Full Te ms & Condi ions o access and use can be ound a
h ps://www. and online.com/ac ion/jou nalIn o ma ion?jou nalCode=iedd20
Expe Opinion on D ug Deli e y
ISSN: (P in ) (Online) Jou nal homepage: h ps://www. and online.com/loi/iedd20
Diabe ic eye: associa ed diseases, d ugs in clinic,
and ole o sel -assembled ca ie s in opical
ea men
Axel Ka a , Angel Conchei o & Ca men Al a ez-Lo enzo
To ci e his a icle: Axel Ka a , Angel Conchei o & Ca men Al a ez-Lo enzo (2021) Diabe ic eye:
associa ed diseases, d ugs in clinic, and ole o sel -assembled ca ie s in opical ea men , Expe
Opinion on D ug Deli e y, 18:11, 1589-1607, DOI: 10.1080/17425247.2021.1953466
To link o his a icle: h ps://doi.o g/10.1080/17425247.2021.1953466
© 2021 The Au ho (s). Published by In o ma
UK Limi ed, ading as Taylo & F ancis
G oup.
Published online: 01 Sep 2021.
Submi you a icle o his jou nal
A icle iews: 453
View ela ed a icles
View C ossma k da a
REVIEW
Diabe ic eye: associa ed diseases, d ugs in clinic, and ole o sel -assembled ca ie s
in opical ea men
Axel Ka a , Angel Conchei o and Ca men Al a ez-Lo enzo
Depa amen o de Fa macología, Fa macia y Tecnología Fa macéu ica, I+D Fa ma G oup (GI-1645), Facul ad de Fa macia and Heal h Resea ch
Ins i u e o San iago de Compos ela (IDIS), Uni e sidade de San iago de Compos ela, San iago de Compos ela, Spain
ABSTRACT
In oduc ion: Diabe es is a pandemic disease ha causes ele an ocula pa hologies. Diabe ic e ino-
pa hy, macula edema, ca a ac s, glaucoma, o ke a opa hy s ongly impac he quali y o li e o he
pa ien s. In addi ion o glycemic con ol, in ense esea ch is de o ed o inding mo e e icien ocula
d ugs and imp o ed deli e y sys ems ha can o e come eye ba ie s.
A eas co e ed: The aim o his e iew is o e isi i s he ole o diabe es in he de elopmen o
ch onic eye diseases. Then, comme cially a ailable d ugs and new candida es in clinical ials a e
ackled oge he wi h he p os and cons o hei adminis a ion ou es. Subsequen sec ions deal
wi h sel -assembled d ug ca ie s sui able o eye ins illa ion combining pa ien - iendly adminis a ion
wi h high ocula bioa ailabili y. Pe o mance o opically adminis e ed polyme ic micelles, liposomes,
and niosomes o he managemen o diabe ic eye diseases is analyzed in he ligh o ex i o and
in i o esul s and ou comes o clinical ials.
Expe opinion: Sel -assembled ca ie s a e being shown use ul o e icien deli e y o no only
a a ie y o small d ugs bu also mac omolecules (e.g. an ibodies) and genes. Success ul design o
d ug ca ie s may o e al e na i es o in aocula injec ions and imp o e he ea men o bo h an e io
and pos e io segmen s diabe ic eye diseases.
ARTICLE HISTORY
Recei ed 27 Ap il 2021
Accep ed 6 July 2021
KEYWORDS
Diabe ic eye; opical ocula
deli e y; liposomes;
polyme ic micelles;
niosomes; clinical ials
1. In oduc ion
Diabe es melli us cu en ly a ec s 8.5% people wo ldwide,
and i is expec ed o impac on he li es o 570 million people
in 2025 [1]. The e a e i e di e en o ms o diabe es, wi h
diabe es ype 1 ( ailu e in he p oduc ion o insulin) and ype 2
(de icien insulin sensi i i y) being he mos common. The
o he h ee o ms a e monogenic diabe es, which is he edi a y
due o a single gene mu a ion; ges a ional diabe es, ela ed o
p egnancy; and cys ic ib osis- ela ed diabe es, which is linked
o sca ing o he panc eas ha leads o insulin abno mali ies.
Fo people wi h ype 1 diabe es, he immune sys em a acks
panc ea ic cells esponsible o he p oduc ion o insulin, dis-
up ing hei no mal unc ion. Bo h gene ic and en i onmen al
ac o s ha e been iden i ied as causal agen s. Type 2 diabe es
is indica i e o insulin esis ance, which may be caused by
excess body weigh .
Diabe es is conside ed a pandemic disease wi h an inc eas-
ing mo bidi y and he highes a e in yea s o li e los due o
disabili y in bo h high-income and lowe -middle-income
coun ies [2]. Such a high incidence esul s in an inc ease in
diseases seconda y o diabe es. Diabe es-associa ed diseases
ange om ca dio ascula p oblems o diabe ic neu opa hy
including kidney ailu es and ocula diseases. Indeed, he e m
diabe ic eye disease has a b oad meaning as i may encom-
pass mul iple illnesses in di e en pa s o he eye, mainly
diabe ic e inopa hy, macula edema, ca a ac s, glaucoma,
and ke a opa hy [3–6].
Con ol o hype glycemia is a c i ical main measu e o
a oid a as p og ession o damage in ocula s uc u es.
Depending on he ime lag be ween he i s symp oms o
diabe es and e ec i e egula ion o glycemia le els, he eyes
may al eady be a ec ed when he apeu ic measu emen s a e
aken. The e o e, ea ly diagnosis may p e en he appa i ion
o diabe es-associa ed diseases. Ne e heless, con inuous high
basal glucose le els o e ime ine i ably cause damage o
a wide a ie y o issues, especially hose whe e glucose is
eely accessible [7].
Since diabe es is a ch onic disease, ocula ea men s may
ha e o be applied o yea s. The e o e, inding d ug deli e y
sys ems ha combine he pa ien - iendly adminis a ion o
opical o mula ions wi h he high ocula bioa ailabili y o
in aocula injec ions is an unme clinical need. In he las
decades, eye d ops in which he d ug molecules a e encapsu-
la ed in nanoca ie s ha e demons a ed no able enhance-
men s in d ug le els in bo h an e io and pos e io eye
segmen s [8,9]. Nanomicelles, liposomes, lipid nanopa icles,
and polyme nanosphe es p o ide p o ec ion agains p ema-
u e deg ada ion, enhanced e en ion on eye su ace, and
no el pa hways o pene a ion h ough co neal and ans-
scle al ou es [10,11]. Ca ie s ha a e spon aneously o med
by sel -assembly o hei componen s in wa e a e
CONTACT Ca men Al a ez-Lo enzo [email p o ec ed] Depa amen o de Fa macología, Fa macia y Tecnología Fa macéu ica, I+D
Uni e sidade de San iago de Compos ela, 15782- San iago de Compos ela, Spain
EXPERT OPINION ON DRUG DELIVERY
2021, VOL. 18, NO. 11, 1589–1607
h ps://doi.o g/10.1080/17425247.2021.1953466
© 2021 The Au ho (s). Published by In o ma UK Limi ed, ading as Taylo & F ancis G oup.
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion-NonComme cial-NoDe i a i es License (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/),
which pe mi s non-comme cial e-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, and is no al e ed, ans o med, o buil upon in any way.
ad an ageous in e ms o p epa a ion and scale up because
only ew s eps and ene gy a e equi ed. Polyme ic micelles
ha e ou s anding capabili y o encapsula e hyd ophobic
d ugs inc easing appa en d ug solubili y, al hough conce ns
abou p ema u e disassembly may a ise [12]. Lipid-based esi-
cles, such as liposomes, may hos bo h hyd ophobic and
hyd ophilic ac i e subs ances [13], bu he cons i uen lipids
may be p one o chemical deg ada ion [14,15]. In his con ex ,
niosomes as esicles made o sel -assembled nonionic su ac-
an s may ga he he ad an ages o bo h micelles and lipo-
somes while p o iding imp o ed physical and chemical
s abili y. The de elopmen o niosomes as eye d ops compo-
nen s is s ill incipien , bu p elimina y esul s ha e e idenced
hei po en ial [16]. O he sup amolecula s uc u es such as
sel -assembling polypep ides ha e shown o be excellen d ug
ca ie s o o he adminis a ion ou es and may o e new
a enues in he ea men o eye diseases no only as ca ie s
bu also as he apeu ic agen s [17–19].
The aim o his e iew is o e isi i s he ole o diabe es
in he de elopmen o eye diseases. Then, he p os and cons
o di e en d ug adminis a ion ou es o diabe ic eye ea -
men s a e conside ed. Comme cially a ailable d ugs as well as
hose in clinical ials a e analyzed in de ail. Subsequen sec-
ions deal wi h he main sel -assembled nano- and mic o-
ca ie s sui able o opical eye adminis a ion, namely, poly-
me ic micelles, liposomes, and niosomes. Nanoca ie s o
ea men o diabe es-associa ed diseases using o he admin-
is a ion ou es ha e been ackled elsewhe e [20]. Finally,
ecen ad ances in he design o sel -assembled ca ie s o
opical diabe ic eye d ug adminis a ion a e p esen ed.
Publica ions con aining ex i o o in i o esul s o epo ing
on clinical ials ha e been p io i ized.
2. Diabe ic eye diseases
Diabe es may a ec he an e io segmen igge ing he de el-
opmen o ca a ac s, d y eye synd ome, co neal ulce s, wa s,
o uous conjunc i al essels, and ke a opa hy [4,21]. In he
pos e io segmen , diabe es may con ibu e o glaucoma, e i-
nopa hy, and macula edema [22]. Diabe ic pa ien s can also
su e om ocula neu opa hy, di icul ies in healing ocula
wounds, and inc eased in ec ion p obabili ies [4].
Ca a ac s a e desc ibed as he clouding o he lens. Th ee
pa hogenesis ou es ha e been desc ibed [23]: he polyol
pa hway whe e an accumula ion o so bi ol induces hyd opic
lens ibe degene a ion, he oxida i e and osmo ic s ess lead-
ing o apop osis o epi helial cells o he lens, and he au o-
immuni y. The polyol pa hway is he one e e ed o mos
o en and he mos esea ched [24]. Suga s (e.g. glucose and
galac ose) a ele a ed concen a ions a e a o able subs a es
o aldose educ ase and gene a e in ense osmo ic s ess (as
explained in Sec ion 3.1). Also, educing suga s p omo e gly-
ca ion (i.e. non-enzyma ic glycosyla ion) o lens p o eins, ig-
ge ing ca a ac o ma ion [25].
D y eye synd ome, which is cha ac e ized by an abno mal
ea ilm, can be classi ied as ei he aqueous ea -de icien o
e apo a i e (associa ed o a de icien ea ilm lipid laye ) [26].
Di ec co ela ions ha e been ound be ween p e alence o
he synd ome and glyca ed hemoglobin and du a ion o dia-
be es. In i o s udies sugges ha lach ymal glands unde go
his ological changes in diabe ic pa ien s and ha oxida i e
s ess de i ed om hype glycemia migh be in ol ed in d y
eye synd ome [27].
Co neal ulce s a e so es on he co nea ha can al e he
ision [28]. The p ima y cause o co neal ulce s may be un e-
la ed o diabe es (eye su ge y, acciden s), bu he leng hie
wound healing p ocess makes ulce s a hea ie bu den o
diabe ic pa ien s [29,30]. The apeu ic app oaches o deal
wi h diabe ic ke a opa hy ha e been e iewed elsewhe e [31].
Glaucoma is he leading cause o blindness wo ldwide and
is de ined by damage o he e inal ganglion cells, leading o
i e e sible damage o he op ic ne e [32]. This is o en
accompanied by a ise o he in aocula p essu e (IOP) ig-
ge ed h ough di e en mechanisms. Open-angle glaucoma is
caused by blocking o he abecula meshwo k, which in u n
hinde s luid d ainage and inc eases p essu e. This is he mos
common o m o glaucoma and happens a slow pace. Angle
closu e glaucoma is p o oked by he i is coming o wa d and
blocking he d ainage angle be ween he i is and he co nea.
I can happen o e ime o suddenly. Seconda y angle closu e
glaucoma, in which he angle can be opened o closed, is
caused by a seconda y ac o ha leads o d ainage hind ance,
o example excessi e pigmen elease blocking he abecula
meshwo k (pigmen a y glaucoma). Al hough he ole o dia-
be es is unclea , di ec co ela ions we e ound be ween
A icle highligh s
●Diabe es melli us cu en ly a ec s 8.5% people wo ldwide and causes
he highes los in yea s o quali y o li e due o disabili y.
●The e m ‘diabe ic eye disease’ has a b oad meaning as i may
encompass mul iple illnesses in di e en eye issues.
●Pha macological ea men s o diabe ic eye ely on educing he
in aocula p essu e, blocking he abno mal g ow h o blood essels,
o inhibi ing nega i e chemical pa hways.
●Mo e han hal a housand clinical s udies in phases 1–4 a e cu en ly
in p og ess wi h a a ie y o d ugs, biologics and gene he apy o
diabe ic eye diseases.
●Ch onic ocula ea men s demand d ug deli e y sys ems ha can
become an al e na i e o in aocula injec ions combining pa ien -
iendly adminis a ion and high ocula bioa ailabili y.
●D ug ca ie s o opical ins illa ion p e en om p ema u e deg ada-
ion, enhance he e en ion on eye su ace, and use al e na i e
pa hways o co nea and scle a pene a ion.
●Polyme ic micelles wi h hyd ophobic co e and hyd ophilic shell show
a pola i y g adien om inside o ou side acili a ing he encapsula-
ion o apola d ugs.
●Bilaye ed esicles o med by amphiphilic componen s assembled as
concen ic cell memb ane-like bilaye s show s epped apola -pola
egions, which allow o encapsula ion o bo h hyd ophilic and
hyd ophobic compounds.
●Niosomes as esicles made o sel -assembled nonionic su ac an s
ga he he ad an ages o micelles and liposomes while p o iding
imp o ed physical and chemical s abili y.
●The de elopmen o d ug-loaded niosomes as eye d ops is s ill
incipien , bu p elimina y esul s ha e e idenced hei po en ial.
●Despi e he success o sub e inal and in a i eal adminis a ion o
nioplexes, hei sui abili y o opical ocula adminis a ion is s ill o
be explo ed.
●This box summa izes key poin s con ained in he a icle.
1590 A. KATTAR ET AL.
diabe es du a ion and as ing glucose le els and he inc ease
in IOP [33].
Diabe ic e inopa hy in ol es damage o he e inal blood
essels, which has disas ous e ec s on he e ina [34]. In
nonp oli e a i e diabe ic e inopa hy, he e inal blood essels
a e damaged and s a leaking, which inc eases he p essu e in
he issue. This condi ion can p og ess om mic oaneu ysms
o se e e macula edema. In he p oli e a i e diabe ic e ino-
pa hy, he damaged blood essels close and new blood es-
sels s a o g ow abno mally. The consequences may include
inc eased IOP, accumula ion o sca issue, and ul ima ely
ne e damage. Diabe ic e inopa hy a ec s one ou o wo
pe sons wi h ype 1 diabe es [35]. The du a ion o diabe es is
a isk ac o , and he p e alence o diabe ic e inopa hy
inc eases om 8% a e 3 yea s o diabe es o 80% a e
15 yea s [36].
Diabe ic macula edema may be a consequence o diabe ic
e inopa hy, whe e leaking blood essels inc ease he luid
olume in he macula, esul ing in ision loss [37]. Two ypes
o diabe ic macula edema can be clinically di e en ia ed:
ocal macula edema, which is cha ac e ized by mic oaneu -
ysms on he e inal capilla ies, and di use macula edema,
which shows leakage om he blood- e inal ba ie due o
gene alized damage [38].
3. Deli e y o d ugs o diabe ic eye
3.1. Main d ug classes and cu en adminis a ion ou es
As desc ibed ea lie , diabe es- ela ed eye diseases a e a ied
and e ol e along ime o become ch onic. This means ha
hei ea men should be designed acco ding o he p o-
longed ime he d ug should be adminis e ed. In his ega d,
h ee main s a egies a e so a he mos in es iga ed and
used ones: (i) opical adminis a ion, mos ly o he ea men
o an e io segmen diseases, wi h he limi a ion o poo ocu-
la bioa ailabili y; (ii) in aocula adminis a ion, which is mo e
e icien in e ms o ocula bioa ailabili y bu en ails ele an
isks o he pa ien ; and (iii) o al adminis a ion, which is he
mos pa ien iendly ou e, bu he ocula bioa ailabili y is
qui e low e en when la ge doses a e adminis e ed. P os and
cons o he di e en adminis a ion ou es a e explained in
Table 1.
E icien ocula d ug deli e y is a di icul goal o each in
any case. Depending on he adminis a ion p ocedu e and he
dosage o m, ocula ba ie s can be ei he physiological o
ana omical, and ei he s a ic o dynamic [39]. Di e en ba ie s
loca ed in he an e io and he pos e io segmen s p o ec he
eye agains o eign subs ances coming om ou side o inside
he body (e.g. he bloods eam). Also, he goal o d ug deli e y
can be di e en depending on he a ge cells. I he d ug
mus each a issue p o ec ed by many ba ie s, d ug pe mea-
ion h ough hese ba ie s is c i ical; p od ugs, pene a ion
enhance s, and encapsula ion in nanoca ie s may be help ul
ools [40,41]. I he aim is o con inuously supply he d ug o
an a ea wi h impo an dynamic u no e o luids, sus ained
d ug deli e y sys ems may be equi ed [42].
Rega ding opical adminis a ion, he eye is dynamically
p o ec ed by he blinking e lex, he ea clea ance a e, and
he nasolac imal d ainage. Adhesion o he co neal su ace
and p omo ion o he pene a ion migh o e come hese
ba ie s. D ugs can ollow h ee ou es: co neal, scle al, and
conjunc i al [43–47]. Majo s a ic co neal ba ie s a e he co -
neal epi helium, which limi s he abso p ion o mac omole-
cules and hyd ophilic d ugs h ough igh junc ions, and he
co neal s oma, which limi s he pene a ion o lipophilic
molecules due o i s high aqueous con en [44]. Thus, mid-
lipophilic d ugs a e he mos sui able candida es o co neal
pene a ion and subsequen di usion h ough aqueous
humo o in aocula dis ibu ion. The i is and he nonpig-
men ed cilia y epi helium u he block d ugs om passing o
he aqueous humo , making make up he blood–aqueous
ba ie [47]. Fu he mo e, he aqueous humo low om he
cilia y body o he co nea coun e ac s he di usion o hyd o-
philic molecules ying o en e u he in he eye. On his
blood–aqueous ba ie and also on he co neal epi helium,
he e a e e lux pumps ha expel he d ugs back o he
on o he eye [48].
The conjunc i a opposes o d ug en y in he eye issues
mainly due o he p esence o conjunc i al blood capilla ies
and lymph essels, which e ou e a majo ac ion o he d ug
dose o he blood s eam. D ug access h ough he conjunc-
i a o he pos e io segmen may occu ia passi e o ac i e
anspo [45]. Al hough he e a e igh junc ions among con-
junc i al epi helium cells, pola solu es up o 20 kDa can en e
h ough pa acellula di usion ac oss 5-nm po es [49]. Pep ides
and p o eins may ind he addi ional ba ie o enzyma ic
deg ada ion and equi e co-adminis a ion wi h a p o ease
inhibi o [50]. Lipophilic d ugs can s ill pene a e be e ia
he anscellula ou e; he su ace a ea is la ge han o
pa acellula pa hway, al hough e lux pumps pose a ele an
challenge. In ense ac i e ca ie -media ed anspo occu s a
Table 1. Adminis a ion ou es o deli e y o d ugs o he eye.
Adminis a ion
ou e Ad an ages Disad an ages
Topical Nonin asi e app oach, well
accep ed by he pa ien
All ba ie s excep he
blood–eye ba ie s mus
be o e come
Sel -adminis a ion may
be no easible in all
cases
O al High pa ien compliance, no
co neal o an e io
segmen ba ie s
Sys emic un owa d e ec s,
blood- e inal ba ie , low
on-si e concen a ion
In acame al High d ug concen a ion in
he an e io chambe
Clinical injec ion
Subconjunc i al Scle al ou e o he e ina,
sui able o depo
o mula ions
Clinical injec ion
In a i eal High d ug concen a ion in
he pos e io segmen ,
hyd aulic p essu e
g adien
Clinical injec ion (mo e
in asi e han
subconjunc i al),
dependen on i eous
di usion, he isual axis
can be obscu ed i he
o mula ion is opaque
Re obulba Low isk o in ao bi al
inju y, low in luence on
IOP
Clinical injec ion, isk o
op ic ne e damage
Pe ibulba Low isk o in ao bi al inju y Clinical injec ion
Pos e io jux a
scle al
A ailable o inse s Re inal pigmen epi helium
is s ill a ba ie
EXPERT OPINION ON DRUG DELIVERY 1591
conjunc i a o some ions and nu ien s, which may be
exploi ed o d ug and p od ug abso p ion [46]. D ugs encap-
sula ed in nanoca ie s ake bene i o he addi ional pa hway
o endocy osis, which is easible bo h in co nea and conjunc-
i a [51–53].
Once conjunc i a is c ossed, he d ug can mo e h ough
scle a in o he u ea and he e inal pigmen ed epi helium, and
hen mo e o wa d o neu al e ina and i eous humo . The
scle a pe o ms as a size exclusion ba ie , wi h he pe me-
abili y dec easing exponen ially wi h molecula adius and
lipophilici y [54]. The scle a is nega i ely cha ged a physiolo-
gical pH and he e o e elec os a ic in e ac ions mus be con-
side ed oo. B uch’s–cho oid complex aps posi i ely cha ged
lipophilic d ugs [55], and since B uch’s memb ane becomes
less elas ic wi h age (due o calci ica ion o elas in and c oss-
linking o collagen) d ug di usion is hinde ed in elde ly
pa ien s.
Sys emic adminis a ion o ocula d ugs is comp omised by
he blood- e inal ba ie . The inne limi ing memb ane o he
e inal pigmen epi helium p e en s passage o high-
molecula -weigh molecules om blood o i eous and ice
e sa [56]. Mülle cells and as ocy es o m igh junc ions o
egula e he passage o molecules be ween he ou e cho oid
and he inne e ina. Al hough he in o ma ion on ocula
bioa ailabili y a e d ug sys emic adminis a ion in humans
is limi ed, some epo s e idenced ha o small d ugs, such as
cip o loxacin, simila d ug le els can be ob ained in aqueous
humo a e opical ins illa ion o he ee d ug o o al admin-
is a ion. The le els in i eous humo a e commonly highe
a e o al adminis a ion, bu a expenses o exposing he
whole o ganism o high d ug dose [57]. Also, in e es ingly,
he d ug can be ound in ea luid a e o al adminis a ion
bu no because o dis ibu ion h ough he eye, as epo ed
o cyclospo ine A [58]. The blood- e inal ba ie e icien ly
p e en s cyclospo ine A di usion om blood o he an e io
segmen , excep du ing concomi ance o in lamma o y p o-
cesses [59].
Pha macological ea men s in ended o s op ocula
damage caused by hype glycemia o a leas delay he p o-
cess ely on (i) educing IOP (Table 2), (ii) blocking he abno -
mal g ow h o blood essels, o (iii) inhibi ing nega i e
chemical pa hways. D ugs like p os aglandins [60], ho kinase
inhibi o s [61], ni ic oxides [62], o mio ic/choline gic agen s
[63] d ain ocula luids. Alpha-ad ene gic agonis s, β-blocke s,
and ca bonic anhyd ase inhibi o s lowe he amoun o luid
p oduced in he eye [64]. Bo h s a egies esul in a lowe ing
o he IOP and a e usually add essed using eye d ops (Table
2). Addi ionally, new d ug candida es a e in ended o ac on
he heme oxygenase 1 (HO-1)/ca bon monoxide (CO) physio-
logical pa hway ha egula es he IOP. The HO-1 p oduces
p o ec ion agains ischemic insul by p oducing CO, which has
an i-in lamma o y p ope ies. Inciden ally, CO p o ec s e inal
ganglion cells om ischemic/ epe usion inju y. Dec eased CO
le els ha e been ela ed o inc eased IOP and, he e o e,
d ugs ha elease CO may be use ul in glaucoma ea -
men [65].
The g ow h o abno mal ocula blood essels can be handled
wi h an i- ascula endo helial g ow h ac o (an i-VEGF) d ugs
[66]. Be acizumab and anibizumab, which a e espec i ely ull
an ibody and an ibody agmen ha bind VEGF-A, and a libe -
cep , a ecombinan p o ein ha aps VEGF-A and VEGF-B, a e
he co ne s ones o he he apy o diabe es- ela ed macula
edema and e inopa hy [67]. They equi e in a i eal injec ion,
which is no absen o complica ions [68]. In aocula injec ions
should be used as in equen ly as possible, acco ding o p o e
na a o ea -and-ex end p o ocols [69]. Biodeg adable deli e y
sys ems ha sus ain in aocula elease a oiding mul iple ea -
men and main aining d ug s abili y a e unde in es iga ion
[70,71]. Since each a ailable an i-VEGF agen in e ac s qui e
di e en ly wi h VEGF, cha ac e iza ion o he molecula in e ac-
ions can imp o e he design o no el biological d ugs po en-
ially use ul in clinical p ac ice [72].
Hype glycemia is also esponsible o igge ing he polyol
pa hway. Unde no moglycemic condi ions, he Embden–
Meye ho –Pa nas ca abolism ou e ha ans o ms glucose
in o py u a e, NADH, and ATP becomes sa u a ed.
Consequen ly, he polyol pa hway, which commonly ans o ms
3% glucose, en e s in o ac ion wi h he pa icipa ion o wo
enzymes: (i) aldose educ ase ha ans o ms glucose in o so -
bi ol wi h he consump ion o NADPH and (ii) so bi ol dehyd o-
genase ha slowly con e s so bi ol in o uc ose while
consuming NAD+. The polyol pa hway, which is e y ac i e in
e ina and lens, me abolizes mo e han 30% glucose unde
diabe ic condi ions [73]. Accumula ion o so bi ol causes osmo-
ic s ess, igge s leukocy e accumula ion, dis up s blood- e inal
ba ie , a o s cells apop osis, and s a s a cascade o oxida i e
s ess-media ed eac ions [74]. The excess o uc ose ac s as
p ecu so o ad anced glyca ion-end p oduc s (AGEs). In his
con ex , aldose educ ase inhibi o s a e gaining inc eased a en-
ion, and epal es a is app o ed in some coun ies o o al
adminis a ion. As an al e na i e, d ugs ha accele a e he
me abolic a e o so bi ol dehyd ogenase and, hus, dec ease
he le els o so bi ol a e being es ed [73].
In he la e s ages o he disease, lase ea men (mainly o
pho ocoagula ion) o su ge y (when blood essel leakage
becomes excessi e o he e is sca issue) can be p oposed
Table 2. Some ac i e subs ances o medicines used o educe he IOP. Da a
om he Eu opean Medicines Agency, h ps://www.ema.eu opa.eu/en/
medicines.
D ug class D ug Dosage o m
P os aglandin o analog T a op os Eye d op
Bima op os Eye d op
La anop os Eye d op
Unop os one Eye d op
P os aglandin analog ni ic
oxide
La anop os ene
bunod
Eye d op
Rho kinase inhibi o Ne a sudil Eye d op
Ripasudil Eye d op
Mio ic agen Piloca pine Eye d op
Choline gic agonis Ca bachol Eye d op o in aocula
injec ion
Alpha-ad ene gic agonis B imonidine Eye d op
Ap aclonidine Eye d op
Be a blocke Be axolol Eye d op o o al able
Timolol Eye d op
Ca eolol Eye d op
Ca bonic anhyd ase
inhibi o
Me hazolamide O al able
Ace azolamide Eye d op
B inzolamide Eye d op
Do zolamide Eye d op
1592 A. KATTAR ET AL.
[75,76]. Vi eo e inal su ge y, o example, in ol es he
emo al o pa o he i eous and sca issue in o de o
amelio a e he pa ien ’s ision [77].
3.2. D ugs, biologics, and gene he apy in clinical ials
Rele ance o he mo bidi y caused by diabe es on eye s uc-
u es is exempli ied by he 868 clinical s udies in phases 1 o 4
in Feb ua y 2021 when sea ching o ‘diabe ic eye’ in he
ClinicalT ials.go da abase. Re inemen o he in o ma ion o
selec ec ui ing, en olling, ac i e, e mina ed, o comple ed
ails ende ed an ou come o 657 s udies, wi h an ample
dis ibu ion wo ldwide (Figu e 1). Mos clinical ials a e
ocused on he e icacy and sa e y o new molecules o
no el adminis a ion ou es, d ug combina ions, o deli e y
sys ems such as implan s, mic opa icle depo o mula ions,
o biopolyme –an ibody conjuga es. Mic oneedle pa ches ha
can be applied on o co nea o scle a o di ec d ug deli e y in
he aqueous o i eous humo , espec i ely, a e gaining
inc easing in e es , al hough s ill in he p eclinical phase
[78–80].
Mos clinical ials ela ed o diabe ic eye e e o he con-
di ions macula edema (Table 3) and e inopa hy (Table 4),
and mos in e en ions deal wi h d ugs o biologics, pa icu-
la ly in a i eal injec ion o an ibodies. Howe e , he in e es
o o al adminis a ion as well as opical o mula ions does no
dec ease bu is gaining a en ion, spea headed by he sea ch
o no el ac i e subs ances wi h imp o ed ocula bioa ailabil-
i y and new he apeu ic a ge s. In ense esea ch on small
molecules ha pe o m as an i-in lamma o y (e.g. nepa emac,
lo ep ednol e abona e) o as an i-angiogenic/angioly ic (e.g.
EXN407, OC-10X) is being ca ied ou .
Fo co neal epi helial de ec s, clinical ials deal wi h com-
bina ions o an i-in lamma o y and an imic obial d ugs o
au ologous se um [81]. Fonadelpa (SJP 0035), a pe oxisome
p oli e a o -ac i a ed ecep o del a agonis , is in Phase III o
d y eyes and Phase II o co neal diso de s [82]. Topical insulin
and nal exone eye d ops ha e been shown o accele a e
co neal epi helial healing and amelio a e d y eye symp oms
in a a ie y o animal models [83,84]. Resul s o opical insulin
and nal exone clinical ials ha e no been pos ed ye [85,86].
Gene he apy o diabe ic eye diseases is also an ac i e ield
o esea ch and clinical ansla ion. The app o al o Lux u na®,
a i us-based gene deli e y sys em o inhe i ed e inal dys-
ophy, pa ed he oad o o he de elopmen s [87–89]. The e
a e cu en ly 492 ec ui ing o ac i e clinical ials on ocula
gene he apy, mos o which use adeno-associa ed i uses as
ca ie s, acco ding o ClinicalT ials.go , clinical ials egis e .eu
and c po al.niph.go.jp. Di e en ly o he epea ed adminis-
a ion o d ugs and biologics, gene he apy app oaches pu -
sue po en ial one- ime ea men , namely he cells a e
ins uc ed once o p oduce he needed he apeu ic subs ance
o o no p oduce he ha m ul subs ance. In he case o
diabe es- ela ed macula edema, h ee clinical ials wi h in a-
i eal o mula ions and one clinical ial wi h a sup acho oidal
o mula ion o gene he apy a e ongoing (Table 3). ADVM-022
(AAV.7m8-a libe cep ) and RGX-314 (AAV8 ec o con aining
a ansgene o an i-VEGF ab) a e in ended o p o ide du able
exp ession o an an i-VEFG an ibody [90,91]. RGX-314 is also
being es ed o diabe ic e inopa hy [92].
RNA in e e ence he apy is in clinical ials oo, al hough
i may equi e epea ed injec ions [93]. Fo example, iCo-007
is a single-s anded an isense ha deg ades messenge RNA
in ended o a ge c-Ra kinase o diabe ic macula edema
ea men . Phase II esul s using in a i eal injec ions we e
no conclusi e abou sa e y and e icacy [94]. PF-04523655
(RTP801I-14), a small-in e e ing RNA (siRNA) ha may inhi-
bi RTP801 gene ansc ip ion, is unde e alua ion as di ec
in a i eal injec ion. RTP801 is s ongly up egula ed in dia-
be ic eyes and is associa ed wi h hypoxia and s ess- ela ed
damage o e ina cells [95]. Gene he apy also o e s excel-
len oppo uni ies o add ess ocula in lamma ion igge ed
by so bi ol accumula ion and AGEs [74,96,97]. Gene he apy
may allow o egula ion o p o- and an i-in lamma o y
cy okines and neo ascula iza ion in ke a i is, as e iewed
elsewhe e [98].
Figu e 1. Regional dis ibu ion o clinical ials ela ed o diabe ic eye. Da a sou ce: ClinicalT ials.go . The e we e 657 ou comes o ‘diabe ic eye’ on Feb ua y 2021.
Applied il e s we e Rec ui ing, Ac i e no ec ui ing, Comple ed, En olling by in i a ion, and Te mina ed.
EXPERT OPINION ON DRUG DELIVERY 1593
Table 3. Pha macological ea men s in clinical ials o diabe es- ela ed macula edema classi ied as a unc ion o he adminis a ion ou e, d ug/biologic ac i e
subs ance, and numbe o clinical s udies.
Adminis a ion
ou e D ug/Biologic class Ac i e subs ance
Numbe o clinical
ials
In a i eal An ibodies o
blocke s
A libe cep and biosimila s 42
An i-angiopoie in-2 an ibody REGN910 1
REGN910-3 (co- o mula ion o REGN910 and a libe cep ) 1
An i-e y h opoie in LKA651 1
An i-PlGF ecombinan monoclonal an ibody 1
An i-ROBO
4
an ibody DS-7080a 1
Be acizumab 16
Be asi anib 1
To aci inib (BI 764,524) 1
Conbe cep (KH902) 1
Fa icimab 1
In liximab, an i-TNFα 1
OPT-302, an i-VEGF-C and an i-VEGF-D 1
Pegap anib 7
Ranibizumab 40
Tep o umumab 1
Small molecules Dexame hasone 31
Fluocinolone ace onide 9
T iamcinolone ace onide 11
An i-VEGF d ugs 7
KVD001 plasma kallik ein inhibi o 2
AR-13,503, small-molecule inhibi o o bo h Rho kinase and p o ein kinase C 1
UBX1325, inhibi o o Bcl-xL (an i-apop o ic egula o y p o ein) 1
Pep ides AXT107, y osine kinase blocking collagen IV–de i ed pep ide 1
Lumina e (Alg-1001) in eg in inhibi o 1
P o eases Oc iplasmin 1
Gene he apy ADVM-022 gene he apy (AAV.7m8-a libe cep ) 1
iCo-007, a single-s anded an isense ha deg ades messenge RNA (mRNA) 1
PF-04523655, small-in e e ing RNA (siRNA) 1
O al Small molecules GSK2798745, ansien ecep o po en ial anilloid 4 (TRPV4) channel blocke 1
Aliski en 1
Danazol 1
Feno ib a e/pema ib a e 2
Ima inib mesyla e (YD312) 1
Le osulpi ide 1
Minocycline 1
MS-533 p o ein kinase inhibi o 1
Ruboxis au in 1
Semaglu ide 1
Die a y supplemen s Alze ®, Diamel®, o he s 2
Topical eyed ops Small molecules B om enac 1
Dexame hasone 2
Diclo enac 1
EXN407, speci ic se ine/ h eonine-p o ein kinase 1 (SRPK1) inhibi o 1
FOV2304, inhibi o o b adykinin B1 ecep o 1
Fluocinolone ace onide 1
Ke o olac 3
Nepa enac 5
OC-10X ubulin inhibi o 1
Lo ep ednol e abona e 1
Mecamylamine nonspeci ic nACh ecep o blocke 1
SF0166 small-molecule α β3 an agonis 1
Vi amin E 2
Pep ides Elamip e ide (MTP-131), mi ochond ia- a ge ing pep ide 1
In a enous Small molecules Me ho exa e 1
In amuscula Pep ides Oc eo ide ace a e in mic osphe es 1
Episcle al Small molecules Dexame hasone implan 1
Subconjunc i al An ibody Be acizumab 1
Small molecule Rapamycin 2
Subcu aneous Small molecule Razup o a ib (AKB-9778), inhibi o o VE-PTP ( ascula endo helial p o ein y osine
phospha ase)
2
Sub-macula An ibodies Ranibizumab 1
Sup acho oidal Gene he apy RGX-314 (AAV8 ec o con aining a ansgene o an i-VEGF ab) 1
Da a sou ce: ClinicalT ials.go . Ou comes o ‘diabe ic eye AND macula edema’ on Feb ua y 2021. Applied il e s we e Rec ui ing, Ac i e no ec ui ing, Comple ed,
En olling by in i a ion, and Te mina ed.
1594 A. KATTAR ET AL.
4. Sel -assembled nanoca ie s o opical diabe ic
eye d ugs
Mos o d ugs and new d ug candida es in clinical ials o
diabe ic eye he apy, as e e ed in Tables 3 and Table 4, a e
qui e hyd ophobic and mus be o mula ed as suspensions o
oin men s, showing limi ed ocula bioa ailabili y a e ins illa-
ion. Thus, nonin asi e opical he apeu ic app oaches may be
no ably imp o ed i he d ugs a e o mula ed in o deli e y
sys ems ha could enhance hei solubili y and ocula pe ma-
nence. In p eclinical es s, micelles and cyclodex in agg e-
ga es ha e been shown o enhance co nea and scle a
accumula ion and pe mea ion o a ious hyd ophobic diabe ic
eye d ugs [99–101]. E en in he sea ch o no el deli e y
s a egies, con ac lenses ha e been designed speci ically o
deli e epal es a [102] and nal exone [103] and i al-based
gene ec o s [104]. Rega ding in a i eal gene he apy,
siRNAs a e ex emely labile and apidly clea ed, and hus
demand adequa e nanoca ie s. Howe e , mos non- i al ec-
o s a e s ongly ca ionic polyme s o lipids ha may in e ac
wi h nega i ely cha ged glycosaminoglycans in he i eous
humo . Such an in e ac ion may p ema u ely b eak he poly/
lipoplexes o al e he cell ans ec ion and, hus, a e y ine
equilib ium in su ace cha ge o a shell able o minimize
e en ion in i eous is equi ed [105,106].
Table 4. Pha macological ea men s in clinical ials o diabe es- ela ed e inopa hy classi ied as a unc ion o he adminis a ion ou e, d ug/biologic ac i e
subs ance, and numbe o clinical s udies.
Adminis a ion
ou e
D ug/Biologic
class Ac i e subs ance
Numbe o
clinical ials
In a i eal An ibodies o
blocke s
A libe cep and biosimila s 14
An i-PlGF ecombinan monoclonal an ibody 1
Be acizumab 14
To aci inib (BI 764,524) 1
Conbe cep (KH902) 2
Pegap anib 2
Ranibizumab 20
Small
molecules
Dexame hasone 3
T iamcinolone ace onide 5
An i-VEGF D ugs 1
Gene he apy PF-04523655, small-in e e ing RNA (siRNA) 1
O al Small
molecules
Ace azolamide 1
Alpha-lipoic acid 1
Aminoguanidine 1
B imonidine 1
Da apladib 1
Doxycycline 1
Emixus a hyd ochlo ide 1
Empagli ozin 1
Feno ib a e/pema ib a e 3
Fine enone 1
Mela onin 1
RG7774 1
Ruboxis au in 2
Semaglu ide 1
Sineme 1
Sulodexide 1
Tien ine 1
Ubiquinone 1
Die a y
supplemen s
Alpha-lipoic acid, ca o enoid i amins, omega 3, mul i-componen nu i ional supplemen ( i amin C, mixed
ocophe ols/ oco ienols, i amin D, ish oil, lu ein, zeaxan hin, pine ba k ex ac , ben o iamine, g een ea
ex ac , cu cumin), Ocu olin®
5
Topical
eyed ops
Small
molecules
Aneco a e ace a e 1
Ci icoline 1
Cu cumin, homo au ine, and i amin D3 1
Dexame hasone 1
Diclo enac 1
Do zolamide 1
Ke o olac 3
La anop os 2
Napa enac 3
OC-10X ubulin inhibi o 2
P ednisolone ace a e 2
Squalamine lac a e 1
TG100801 mul ikinases inhibi o 1
Pep ides Soma os a in (wi h b imonidine) 1
In a enous P o ein Pulsa ile insulin 2
In amuscula Pep ides Oc eo ide ace a e in mic osphe es 4
Subconjunc i al Small molecule Rapamycin 1
Subcu aneous Small molecule Razup o a ib (AKB-9778), inhibi o o VE-PTP ( ascula endo helial p o ein y osine phospha ase) 1
Sup acho oidal Gene he apy RGX-314 (AAV8 ec o con aining a ansgene o an i-VEGF ab) 1
Da a sou ce: ClinicalT ials.go . Ou comes o ‘diabe ic eye AND e inopa hy’ on Feb ua y 2021. Applied il e s we e Rec ui ing, Ac i e no ec ui ing, Comple ed,
En olling by in i a ion, and Te mina ed.
EXPERT OPINION ON DRUG DELIVERY 1595
Sel -assembled d ug ca ie s ha can be p epa ed in ew
s eps and can encapsula e bo h small and la ge ac i e sub-
s ances, while p o iding a highly biocompa ible, s eal h in e -
ace a e gaining inc easing a en ion o ocula deli e y.
Al hough a ple ho a o no el sel -assembled ca ie s a e
being es ed, polyme ic micelles, liposomes, and niosomes
ha e al eady demons a ed in i o p omising pe o mances
[13,16,99,107]. Below, i s he a iables ha d i e he o ma-
ion o hese ca ie s and he main p epa a ion p o ocols a e
e isi ed. Then, speci ic applica ions o managemen o dia-
be ic eye diseases a e analyzed.
4.1. The sel -assembly p ocess
Sel -assembled ca ie s ely on amphiphilic componen s ha
bea egions o di e en a ini y o wa e [108]. The simples
sel -assembled s uc u e is ha o common su ac an
micelles. In con ac wi h wa e , small su ac an s mo e o he
ai –wa e in e ace wi h he pola head imme sed in wa e
Figu e 2. Dependence o he a chi ec u e o he sel -assembled nanoca ie on he c i ical packing pa ame e (CPP).
Figu e 3. P oges e one (PG) appa en solubili y in Soluplus and Plu onic F68 micelles, and pe meabili y coe icien s o co nea and scle a eco ded o PG
encapsula ed in Soluplus 20% micelles o Plu onic F68 20% micelles. Rep oduced om Alambiaga-Ca a aca e al. [126] (C ea i e Commons A ibu ion License).
1596 A. KATTAR ET AL.
employmen , consul ancies, hono a ia, s ock owne ship o op ions, expe
es imony, g an s o pa en s ecei ed o pending, o oyal ies.
Re iewe disclosu es
Pee e iewe s on his manusc ip ha e no ele an inancial o o he
ela ionships o disclose.
ORCID
Axel Ka a h p://o cid.o g/0000-0002-5892-5933
Angel Conchei o h p://o cid.o g/0000-0003-0507-049X
Ca men Al a ez-Lo enzo h p://o cid.o g/0000-0002-8546-7085
Re e ences
Pape s o special no e ha e been highligh ed as ei he o in e es (•) o o
conside able in e es (••) o eade s.
1. Lin X, Xu Y, Pan X, e al. Global, egional, and na ional bu den and
end o diabe es in 195 coun ies and e i o ies: an analysis om
1990 o 2025. Sci Rep. 2020;10:14790.
2. G eine W, Pa el K, C ossman-Ba nes CJ, e al. High-expendi u e dis-
ease in he EU-28: does d ug spend co espond o clinical and eco-
nomic bu den in oncology, au oimmune disease and diabe es?
Pha macoecon Open. 2021. DOI:10.1007/s41669-020-00253-4
3. Na ional Ins i u e o Diabe es and Diges i e and Kidney Diseases.
Diabe ic Eye Disease. [ci ed Feb 2021]. h ps://www.niddk.nih.go /
heal h-in o ma ion/diabe es/o e iew/p e en ing-p oblems/dia
be ic-eye-disease
4. Zhu L, Ti one R, Robe son DM. The impac o hype glycemia on
he co neal epi helium: molecula mechanisms and insigh . Ocul
Su . 2019;17:644–654.
5. Sayin N. Ocula complica ions o diabe es melli us. Wo ld
J Diabe es. 2015;6:92.
6. Han SB, Yang HK, Hyon JY. In luence o diabe es melli us on an e-
io segmen o he eye. Clin In e Aging. 2019;14:53–63.
7. Gi i B, Dey S, Das T, e al. Ch onic hype glycemia media ed physio-
logical al e a ion and me abolic dis o ion leads o o gan dys unc-
ion, in ec ion, cance p og ession and o he pa hophysiological
consequences: an upda e on glucose oxici y. Biomed
Pha maco he . 2018;107:306–328.
8. Madni A, Rahem MA, Tahi N, e al. Non-in asi e s a egies o
a ge ing he pos e io segmen o eye. In J Pha m.
2017;530:326–345.
9. Jumelle C, Gholizadeh S, Annabi N, e al. Ad ances and limi a ions
o d ug deli e y sys ems o mula ed as eye d ops. J Con ol
Release. 2020;321:1–22.
• Recen e iew on he mos ecen ad ances in deli e y sys ems
o opical eye adminis a ion and he challenges o each he
ma ke .
10. Liu S, Jones L, Gu FX. Nanoma e ials o ocula d ug deli e y.
Mac omol Biosci. 2012;12:608–620.
11. Mazu eki Campos P, Pe illi R, Lopez RFV. The p ominence o he
dosage o m design o ea ocula diseases. In J Pha m.
2020;586:119577.
12. Pola H, Ku luay G, Pola M. Analysis o dilu ion induced disin eg a-
ion o micella d ug ca ie s in he p esence o in e and in a
micella species. Colloid Su A-Physicochem Eng Asp.
2020;601:124989.
13. López-Cano JJ, González-Cela-Casamayo MA, And és-Gue e o V,
e al. Liposomes as ehicles o opical oph halmic d ug deli e y
and ocula su ace p o ec ion. Expe Opin D ug Deli . 2021;18
(7):819–847.
• Recen e iew on he design o liposomes o ocula d ug
deli e y.
14. FDA. Liposome D ug P oduc s. Guidance o Indus y. Ap il 2018.
[ci ed Feb 2021]. h ps://www. da.go /media/70837/download
15. Delma KL, Lechan eu A, E a d B, e al. S e iliza ion me hods o
liposomes: d awbacks o con en ional me hods and pe spec i es.
In J Pha m. 2021;597:120271.
16. Du ak S, Rad ME, Ye isgin AA, e al. Niosomal d ug deli e y sys ems
o ocula disease— ecen ad ances and u u e p ospec s.
Nanoma e ials. 2020;10:1191.
• Recen e iew on he design o niosomes o ocula d ug
deli e y.
17. MacEwan SR, Chilko i A. Applica ions o elas in-like polypep ides in
d ug deli e y. J Con ol Release. 2014;190:314–330.
18. Cas illo-Díaz LA, Ruiz-Pacheco JA, Elsawy MA, e al. Sel -assembling
pep ides as an eme ging pla o m o he ea men o me abolic
synd ome. In J Nanomed. 2020;15:10349–10370.
19. S eekuma PG, Kannan R. Mechanisms o p o ec ion o e inal
pigmen epi helial cells om oxidan inju y by humanin and
o he mi ochond ial-de i ed pep ides: implica ions o age- ela ed
macula degene a ion. Redox Biol. 2020;37:101663.
20. Kesha wani P, Go ain B, Low SY, e al. Nano echnology based
app oaches o an i-diabe ic d ugs deli e y. Diabe es Res Clin
P ac . 2018;136:52–77.
21. Adeo i CO, Isawumi MA, Ashaye AO, e al. The an e io segmen o
he eye in diabe es. Clin Oph halmol. 2012;6:667–671.
22. Lu y GA. E ec s o diabe es on he eye. In es ig Oph halmol Vis
Sci. 2013;54:81–87.
23. Kizil op ak H, Tekin K, Inanc M, e al. Ca a ac in diabe es melli us.
Wo ld J Diabe es. 2019;10:140–153.
24. Poll eisz A, Schmid -E u h U. Diabe ic ca a ac —pa hogenesis,
epidemiology and ea men . J Oph halmol. 2010;2010:1–8.
25. Abdelkade H, Alany RG, Pie scionek B. Age- ela ed ca a ac and
d ug he apy: oppo uni ies and challenges o opical an iox-
idan deli e y o he lens. J Pha m Pha macol. 2015;67:537–550.
26. Zhang X, Zhao L, Deng S, e al. D y eye synd ome in pa ien s wi h
diabe es melli us: p e alence, e iology, and clinical cha ac e is ics.
J Oph halmol. 2016;2016:8201053.
27. Módulo CM, Jo ge AG, Dias AC, e al. In luence o insulin ea men
on he lac imal gland and ocula su ace o diabe ic a s. Endoc ine.
2009;36:161–168.
28. Hyndiuk RA, Kaza ian EL, Schul z RO, e al. Neu o ophic co -
neal ulce s in diabe es melli us. A ch Oph halmol.
1977;95:2193–2196.
29. Ioannidis AS, Zago a SL, Wechsle AW. A non-healing co neal ulce
as he p esen ing ea u e o ype 1 diabe es melli us: a case epo .
J Med Case Rep. 2011;5:539.
30. Xu KP, Li Y, Ljubimo AV, e al. High glucose supp esses epide mal
g ow h ac o ecep o / phospha idylinosi ol 3-kinase/ak signaling
pa hway and a enua es co neal epi helial wound healing.
Diabe es. 2009;58:1077–1085.
31. Abdelkade H, Pa el DV, McGhee CN, e al. New he apeu ic
app oaches in he ea men o diabe ic ke a opa hy: a e iew.
Clin Exp Oph halmol. 2011;39:259–270.
32. Wein eb RN, Aung T, Medei os FA. The pa hophysiology and ea -
men o glaucoma. JAMA. 2014;311:1901.
33. Zhao D, Cho J, Kim MH, e al. Diabe es, as ing glucose, and he isk
o glaucoma: a me a-analysis. Oph halmology. 2015;122:72–78.
34. Rübsam A, Pa ikh S, Fo PE. Role o in lamma ion in diabe ic
e inopa hy. In J Mol Sci. 2018;19:1–31.
35. Ma hu R, Douglas I, Bhaska an K, e al. Diabe ic eye disease: a UK
Incidence and P e alence S udy; 2017. [ci ed Feb 2021]. h ps://
www. nib.o g.uk/si es/de aul / iles/Diabe ic%20eye%20disease.%
20A%20UK%20Incidence%20and%20P e alence%20S udy%20-%
20Full%20 epo .pd
36. Fong DS, Aiello L, Ga dne TW, e al. Re inopa hy in diabe es.
Diabe es Ca e. 2004;27:S84–87.
37. Bandello F, Pognuz R, Poli o A, e al. Diabe ic macula edema:
classi ica ion, medical and lase he apy. Semin Oph halmol.
2003;18:251–258.
EXPERT OPINION ON DRUG DELIVERY 1603
38. B owning DJ, Al aweel MM, B essle NM, e al. Diabe ic e inopa hy
clinical esea ch ne wo k. Diabe ic macula edema: wha is ocal
and wha is di use? Am J Oph halmol. 2008;146:649–655.
39. Ag aha i VV, Mandal A, Ag aha i VV, e al. A comp ehensi e
insigh on ocula pha macokine ics. D ug Deli T ansl Res.
2016;6:735–754.
40. Go e V, Ansong M, Pal D. P od ugs and nanomicelles o o e come
ocula ba ie s o d ug pene a ion. Expe Opin D ug Me ab
Toxicol. 2020;16:885–906.
• Recen e iew on he pe o mance o micelles o ocula d ug
deli e y.
41. Tha eja A, Hughes H, Al a ez-Lo enzo C, e al. Pene a ion enhan-
ce s o opical d ug deli e y o he ocula pos e io segmen –
a sys ema ic e iew. Pha maceu ics. 2021;13:276.
42. Sub izi A, del Amo EM, Ko zhiko -Vlakh V, e al. Design p inciples o
ocula d ug deli e y sys ems: impo ance o d ug payload, elease
a e, and ma e ial p ope ies. D ug Disco Today.
2019;24:1446–1457.
43. Ma i K, Ki si H, Seppo K, e al. Cha ac e iza ion o pa acellula and
aqueous pene a ion ou es in co nea, conjunc i a, and scle a.
In es Oph halmol Vis Sci. 1997;38:627–634.
44. Gaudana R, Anan hula HK, Pa enky A, e al. Ocula d ug deli e y.
AAPS J. 2010;12:348–360.
45. Lee SJ, He W, Robinson SB, e al. E alua ion o clea ance mechan-
isms wi h ansscle al d ug deli e y. In es Oph halmol Vis Sci.
2010;51:5205–5212.
46. Hosoya K, Lee VHL, Kim KJ. Roles o he conjunc i a in ocula d ug
deli e y: a e iew o conjunc i al anspo mechanisms and hei
egula ion. Eu J Pha m Biopha m. 2005;60:227–240.
47. Delama e NA. Cilia y body and cilia y epi helium. Ad O gan Biol.
2005;10:127–148.
48. Dahlin A, Geie E, S ocke SL, e al. Gene exp ession p o iling o
anspo e s in he solu e ca ie and ATP-binding casse e supe -
amilies in human eye subs uc u es. Mol Pha m. 2013;10:650–663.
49. Ho ibe Y, Hosoya K, Kim KJ, e al. Pola solu e anspo ac oss he
pigmen ed abbi conjunc i a: size dependen and he in luence o
8-b omo cyclic adenosine monophospha e. Pha m Res.
1997;14:1246–1251.
50. Sun L, Basu SK, Kim KJ, e al. A ginine asop essin anspo and
me abolism in he pigmen ed abbi conjunc i a. Eu J Pha m Sci.
1998;6:47–52.
51. Liu D, Lian Y, Fang Q, e al. Hyalu onic-acid-modi ied lipid-polyme
hyb id nanopa icles as an e icien ocula deli e y pla o m o
moxi loxacin hyd ochlo ide. In J Biol Mac omol.
2018;116:1026–1036.
52. Qaddoumi MG, Gukasyan HJ, Da da J, e al. Cla h in and ca eolin-1
exp ession in p ima y pigmen ed abbi conjunc i al epi helial
cells: ole in PLGA nanopa icle endocy osis. Mol Vis.
2003;9:559–568.
53. Mülle -Lie heim WGK. Why chain leng h o hyalu onan in eye d ops
ma e s. Diagnos ics. 2020;10:511.
54. Amba i J, Adamis AP. T ansscle al d ug deli e y o he e ina and
cho oid. P og Re in Eye Res. 2002;21:145–151.
55. Che u u NPS, Kompella UB. Bo ine and po cine ansscle al solu e
anspo : in luence o lipophilici y and he cho oid-B uch’s laye .
In es Oph halmol Vis Sci. 2006;47:4513–4522.
56. Ramsay E, Hags öm M, Vellonen KS, e al. Role o e inal pigmen
epi helium pe meabili y in d ug ans e be ween pos e io eye
segmen and sys emic blood ci cula ion. Eu J Pha m Biopha m.
2019;143:18–23.
57. Çekiç O, Ba man C, Yasa U, e al. Human aqueous and i eous
humou le els o cip o loxacin ollowing o al and opical
adminis a ion. Eye. 1999;13:555–558.
58. Mo a P, Cegla ek U, Manzo i F, e al. Cyclospo in A in he ocula
luids o u ei is pa ien s ollowing long- e m sys emic adminis a-
ion G ae e’s A ch. Clin Exp Oph halmol. 2008;246:1047–1052.
59. BenEz a D, Ma zi G, De Cou en C, e al. Ocula pene a ion o
cyclospo ine A. III: he human eye. B J Oph halmol.
1990;74:350–352.
60. To is CB, Gabel BT, Kau man PL. Upda e on he mechanism o
ac ion o opical p os aglandins o in aocula p essu e educ ion.
Su Oph halmol. 2008;53(Supplemen 1):107–120.
61. Moshi a M, Pa ke L, Bi dsong OC, e al. Use o ho kinase inhibi-
o s in oph halmology: a e iew o he li e a u e. Med Hypo hesis
Disco Inno Oph halmol J. 2018;7:101–111.
62. Muens e S, Lieb WS, Fab y G, e al. The abili y o ni ic oxide o
lowe in aocula p essu e is dependen on guanylyl cyclase. In es
Oph halmol Vis Sci. 2017;58:4826–4835.
63. Faiq MA, Wolls ein G, Schuman JS, e al. Choline gic ne ous sys-
em and glaucoma: om basic science o clinical applica ions. P og
Re in Eye Res. 2019;72:100767.
64. Schmidl D, Schme e e L, Ga hö e G, e al. Pha maco he apy o
glaucoma. J Ocul Pha macol The . 2015;31:63–77.
65. Bucolo C, D ago F. Ca bon monoxide and he eye: implica ions o
glaucoma he apy. Pha macol The . 2011;130:191–201.
66. Akiyode O, T an C. O e iew o ocula an i- ascula endo helial
g ow h ac o he apy in he managemen o diabe ic eye
complica ions. Diabe es Spec . 2016;29:44–49.
67. Gale MJ, Sc uggs BA, Flaxel CJ. Diabe ic eye disease: a e iew o
sc eening and managemen ecommenda ions. Clin Exp
Oph halmol. 2021;49:128–145.
68. Smi h SJ, Smi h BD, Mohney BG. Ocula side e ec s ollowing
in a i eal injec ion he apy o e inoblas oma: a sys ema ic
e iew. B J Oph halmol. 2014;98:292–297.
69. Augsbu ge M, Sa a GM, Imesch P. T ea and ex end e sus p o e
na a egimens o anibizumab and a libe cep in neo ascula age-
ela ed macula degene a ion: a compa a i e s udy G ae e’s. A ch
Clin Exp Oph halmol. 2019;257:1889–1895.
70. Radhak ishnan K, Sonali N, Mo eno M, e al. P o ein deli e y o he
back o he eye: ba ie s, ca ie s and s abili y o an i-VEGF p o eins.
D ug Disco Today. 2017;22:416–423.
71. Con i B, Bucolo C, Gianna ola C, e al. Biodeg adable mic osphe es
o he in a i eal adminis a ion o acyclo i : in i o/in i o
e alua ion. Eu J Pha m Sci. 1997;5:287–293.
72. Pla ania CB, Di Paola L, Leggio GM, e al. Molecula ea u es o
in e ac ion be ween VEGFA and an i-angiogenic d ugs used in
e inal diseases: a compu a ional app oach. F on Pha macol.
2015;6:248.
73. Pa il KK, Gacche RN. The a e o aldose educ ase inhibi ion and
so bi ol dehyd ogenase ac i a ion. Aus in J Endoc inol Diabe es.
2019;6:1064.
74. Ob oso a IG, Kado PF. Aldose educ ase/polyol inhibi o s o dia-
be ic e inopa hy. Cu Pha m Bio echnol. 2011;12:373–385.
75. E ans JR, Michelessi M, Vi gili G. Lase pho ocoagula ion o p o-
li e a i e diabe ic e inopa hy. Coch ane Da abase Sys Re .
2014;2014:CD011234.
76. C osson JN, Mason L, Mason JO. The ole o ocal lase in he
an i- ascula endo helial g ow h ac o e a. Oph halmol Eye Dis.
2017;9:1179172117738240.
77. Papas e anou VP, Dooley I, Zamba akji H. Managemen o macula
edema in i ec omized pa ien s wi h diabe es. Expe Re
Oph halmol. 2018;13:87–103.
78. Thaku RRS, Tekko IA, Al-Shamma i F, e al. Rapidly dissol ing
polyme ic mic oneedles o minimally in asi e in aocula d ug
deli e y. D ug Deli T ansl Res. 2016;6:800–815.
79. Roy G, Galigama RD, Tho a VS, e al. Mic oneedle ocula pa ch:
ab ica ion, cha ac e iza ion, and ex- i o e alua ion using piloca -
pine as model d ug. D ug De Ind Pha m. 2020;46:1114–1122.
80. Ame M, Chen RK. Sel -adhesi e mic oneedles wi h in e locking
ea u es o sus ained ocula d ug deli e y. Mac omol Biosci.
2020;20:2000089.
81. Chen YM, Hu FR, Huang JY, e al. The e ec o opical au ologous
se um on g a e-epi helializa ion a e pene a ing ke a oplas y.
Am J Oph halmol. 2010;150:352–359.e2.
82. A s udy o assess he sa e y and e ec i eness o sjp-0035 o he
ea men o pa ien s wi h d y eye disease. h ps://clinical ials.go /
c 2/show/NCT03527212
83. Klocek MS, Sassani JW, McLaughlin PJ, e al. Nal exone and insulin
a e independen ly e ec i e bu no addi i e in accele a ing co neal
1604 A. KATTAR ET AL.
epi helial healing in ype I diabe ic a s. Exp Eye Res.
2009;89:686–692.
84. Ionascu I, A gaseala A, Uzun S, e al. A new eye d op o mula ion
used in he managemen o co neal ulce s in dogs and ca s.
Ag oli e Sci J. 2020;9:164–171.
85. Topical Au ologous Insulin Applica ion o he T ea men o
Co neal Epi helium De ec A e Ocula Su ge ies. h ps://clinical
ials.go /c 2/show/s udy/NCT01031888? e m= opical+insulin&
d aw=2& ank=2
86. E ec o Topical Nal exone Oph halmic Solu ion on he Signs and
Symp oms o D y Eye in Diabe ic Subjec s. h ps://ClinicalT ials.
go /show/NCT03660475
87. Keele AM, Flo e TR. Recombinan adeno-associa ed i us gene
he apy in ligh o Lux u na (and Zolgensma and Glybe a): whe e
a e we, and how did we ge he e? Annu. Re Vi ol. 2019;6:601–621.
88. Au icchio A, Smi h AJ, Ali RR. The u u e looks b igh e a e 25
yea s o e inal gene he apy. Hum Gene The . 2017;28:982–987.
89. Bas ola P, Song LJ, Gilge BC, e al. Adeno-associa ed i us
media ed gene he apy o co neal diseases. Pha maceu ics.
2020;12:767.
90. ADVM-022 In a i eal Gene The apy o DME (INFINITY). h ps://
ClinicalT ials.go /show/NCT04418427
91. Liu Y, Fo mann SD, Shen J, e al. AAV8-an iVEGF ab ocula gene
ans e o neo ascula age- ela ed macula degene a ion. Mol
The . 2018;26:542–549.
92. RGX-314 Gene The apy Adminis e ed in he Sup acho oidal Space
o Pa icipan s Wi h Diabe ic Re inopa hy (DR) Wi hou Cen e
In ol ed-Diabe ic Macula Edema (CI-DME) (ALTITUDE). h ps://clin
ical ials.go /c 2/show/ eco d/NCT04567550
93. Jiang J, Zhang X, Tang Y, e al. P og ess on ocula siRNA
gene-silencing he apy and d ug deli e y sys ems. Fundam Clin
Pha macol. 2021;35:4–24.
94. A andomized, mul i-cen e , phase ii s udy o he sa e y, ole -
abili y and bioac i i y o epea ed in a i eal injec ions o
iCo-007 as mono he apy o in combina ion wi h anibizumab
o lase pho ocoagula ion in he ea men o diabe ic macula
edema ( he iDEAL S udy) (iDEAL). h ps://ClinicalT ials.go /show/
NCT01565148
95. Ri enhouse KD, Johnson TR, Vicini P, e al. RTP801 gene exp ession
is di e en ially up egula ed in e inopa hy and is silenced by
PF-04523655, a 19-Me siRNA di ec ed agains RTP801. In es
Oph halmol Vis Sci. 2014;55:1232–1240.
96. Kallinikou D, Solda ou A, Tsen idis C, e al. Diabe ic neu opa hy in
child en and adolescen s wi h ype 1 diabe es melli us: diagnosis,
pa hogenesis, and associa ed gene ic ma ke s. Diabe es Me ab Res
Re . 2019;35:e3178.
97. Papach is o o ou E, Lambadia i V, Ma a ou E, e al. Associa ion o
glycemic indices (hype glycemia, glucose a iabili y, and hypogly-
cemia) wi h oxida i e s ess and diabe ic complica ions. J Diabe es
Res. 2020;2020:7489795.
98. To ecilla J, del Pozo-Rod íguez A, Vicen e-Pascual M, e al.
Ta ge ing co neal in lamma ion by gene he apy: eme ging s a e-
gies o ke a i is. Exp Eye Res. 2018;176:130–140.
99. Mandal A, Bish R, Rupen hal ID, e al. Polyme ic micelles o ocula
d ug deli e y: om s uc u al amewo ks o ecen p eclinical
s udies. J Con ol Release. 2017;248:96–116.
100. Al a ez-Ri e a F, Fe nandez-Villanue a D, Conchei o A, e al. α-
Lipoic acid in Soluplus® polyme ic nanomicelles o ocula ea -
men o diabe es-associa ed co neal diseases. J Pha m Sci.
2016;105:2855–2863.
101. Lo sson T, S e ansson E. Cyclodex ins and opical d ug deli e y o
he an e io and pos e io segmen s o he eye. In J Pha m.
2017;531:413–423.
102. Al a ez-Ri e a F, Conchei o A, Al a ez-Lo enzo C. Epal es a -loaded
silicone hyd ogels as con ac lenses o add ess diabe ic-eye
complica ions. Eu J Pha m Biopha m. 2018;122:126–136.
103. Al a ez-Ri e a F, Se o AP, Sil a D, e al. Hyd ogels o diabe ic eyes:
nal exone loading, elease p o iles and co nea pene a ion. Ma e
Sci Eng C. 2019;105:110092.
104. Al a ez-Ri e a F, Rey-Rico A, Venka esan JK, e al. Con olled
elease o AAV ec o s om APMA- unc ionalized con ac lenses
o co neal gene he apy. Pha maceu ics. 2020;12:335.
105. Huang X, Chau Y. In es iga ing impac s o su ace cha ge on
in aocula dis ibu ion o in a i eal lipid nanopa icles. Exp Eye
Res. 2019;186:107711.
106. Ryoo NK, Lee J, Lee H, e al. The apeu ic e ec s o a no el
siRNA-based an i-VEGF (siVEGF) nanoball o he ea men o cho -
oidal neo ascula iza ion. Nanoscale. 2017;9:15461–15469.
107. Lai S, Wei Y, Wu Q, e al. Liposomes o e ec i e d ug deli e y o
he ocula pos e io chambe . J Nanobio echnol. 2019;17:64.
108. Ak e N, Radiman S, Mohamed F, e al. Sel -assembled po en ial bio
nanoca ie s o d ug deli e y. Mini Re Med Chem.
2013;13:1327–1339.
109. Lu Y, Yue Z, Xie J, e al. Micelles wi h ul alow c i ical micelle
concen a ion as ca ie s o d ug deli e y. Na Biomed Eng.
2018;2:318–325.
110. Kapoo Y, Howell BA, Chauhan A. Liposome assay o e alua ing
ocula oxici y o su ac an s. In es Oph halmol Vis Sci.
2009;50:2727–2735.
111. Ga aszczuk IK, Mon es Mico R, Iskande DR, e al. The ea u no e
and ea clea ance es s – a e iew. Expe Re Med De .
2018;15:219–229. .
112. Owen SC, Chan DPY, Shoiche MS. Polyme ic micelle s abili y. Nano
Today. 2012;7:53–65.
113. Söde man O, He ing on KL, Kale EW, e al. T ansi ion om
micelles o esicles in aqueous mix u es o anionic and ca ionic
su ac an s. Langmui . 1997;13:5531–5538.
114. Du a R, Ghosh S, Bane jee P, e al. Micelle- esicle-micelle ansi ion
in aqueous solu ion o anionic su ac an and ca ionic imidazolium
su ac an s: al e a ion o he loca ion o di e en luo opho es.
J Colloid In e Sci. 2017;490:763–773.
115. A i M, Alexenbe g C, Bodne E, e al. NMR-based molecula ule
o de e mining he dep h o in e calan s wi hin he lipid bilaye .
Pa V: a compa ison o liposomes, bioliposomes and e y h ocy e
ghos s. Chem Phys Lipids. 2014;184:52–60.
116. Is aelach ili JN, Mi chell DJ, Ninham BW. Theo y o sel -assembly o
lipid bilaye s and esicles. BBA - Biomemb . 1977;470:185–201.
117. Sego a S, Tezak D. Spon aneous o ma ion o esicles. Ad Colloid
In e ace Sci. 2006;121:51–75.
118. Naga ajan R. Molecula packing pa ame e and su ac an
sel -assembly: he neglec ed ole o he su ac an ail. Langmui .
2002;18:31–38.
119. Pasquali RC, Tau ozzi MP, B egni C. Some conside a ions abou he
hyd ophilic – lipophilic balance sys em. In J Pha m.
2008;356:44–51.
120. Moghassemi S, Hadjizadeh A. Nano-niosomes as nanoscale d ug
deli e y sys ems: an illus a ed e iew. J Con ol Release.
2014;185:22–36.
121. Bod a i AM, Alexand idis P. Amphiphilic block copolyme s in d ug
deli e y: ad ances in o mula ion s uc u e and pe o mance.
Expe Opin D ug Deli . 2018;15:1085–1104.
122. Pola H, Ku luay G, Pola M. Analysis o dilu ion induced disin eg a-
ion o micella d ug ca ie s in he p esence o in e and in a
micella species. Colloid Su A. 2020;301:124989.
123. Kikuchi H, Ca lsson A, Yachi K, e al. Possibili y o hea s e iliza ion
o liposomes. Chem Pha m Bull. 1991;39:1018–1022.
124. Hwang D, Ramsey JD, Kabano AV. Polyme ic micelles o he
deli e y o poo ly soluble d ugs: om nano o mula ion o clinical
app o al. Ad D ug Deli Re . 2020;156:80–118.
125. Aji h TA. Alpha-lipoic acid: a possible pha macological agen o
ea ing d y eye disease and e inopa hy in diabe es. Clin Exp
Pha macol Physiol. 2020;47:1883–1890.
126. Alambiaga-Ca a aca AM, Cala ayud-Pascual MA, Rodilla V, e al.
Micelles o p oges e one o opical eye adminis a ion: in e spe-
cies and in e issues di e ences in ex i o ocula pe meabili y.
Pha maceu ics. 2020;12:702.
• Expe imen al e idence o in e species di e ences ega ding
d ug pene a ion h ough co nea and scle a.
EXPERT OPINION ON DRUG DELIVERY 1605
127. Sa wa MA, Mansou HF, Hussein AK, e al. Polyme ic micelles o
he ocula deli e y o iamcinolone ace onide: p epa a ion and
in i o e alua ion in a abbi ocula in lamma o y model. D ug
Deli . 2020;27:1115–1124.
128. Di P ima G, Saladino S, Bongio i F, e al. No el inulin-based
mucoadhesi e micelles loaded wi h co icos e oids as po en ial
ansco neal pe mea ion enhance s. Eu J Pha m Biopha m.
2017;117:385–399.
129. Go e V, Mandal A, Alsham ani M, e al. Sel -assembling ac olimus
nanomicelles o e inal d ug deli e y. Pha maceu ics.
2020;12:1072.
130. Pa el S, Ga apa i C, Chowdhu y P, e al. De elopmen and e alua-
ion o dexame hasone nanomicelles wi h po en ial o ea ing
pos e io u ei is a e opical applica ion. J Ocul Pha macol The .
2015;31:215–227.
131. Naga aj R, S ack T, Yi SJ, e al. High densi y display o an an i-
angiogenic pep ide on micelle su aces enhances hei inhibi ion o
α β3 in eg in-media ed neo ascula iza ion in i o. Nanoma e ials.
2020;10:581.
132. Hou Y, Xin M, Li Q, e al. Glycy hizin micelle as a genis ein nano-
ca ie : syne gis ically p omo ing co neal epi helial wound healing
h ough blockage o he HMGB1 signaling pa hway in diabe ic
mice. Exp Eye Res. 2021;204:108454.
133. Ahmed KS, Hussein SA, Ali AH, e al. Liposome: composi ion, cha -
ac e isa ion, p epa a ion, and ecen inno a ion in clinical
applica ions. J D ug Ta ge . 2019;27:742–761.
134. To chilin VP. Recen ad ances wi h liposomes as pha maceu ical
ca ie s. Na Re D ug Disco . 2005;4:145–160.
135. Khan AA, Allemailem KS, Alma oodi SA, e al. Recen s a egies
owa ds he su ace modi ica ion o liposomes: an inno a i e
app oach o di e en clinical applica ions. 3 Bio ech. 2020;10:163.
136. Bogdano P, Samped o J, Solà-Adell C, e al. E ec s o liposomal
o mula ion o ci icoline in expe imen al diabe es-induced e inal
neu odegene a ion. In J Mol Sci. 2018;19:2458.
137. Pa a ano M, Sca inci F, Pa isi V, e al. Ci icoline and i amin B12
eye d ops in ype 1 diabe es: esul s o a 3-yea pilo s udy e alu-
a ing mo pho- unc ional e inal changes. Ad The .
2020;37:1646–1663.
138. Al ami ano-Vallejo JC, Na a o-Pa ida J, Gonzalez-de La Rosa A,
e al. Cha ac e iza ion and pha macokine ics o iamcinolone
ace onide-loaded liposomes opical o mula ions o i eo e inal
d ug deli e y. J Ocul Pha macol The . 2018;34:416–425.
139. Gonzalez-de La Rosa A, Na a o-Pa ida J, Al ami ano-Vallejo JC,
e al. No el iamcinolone ace onide-loaded liposomes opical o -
mula ion o he ea men o cys oid macula edema a e ca a ac
su ge y: a pilo s udy. J Ocul Pha macol The . 2019;35:106–115.
• Clinical s udy ha e idenced he capabili y o liposomes o
p o ide iamcinolone ace onide he apeu ic le els in i eous
and e ina.
140. Li J, Cheng T, Tian Q, e al. A mo e e icien ocula deli e y sys em
o iamcinolone ace onide as eye d op o he pos e io segmen o
he eye. D ug Deli . 2019;26:188–198.
141. Lai S, Wei Y, Wu Q, e al. Liposomes o e ec i e d ug deli e y o
he ocula pos e io chambe . J Nanobio echnol. 2019;17:64.
142. Da is BM, No mando EM, Guo L, e al. Topical deli e y o a as in o
he pos e io segmen o he eye in i o using annexin
A5-associa ed liposomes. Small. 2014;10:1575–1584.
143. Giambanco I, Pula G, Cecca elli P, e al. Immunohis ochemical
localiza ion o annexin V (CaBP33) in a o gans. J His ochem
Cy ochem. 1991;39:1189–1198.
• Liposomes ha can bind o he calcium-dependen phospholi-
pid binding p o ein annexin A5 acili a e he pene a ion o
be acizumab (a as in) owa ds i eous and e ina/cho oid.
144. U i A. Commen on “Topical Deli e y o A as in o he Pos e io
Segmen o he Eye In Vi o Using Annexin A5-Associa ed
Liposomes”: opical Liposomal Be acizumab Resul s in Negligible
Re inal Concen a ions. Small. 2019;15:1805199.
145. Malakou i-Nejad M, Ba dania H, Aliakba i F, e al. Fo mula ion o
nanoliposome-encapsula ed be acizumab (A as in): s a is ical
op imiza ion o enhanced d ug encapsula ion and p ope ies
e alua ion. In J Pha m. 2020;590:119895.
146. Pla ania CBM, Fisichella V, Fidilio A, e al. Topical ocula deli e y o
TGF-β1 o he back o he eye: implica ions in age- ela ed neu o-
degene a i e diseases. In J Mol Sci. 2017;18:2076.
• In i o demons a ion ha ocula ins illa ion o annexin A5-
based unilamina esicles may p o ide he apeu ical le els o
TGF-β1 in he i eous.
147. So iano-Romaní L, Al a ez-T abado J, López-Ga cía A, e al.
Imp o ed in i o co neal deli e y o a h ombospondin-1-de i ed
pep ide using a liposomal o mula ion. Exp Eye Res.
2018;167:118–121.
148. Pee e s L, Sande s NN, Jones A, e al. Pos -pegyla ed lipoplexes a e
p omising ehicles o gene deli e y in RPE cells. J Con ol Release.
2007;121:208–217.
149. Lajunen T, Hisazumi K, Kanazawa T, e al. Topical d ug deli e y o
e inal pigmen epi helium wi h mic o luidize p oduced small
liposomes. Eu J Pha m Sci. 2014;62:23–32.
150. Hanjdani-Vila RM, Ribie A, Rondo B, e al. Dispe sions o lamella
phases o non-ionic lipids in cosme ic p oduc s. In J Cosme Sci.
1979;1:303–314.
151. Biswas GR, Majee S. Niosomes in ocula d ug deli e y. Eu J Pha m
Med Res. 2018;4:813–819.
152. Ma ianecci C, Di Ma zio L, Rinaldi F, e al. Niosomes om 80s o
p esen : he s a e o he a . Ad Colloid In e ace Sci.
2014;205:187–206.
153. Ri wise A, K ongsuk S, Roy J. Molecula s uc u e and dynamical
p ope ies o niosome bilaye s wi h and wi hou choles e ol inco -
po a ion: a molecula dynamics simula ion s udy. Appl Su Sci.
2016;380:23–31.
154. Ma ianecci C, Di Ma zio L, Del Fa e o E, e al. Niosomes as d ug
nano ec o s: mul iscale pH-dependen s uc u al esponse.
Langmui . 2016;32:1241–1249.
155. Mandal D, Das S. Glucose- igge ed dissolu ion o phenylbo onic
acid- unc ionalized choles e ol-based niosomal sel -assembly o
uneable d ug elease. New. J. Chem. 2019;43:7855–7865.
156. Baillie AJ, Flo ence AT, Hume LR, e al. The p epa a ion and p ope -
ies o niosomes—non-ionic su ac an esicles. J Pha m
Pha macol. 1985;37(12):863–868.
157. Machado ND, Ga cia-Man ique P, Fe nandez MA, e al.
Choles e ol ee niosome p oduc ion by mic o luidics: compa a-
i e wi h o he con en ional me hods. Chem Eng Res Des.
2020;162:162–171.
158. Kha oon M, Shah KU, Din FU, e al. P oniosomes de i ed niosomes:
ecen ad ancemen s in d ug deli e y and a ge ing. D ug Deli .
2017;24:56–69.
159. Pa dakh y A, Moazeni E, Va shosaz J, e al. Pha macokine ic s udy
o niosome-loaded insulin in diabe ic a s. DARU. 2011;19:404–411.
160. Hasan AA, Madko H, Wageh S. Fo mula ion and e alua ion o
me o min hyd ochlo ide-loaded niosomes as con olled elease
d ug deli e y sys em. D ug Deli . 2013;20:120–126.
161. Samed N, Sha ma V, Sunda amu hy A. Hyd ogen bonded nio-
somes o encapsula ion and elease o hyd ophilic and hyd opho-
bic an i-diabe ic d ugs: an e icien sys em o o al an i-diabe ic
o mula ion. Appl Su Sci. 2018;449:567–573.
162. Kamble B, Tal eja S, Gup a A, e al. De elopmen and biological
e alua ion o Gymnema syl es e ex ac -loaded nonionic
su ac an -based niosomes. Nanomedicine. 2013;8:1295–1305.
163. Abdelkade H, Ismail S, Kamal A, e al. P epa a ion o niosomes as
an ocula deli e y sys em o nal exone hyd ochlo ide: physico-
chemical cha ac e iza ion. Pha mazie. 2010;65:811–817.
164. Uchegbu IF, Vyas SP. Non-ionic su ac an based esicles (nio-
somes) in d ug deli e y. In J Pha m. 1998;172:33–70.
165. Abdelkade H, Ismail S, Kamal A, e al. Design and e alua ion o
con olled- elease niosomes and discomes o nal exone hyd o-
chlo ide ocula deli e y. J Pha maceu ical Sci. 2011;100
(5):1833–1846.
166. El-Sayed MM, Hussein AK, Sa han HA, e al. Flu bip o en-loaded
niosomes-in-gel sys em imp o es he ocula bioa ailabili y o
1606 A. KATTAR ET AL.
lu bip o en in he aqueous humo . D ug De Ind Pha m.
2017;43:902–910.
167. Fa halla D, Fouad EA, Soliman GM. La anop os niosomes as
a sus ained elease ocula deli e y sys em o he managemen o
glaucoma. D ug De Ind Pha m. 2020;46:806–813.
• Topical adminis a ion o no mo ensi e abbi s o la anop os -
loaded niosome gel caused sus ained dec ease in in aocula
p essu e.
168. Fouda NH, Abdel ehim RT, Hegazy DA, e al. Sus ained ocula deli e y
o do zolamide-HCl ia p oniosomal gel o mula ion: in- i o cha ac-
e iza ion, s a is ical op imiza ion, and in- i o pha macodynamic e a-
lua ion in abbi s. D ug Deli . 2018;25:1340–1349.
169. Emad Eldeeb A, Salah S, Gho ab M. P oniosomal gel-de i ed
niosomes: an app oach o sus ain and imp o e he ocula
deli e y o b imonidine a a e; o mula ion, in- i o cha ac e -
iza ion, and in- i o pha macodynamic s udy. D ug Deli .
2019;26:509–521.
170. Al Q aish N, Gallego I, Villa e-Bei ia I, e al. Niosome-based
app oach o in si u gene deli e y o e ina and b ain co ex as
immune-p i ileged issues. Pha maceu ics. 2020;12:198.
171. Villa e-Bei ia I, Gallego I, Ma inez-Na a e e G, e al. Polyso ba e 20
non-ionic su ac an enhances e inal gene deli e y e iciency o
ca ionic niosomes a e in a i eal and sub e inal adminis a ion.
In J Pha m. 2018;550:388–397.
172. Qin Y, Tian Y, Liu Y, e al. Hyalu onic acid-modi ied ca ionic
niosomes o ocula gene deli e y: imp o ing ans ec ion e i-
ciency in e inal pigmen epi helium. J Pha m Pha macol.
2018;70:1139–1151.
EXPERT OPINION ON DRUG DELIVERY 1607
