouno eac i i y: magni ica ion x20, all ep esen a i e da a).
4. Conclusions
O e he pas decades, CD-based sup amolecula hyd ogels aised g owing in e es as
bioma e ials o d ug and gene deli e y app oaches. Because o hei unique p ope ies o
hixo opici y, biosa e y, and easy modi ica ion, CD-based polypseudo o axane hyd ogels can be
used as p omising injec able deli e y sys ems o con olled gene deli e y. Likewise, he dilu ion
p ocess o hese sys ems in con ac wi h body luids may be modula ed by adjus ing injec ion imes
o changing he molecula weigh o he polyme ic backbone [38].
Di e en CD-based polypseudo o axane hyd ogels ha e been p oduced o design sys ems able
o p o ide a long e m local a ailabili y o DNA ec o s a a speci ic loca ion and o s imula e se e al
physiological mechanisms able o enhance he epai o inju ed issues.
Au ho Con ibu ions: A.R.-R. and M.C. con ibu ed equally o he concep ion and w i ing o he wo k.
Acknowledgmen s: Ana Rey-Rico hanks he InTalen p og am om UDC-Indi ex o he esea ch g an and
Magali Cucchia ini he Deu sche A h ose-Hil e e.V.
Con lic s o In e es : The au ho s decla e no con lic s o in e es .
Re e ences
1. Simoes, S.M.; Rey-Rico, A.; Conchei o, A.; Al a ez-Lo enzo, C. Sup amolecula cyclodex in-based d ug
nanoca ie s. Chem. Commun. 2015, 51, 6275–6289.
Figu e 2. Con .
Polyme s 2019,11, 514 7 o 9
Polyme s 2018, 10, x FOR PEER REVIEW 7 o 10
Figu e 2. Con olled deli e y o AAV-lacZ (A) o AAV-FLAG-hsox9 (B) ia polypseudo a axane
hyd ogels. Pelle s we e cul u ed in he absence (posi i e con ol; ee AAV o m) o p esence o
AAV-loaded hyd ogels sys ems (Plu onic® F68 (PF68)/ chond oi in sul a e (CS)/alpha-cyclodex ins
(α-CD) o PF68/ hyalu onic acid (HA)/α-CD) o 21 days and moni o ed o chond ogenic
di e en ia ion (A, B: Toluidine blue s aining: magni ica ion x4, all ep esen a i e da a) and
β-galac osidase ac i i y (A: β-gal immunouno eac i i y: magni ica ion x20, all ep esen a i e da a).
4. Conclusions
O e he pas decades, CD-based sup amolecula hyd ogels aised g owing in e es as
bioma e ials o d ug and gene deli e y app oaches. Because o hei unique p ope ies o
hixo opici y, biosa e y, and easy modi ica ion, CD-based polypseudo o axane hyd ogels can be
used as p omising injec able deli e y sys ems o con olled gene deli e y. Likewise, he dilu ion
p ocess o hese sys ems in con ac wi h body luids may be modula ed by adjus ing injec ion imes
o changing he molecula weigh o he polyme ic backbone [38].
Di e en CD-based polypseudo o axane hyd ogels ha e been p oduced o design sys ems able
o p o ide a long e m local a ailabili y o DNA ec o s a a speci ic loca ion and o s imula e se e al
physiological mechanisms able o enhance he epai o inju ed issues.
Au ho Con ibu ions: A.R.-R. and M.C. con ibu ed equally o he concep ion and w i ing o he wo k.
Acknowledgmen s: Ana Rey-Rico hanks he InTalen p og am om UDC-Indi ex o he esea ch g an and
Magali Cucchia ini he Deu sche A h ose-Hil e e.V.
Con lic s o In e es : The au ho s decla e no con lic s o in e es .
Re e ences
1. Simoes, S.M.; Rey-Rico, A.; Conchei o, A.; Al a ez-Lo enzo, C. Sup amolecula cyclodex in-based d ug
nanoca ie s. Chem. Commun. 2015, 51, 6275–6289.
Figu e 2.
Con olled deli e y o AAV-lacZ (
A
) o AAV-FLAG-hsox9 (
B
) ia polypseudo a axane
hyd ogels. Pelle s we e cul u ed in he absence (posi i e con ol; ee AAV o m) o p esence o
AAV-loaded hyd ogels sys ems (Plu onic
®
F68 (PF68)/ chond oi in sul a e (CS)/alpha-cyclodex ins
(
α
-CD) o PF68/ hyalu onic acid (HA)/
α
-CD) o 21 days and moni o ed o chond ogenic
di e en ia ion (
A
,
B
: Toluidine blue s aining: magni ica ion
×
4, all ep esen a i e da a) and
β-galac osidase ac i i y (A:β-gal immunouno eac i i y: magni ica ion ×20, all ep esen a i e da a).
4. Conclusions
O e he pas decades, CD-based sup amolecula hyd ogels aised g owing in e es as
bioma e ials o d ug and gene deli e y app oaches. Because o hei unique p ope ies o
hixo opici y, biosa e y, and easy modi ica ion, CD-based polypseudo o axane hyd ogels can be
used as p omising injec able deli e y sys ems o con olled gene deli e y. Likewise, he dilu ion
p ocess o hese sys ems in con ac wi h body luids may be modula ed by adjus ing injec ion imes o
changing he molecula weigh o he polyme ic backbone [38].
Di e en CD-based polypseudo o axane hyd ogels ha e been p oduced o design sys ems able o
p o ide a long e m local a ailabili y o DNA ec o s a a speci ic loca ion and o s imula e se e al
physiological mechanisms able o enhance he epai o inju ed issues.
Au ho Con ibu ions: A.R.-R. and M.C. con ibu ed equally o he concep ion and w i ing o he wo k.
Acknowledgmen s:
Ana Rey-Rico hanks he InTalen p og am om UDC-Indi ex o he esea ch g an and
Magali Cucchia ini he Deu sche A h ose-Hil e e.V.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
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