applied
sciences
Re iew
Su ace Func ionaliza ion o PLGA Nanopa icles o Inc ease
T anspo ac oss he BBB o Alzheime ’s Disease
Lau a Del Amo 1, Amanda Cano 1,2,3,4 , Mi en E che o 3,5 , Eliana B. Sou o 6,7, Ma a Espina 1,2 ,
An oni Camins 3,5 , Ma ia Luísa Ga cía1,2,3 and Elena Sánchez-López 1,2,3,*


Ci a ion: Del Amo, L.; Cano, A.;
E che o, M.; Sou o, E.B.; Espina, M.;
Camins, A.; Ga cía, M.L.; Sánchez-
López, E. Su ace Func ionaliza ion o
PLGA Nanopa icles o Inc ease
T anspo ac oss he BBB o
Alzheime ’s Disease. Appl. Sci. 2021,
11, 4305. h ps://doi.o g/10.3390/
app11094305
Academic Edi o : Ca la Sa do
Recei ed: 31 Ma ch 2021
Accep ed: 29 Ap il 2021
Published: 10 May 2021
Publishe ’s No e: MDPI s ays neu al
wi h ega d o ju isdic ional claims in
published maps and ins i u ional a il-
ia ions.
Copy igh : © 2021 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
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A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
1
Depa men o Pha macy, Pha maceu ical Technology and Physical Chemis y, Facul y o Pha macy and Food
Sciences, Uni e si y o Ba celona, 08028 Ba celona, Spain; [email p o ec ed] (L.D.A.);
[email p o ec ed] (A.C.); [email p o ec ed] (M.E.); [email p o ec ed] (M.L.G.)
2Ins i u e o Nanoscience and Nano echnology (IN2UB), Uni e si y o Ba celona, 08028 Ba celona, Spain
3
Cen o de In es igación Biomédica en Red de En e medades Neu odegene a i as (CIBERNED), Uni e si y o
Ba celona, 08028 Ba celona, Spain; mi [email p o ec ed] (M.E.); [email p o ec ed] (A.C.)
4Resea ch Cen e and Memo y Clinic, FundacióACE. Ins i u Ca alàde Neu ociències
Aplicades—In e na ional Uni e si y o Ca alunya (UIC), 08017 Ba celona, Spain
5Depa men o Pha macology, Toxicology and The apeu ic Chemis y, Facul y o Pha macy and Food
Sciences, Uni e si y o Ba celona, 08028 Ba celona, Spain
6CEB—Cen e o Biological Enginee ing, Uni e si y o Minho, Campus de Gual a , 4710-057 B aga, Po ugal;
[email p o ec ed]
7Depa men o Pha maceu ical Technology, Facul y o Pha macy, Uni e si y o Coimb a,
3000-458 Coimb a, Po ugal
*Co espondence: [email p o ec ed]
Abs ac :
Alzheime ’s disease (AD) is a ch onic neu odegene a i e diso de ha accoun s o abou
60% o all diagnosed cases o demen ia wo ldwide. Al hough he e a e cu en ly se e al d ugs ma -
ke ed o i s ea men , none a e capable o slowing down o s opping he p og ession o AD. The ole
o he blood-b ain ba ie (BBB) plays a key ole in he design o a success ul ea men o his neu-
odegene a i e disease. Nanosized pa icles ha e been p oposed as sui able d ug deli e y sys ems
o o e come BBB wi h he pu pose o inc easing bioa ailabili y o d ugs in he b ain. Biodeg adable
poly (lac ic-co-glycolic acid) nanopa icles (PLGA-NPs) ha e been pa icula ly ega ded as p omising
d ug deli e y sys ems as hey can be su ace- ailo ed wi h unc ionalized molecules o si e-speci ic
a ge ing. In his e iew, a ho ough discussion abou he mos ecen unc ionaliza ion s a egies
based on PLGA-NPs o AD and hei mechanisms o ac ion is p o ided, oge he wi h a desc ip ion
o AD pa hogenesis and he ole o he BBB in b ain a ge ing.
Keywo ds:
unc ionalized PLGA nanopa icles; b ain deli e y; blood-b ain ba ie ; Alzheime ’s disease
1. In oduc ion
Alzheime ’s disease (AD) is ecognised as a ch onic neu odegene a i e disease cha -
ac e ized by amyloid be a accumula ion and b ain in acellula neu o ib illa y angles [
1
].
Despi e he se e al d ugs app o ed by he Food and D ug Adminis a ion (FDA) o he
ea men o AD, hey a e no ully e ec i e in amelio a ing he symp oms and lose e ec-
i eness o e ime. We s ill ace an unme medical need wi h espec o e ec i e ea men
and managemen o his neu odegene a i e diso de .
To design and de elop a success ul ea men s a egy o AD, he ole o he blood-
b ain ba ie (BBB) has o be aken in o accoun [
2
]. The BBB consis s o a con inuous laye o
di e en ia ed endo helial cells linked oge he by igh junc ions, pe icy es, non enes a ed
basal lamina and as ocy ic oo p ocesses [
3
]. Due o i s p ope ies, his complex ba ie
makes he CNS a challenging mic oen i onmen o be eached by d ug molecules h ough
con en ional app oaches [
2
]. The BBB is hus a limi ing ba ie o con en ional d ug
deli e y [3].
Appl. Sci. 2021,11, 4305. h ps://doi.o g/10.3390/app11094305 h ps://www.mdpi.com/jou nal/applsci
Appl. Sci. 2021,11, 4305 2 o 27
The e o e, se e al inno a i e s a egies ha e been p oposed o enhance he ans-
po o he apeu ics h ough he BBB [
3
]. Among di e en ypes o nanosized pa icles,
polyme ic (e.g., PLGA-NPs, PLA-NPs, polyme ic micelles, dend ime s) and lipid (e.g.,
liposomes, solid lipid nanopa icles) nanopa icles ha e been ex ensi ely s udied o deli e
he apeu ic d ugs and mac omolecules o he b ain [4].
In his a ea, polyme ic nanopa icles can be made o biocompa ible copolyme s o
poly(D,L-lac ic-co-glycolic) acid ha ha e low solubili y in wa e [
5
,
6
]. Mo eo e , cha -
ac e is ics such as size, ze a po en ial and hyd ophilici y can be con olled by su ace
modi ica ions, such as su ac an coa ing, o enhance b ain up ake [
7
]. In addi ion, ligands
known o a ge he su ace ecep o s on endo helial cells o he BBB (e.g., ans e in,
insulin and lipop o ein ecep o s) can be linked o he su ace o PLGA-NPs o p o ide
a ge ed b ain deli e y and imp o e NP up ake [8].
PLGA is, indeed, one o he mos success ul polyme ic ma e ials used o p oduce
unc ionalized pa icles, gi en i s biodeg adabili y and biocompa ibili y p ope ies ha
ha e con ibu ed o i s app o al by he FDA and EMA (1986) o pa en e al adminis a ion.
Besides, he loading o d ugs in o a polyme ic ma ix co e o nanopa icles p omo es d ug
p o ec ion agains deg ada ion and o e s he possibili y o modi y he elease p o ile bo h
in i o and in i o [9].
The aim o he p esen wo k is o iden i y di e en s a egies o PLGA-NPs su ace
unc ionaliza ion o enhance hei anspo h ough he BBB o success ul ea men o
neu odegene a i e diseases, in pa icula o AD. In o de o unde ake his objec i e, some
seconda y aims ha e been es ablished, such as he ho ough analysis o AD pa hology
highligh ing he challenges encoun e ed in he physiological p ope ies o he BBB o d ug
deli e y, he ole o PLGA NPs and hei su ace a ge ing o inc ease anspo h ough
he BBB o AD ea men .
2. Ma e ials and Me hods
Di e en da abases we e used o he li e a u e sea ch: PubMed, Sp inge Link, Sci-
enceDi ec , making use o he ollowing key wo ds: “ unc ionalized/ a ge ed PLGA
nanopa icles”, “Alzheime ’s disease”, “b ain deli e y” and “blood-b ain ba ie ”. Rele-
an s udies we e selec ed based on he yea o publica ion (a e 2010) and he di e en
s a egies used o enhance BBB c ossing. A o al o 13 pape s on unc ionalized PLGA
NPs o AD ea men we e used. In o ma ion abou NP cha ac e is ics,
in i o
and
in i o
models, and he mos ele an indings we e d awn om selec ed pape s, and a e
also summa ised.
3. Alzheime ’s Disease
3.1. P e alence and Incidence
Alzheime ’s disease (AD) accoun s o abou 60% o all demen ia cases wo ldwide,
wi h an es ima ed global incidence o 24.3 million cases, which inc eases wi h he ag-
ing popula ion [
10
,
11
] wi h an incidence a e ha inc eases exponen ially wi h age un il
85 yea s [12,13].
Age o he onse can hus be used as c i e ion o he ca ego iza ion o ea ly-onse
AD (EOAD) and la e-onse AD (LOAD). The o me accoun s o abou 1–6% o all cases,
wi h ages anging om 30 o 60–65 yea s old. The la e is he mos common o m o he
disease, wi h an onse la e han 60–65 yea s [
11
]. Bo h EOAD and LOAD a e cha ac e ized
by a p og essi e loss o memo y and o ien a ion oge he wi h o he cogni i e de ici s
ha e en ually become incapaci a ing, including impai ed judgmen and decision making,
ap axia and language dis u bances. In addi ion, hese a e ypically ollowed by o he
neu opsychia ic symp oms such as dep ession, anxie y, apa hy, delusions, agi a ion o
hallucina ions [14].
Mo eo e , in pa allel wi h li e ime expec ancy, he inc easing numbe s o pa ien s
diagnosed wi h AD cons i u e a global heal h conce n wi h huge implica ions o pa ien s
and ca e ake s [
15
]. This has led o an eno mous inc ease in esea ch ocused on unde -
Appl. Sci. 2021,11, 4305 3 o 27
s anding AD pa hogenesis in o de o disco e d ugs o p e en ion and ea men o he
disease [16].
3.2. Neu opa hology
The majo pa hological hallma ks o AD a e he se -up o ex acellula amyloid plaques
and in aneu onal neu o ib illa y angles (NFTs) in he b ain. Al hough plaques and
angles a e also iden i ied in cogni i ely no mal age-ma ched con ols, hei densi y and
dis ibu ion a e signi ican ly mo e se e e in AD pa ien s [17].
Amyloid plaques a e mainly composed o he amyloid-
β
(A
β
) pep ide ha accumula e
in he ex acellula co ex [
18
]. The 40 amino acids-pep ide is he mos common o m o
A
β
in humans and is called A
β
40, whe eas a 42-amino-acid-long agmen , called A
β
42, is
less abundan . The only di e ence is ha A
β
42 has wo addi ional amino acid esidues a
he C- e minus [
19
]. Howe e , A
β
42 has been associa ed wi h AD because i is mo e p one
o agg ega ion han A
β
40, and hus would be deposi ed be o e A
β
40 [
20
], leading o he
o ma ion o hese amyloid plaques.
The gene o he amyloid p ecu so p o ein (APP) ha o igina es he A
β
pep ide is
loca ed in ch omosome 21 in humans wi h h ee majo iso o ms a ising om al e na i e
splicing [
21
]. Howe e , he physiological unc ion o APP, despi e in ensi e esea ch, is no
ye ully disclosed.
Th ee dis inc sec e ases (
α
,
β
, o
γ
) can induce clea age o ull-leng h APP, which
hus unde goes di e en sequen ial p o eoly ic p ocessing. In he nonamyloidogenic
pa hway, APP is i s clea ed by
α
-sec e ase (non-neu o oxic, “no mal” clea age), eleasing
a la ge soluble ec odomain o APP (sAPP-
α
) in o he ex acellula space. Opposed o
A
β
, sAPP-
α
plays an impo an ole in su i al and in neu onal plas ici y, showing a
p o ec i e e ec agains exci o oxici y. sAPP-
α
also egula es he p oli e a ion o neu al
s em cells, being ins umen al o ea ly neu al de elopmen [
22
]. On he con a y, in
he amyloidogenic p ocessing, APP is i s clea ed by
β
-sec e ase (po en ially neu o oxic,
“abno mal” clea age), eleasing ano he soluble ec odomain o APP (sAPP-
β
) in o he
ex acellula space.
Upon
α
o
β
-clea age, he espec i e ca boxyl e minal agmen s (CTFs) o APP
(
α
-CTF and
β
-CTF) a e kep in he cell memb ane and su e
γ
-sec e ase-media ed clea age.
Subsequen o his,
γ
-clea age,
α
-CTF and
β
-CTF gene a e p83 and A
β
, espec i ely,
(Figu e 1). I should be no ed ha
γ
-sec e ase clea age occu s in he ansmemb ane
domain, e en hough he exac si e may a y. Indeed, majo si es o
γ
-sec e ase clea age
a e he A
β
40 and 42 posi ions [
14
], esul ing in he p oduc ion o A
β
40 o A
β
42, i.e., wo
main o ms o Aβconsis ing, espec i ely, o ei he 40 o 42 amino acid esidues.
The p e alen heo y o AD pa hogenesis is cu en ly accep ed o be he amyloid hy-
po hesis, sugges ing he accumula ion o insoluble o ms o A
β
as he p ima y pa hological
p ocess, which esul s om he imbalance be ween A
β
p oduc ion and A
β
clea ance [
23
].
Indeed, he A
β
40/A
β
42 a io is key in he se -up o his disease. A
β
42 is he p edominan
o m o A
β
ound in he b ain pa enchyma o AD pa ien s, whe eas A
β
40 is mos ly ound
in he ce eb al ascula u e [
24
]. Since A
β
42 is he mos soluble o m, i has he isk o
oligome izing o o m A
β
- ib ils and p o o ib ils esponsible o he o ma ion o amyloid
plaques. Al hough amyloid plaques a e assumed o be non oxic, he o ma ion o amyloid
oligome s may be esponsible o neu o oxici y. As a esul , he amyloid cascade would
lead o he clinical synd ome o AD [14].
This cascade o e en s includes local oxida ion, in lamma ion, exci o oxici y (due o
excessi e glu ama e) and au hype phospho yla ion [
14
]. In his con ex , he o ma ion
o NFTs is conside ed a downs eam p ocess in which au p o eins agg ega e in a soluble
o m, which esul s in neu onal dys unc ion and neu odegene a ion. Mo eo e , his
p og essi e neu onal degene a ion would esul in an imbalance and sho age o se e al
neu o ansmi e s (e.g., se o onin, dopamine, ace ylcholine), he eby leading o he known
cogni i e AD de iciencies [
25
]. The b ain changes caused by he disease a e shown in
Figu e 2.
Appl. Sci. 2021,11, 4305 4 o 27
Figu e 1.
Schema ic ep esen a ion o nonamyloidogenic and amyloidogenic pa hways o APP
p ocessing. APP clea age akes place ei he by alpha-sec e ase ( he nonamyloidogenic pa hway)
gene a ing sAPP-alpha and C83, o by be a-sec e ase ( he amyloidogenic pa hway) gene a ing
sAPP-be a and C99 (based on [22]).
Figu e 2.
Di e ences be ween human b ain. (
A
) Heal hy b ain and (
B
) AD b ain (exce p ed
om BioRende ).
Al hough a good deal o da a, collec ed o e decades o scien i ic and clinical esea ch
o his disease, s ill suppo s he ole o A
β
as he p ima y ini ia o o he AD complex
pa hogenic cascade, an inc easing numbe o indica o s poin ou ha while he igge ing
e ec o A
β
seems necessa y, i does no seem c ucial in la e s ages o he disease [
26
].
The e o e, o he hypo heses explaining AD pa hogenesis ha e been de eloped.
As al eady men ioned, NFTs (composed o Tau p o ein) cons i u e ano he pa hologi-
cal AD hallma k. Tau is a mic o ubule-associa ed p o ein abundan in he neu ons o he
CNS ha wo ks as a sca old p o ein, main aining he s abili y o mic o ubules in axons.
Unde pa hological condi ions, au hype phospho yla ion is inc eased, which esul s in
he Tau emo al om he mic o ubule, which causes he collapse o he mic o ubule and
impai s neu onal axons, causing neu odegene a ion [
27
–
30
]. In addi ion, his hype phos-
pho yla ion gene a es au agg ega es ha e en ually o m neu o ib illa y angles [
29
–
31
],
leading o loss o neu onal unc ion and esul ing in apop osis [
32
]. The e o e, se e al
s udies on bioma ke s poin ou ha Tau pa hology is in ima ely ela ed o he p og ession
o neu odegene a ion [33].
Appl. Sci. 2021,11, 4305 5 o 27
Mo eo e , esea che s also sugges ha neu oin lamma ion [
34
], choline gic neu-
onal damage and oxida i e s ess [
27
] play an impo an ole in he neu opa hological
p og ession o AD.
3.3. T ea men
Despi e all he ad ances made since D . Alois Alzheime desc ibed he i s case o AD
in 1907, he p ecise mechanisms o amyloid and au pa hology behind AD pa hogenesis
ha e s ill no been clea ly iden i ied. As a esul , he e a e s ill no e ec i e pha maco he -
apeu ic al e na i es o p ophylaxis, managemen and ea men o AD [
14
]. Al hough
an idemen ia agen s de eloped o he ea men o AD can be ca ego ized as symp oma ic
o disease-modi ying [
35
], none o he es ablished ea men s can ully amelio a e AD
p og ession [36].
Some o hese cu en symp oma ic ea men s include ace ylcholines e ase (AChE)
inhibi o s and N-me hyl-D-aspa a e (NMDA) ecep o an agonis s, such as meman ine.
Howe e , all hese d ugs (Table 1) can only alle ia e AD symp oms. Fu he mo e, he
e iciency o he d ugs a ies be ween pa ien s and disease s ages. In addi ion, hey possess
se e al ad e se e ec s such as nausea, omi ing and dia hoea [37].
Besides, an ipsycho ic and an idep essan ea men s a e also used o amelio a e he
beha iou al symp oms [
38
]. In addi ion, compounds ha ac on he pa hological subs a e
o he disease, namely on ex acellula A
β
plaques and in acellula NFTs, a e cu en ly
unde esea ch [14].
Table 1. FDA-app o ed d ugs o AD (based on [39]).
D ug Donepezil
(A icep ®, 1996)
Ri as igmine
(Exelon®, 2000)
Galan amine
(Razadyne®, 2001)
Meman ine
(Ebixa®, 2003)
Pha maceu ical company P ize , New Yo k, USA No a is, Basel,
Swi ze land Janssen, New Je sey, USA Lundbeck, Valby,
Denma k
Class and indica ion
AChE inhibi o p esc ibed
o ea symp oms o
mild- o-mode a e and
mode a e- o-se e e AD
AChE inhibi o p esc ibed
o ea symp oms o
mild- o-mode a e AD
AChE inhibi o p esc ibed
o ea symp oms o
mild- o-mode a e AD
NMDA ecep o
an agonis p esc ibed o
ea symp oms o
mode a e- o-se e e AD
Mechanism o ac ion P e en s he b eakdown
o ACh in he b ain
P e en s he b eakdown
o Ach and bu y ylcholine
in he b ain
P e en s he b eakdown
o ACh and s imula es
nico inic ecep o s o
elease mo e ACh in
he b ain
Blocks he oxic e ec s
associa ed wi h excess
glu ama e and egula es
glu ama e ac i a ion
Common
ad e se e ec s
Nausea (3–19%), omi ing
(3–9%), dia hea (5–15%)
Nausea (17–47%),
omi ing (13–31%),
dia hea (5–19%), loss o
appe i e (≥17%), weigh
loss (3–26%), muscle
weakness
Nausea (21%), omi ing
(11%), dia hea (7%), loss
o appe i e (7%),
weigh loss
Dizziness (5–7%),
headache (6%),
cons ipa ion (3–5%),
con usion
I is also wo h no ing ha he limi ed o unsuccess ul de elopmen o new he apeu ic
agen s o AD is equen ly a ibu ed o he p esence o he BBB, whose p ope ies make
he CNS one o he mos complex mic oen i onmen s o he body, hus comp omising he
de elopmen o no el e ec i e compounds [2].
4. The Blood-B ain-Ba ie
On a e age, he adul human b ain accoun s o abou 2% o body weigh . Despi e
i s ela i ely small size, i consumes abou 20% o glucose-de i ed ene gy [
40
]. Indeed,
he mammalian b ain depend upon glucose as i s main sou ce o ene gy. Fu he mo e,
neu ons wi hin he CNS ha e a high ene gy demand, equi ing a con inuous supply o
ene gy subs a es (mainly glucose) and nu ien s om he blood [41].
Mo eo e , neu ons communica e using se e al chemical (ions, neu o ansmi e s,
neu omodula o s and neu opep ides) and elec ical signals (synap ic and ac ion po en ials).
The e o e, an accu a e egula ion o he axons and synap ic ionic mic oen i onmen s is

Appl. Sci. 2021,11, 4305 6 o 27
c i ical o heal hy b ain physiology [
42
]; hus, eliable neu al signaling is go e ned by he
ba ie laye s exis ing be ween blood and neu al issue [43].
The adul b ain is composed o wo main in e acial ba ie s, namely: (i) he blood-
ce eb ospinal luid ba ie , which is composed o epi helial cells o he cho oid plexus
acing he ce eb ospinal luid [
42
] and (ii) he a ascula a achnoid epi helium, unde lying
du a and enclosing CNS, also o ms a ba ie laye , e en hough i s a ascula na u e and
small su ace a ea do no p omo e a signi ican su ace ex ension o exchange be ween he
blood and he CNS [
44
]. Besides hese wo ba ie s, he BBB ep esen s he la ges in e ace
o blood-b ain exchange, and is c ea ed by he endo helial cells ha o m he walls o he
capilla ies [
42
]. As a esul , he e is a di ec in e ac ion wi h he ci cula ing blood, making
he BBB he mos selec i e physical ba ie and allowing i o exe he igh es con ol
o e he immedia e mic oen i onmen o b ain cells [
45
]. In ac , he BBB is p esen in all
o ganisms wi h a well-de eloped CNS [
46
], and is esponsible o ensu ing he p ope
en i onmen o neu onal ne wo k unc ionali y and b ain homeos asis. The BBB p o ec s
he b ain agains pa hogenic agen s and i egula es he in lux and e lux o luids by means
o dynamic combina ions o ionic, molecula , ascula and cellula ac o s [47].
4.1. S uc u e
Al hough endo helial cells o he CNS ascula u e o m he main ba ie agains
he en y o xenobio ics in he b ain, hese cells do no unc ion independen ly om
o he s, bu a he ac as modules wi hin he mul icellula neu o ascula uni . In ac ,
ci cula ing immune cells, neu ons, mic oglia, pe icy es and as ocy es a e in ima ely linked
wi h he endo helium and play suppo ing oles in main aining and unc ioning his
ba ie [
43
,
48
,
49
] due o an in ica e ne wo k o molecula c oss alk be ween hem [
45
]
(Figu e 3).
Figu e 3. Schema ic ep esen a ion o he cellula ne wo ks o he BBB. The pa acellula pa hway is
go e ned by he igh junc ions c ea ed by he b ain endo helial cells. Foo p ocesses om as ocy es
o m a complex ne wo k su ounding he capilla ies and p o ide links o neu ons. Pe icy es a e
dis ibu ed discon inuously along he leng h o he b ain capilla ies and pa ially su ound he
endo helium. Mic oglia a e CNS- esiden immune cells (based on [50]).
Appl. Sci. 2021,11, 4305 7 o 27
Indeed, in addi ion o he CNS endo helial cells, se e al unc ional laye s exis be ween
he blood and b ain. This is he case o he basemen memb ane, which comple ely co e s
he capilla ies and is made o laminin, ib onec in and ype IV collagen, and con ains
pe icy es; as ocy es also su ound his basemen memb ane o he BBB. Each o hese
laye s may con ibu e o solu e mo emen h ough BBB [51].
Howe e , he endo helial cells lining he ce eb al blood essels s ill ep esen he
main ana omical s uc u e o he BBB and can be dis inguished, bo h unc ionally and
mo phologically, om he pe iphe al endo helial cells. Fo example, hey ha e a high
concen a ion o mi ochond ia, which is an indica ion o a high ene gy expendi u e [52].
Mo eo e , endo helial cells om he CNS composing he igh junc ions, g ea ly
limi pa acellula pe meabili y [
53
–
55
]. They also display low a es o anscy osis when
compa ed o pe iphe al endo helial cells, e ec i ely educing esicle-media ed anscellula
anspo [56].
As a esul o his igh pa acellula and anscellula ba ie , endo helial cells a e pola -
ized, p esen ing dis inc abluminal and luminal su aces wi h e lux and in lux anspo e s
and ecep o s, which oge he con ol he mo emen be ween blood and b ain [52].
In addi ion, hese endo helial cells ha e a ne nega i e su ace cha ge, epelling
nega i ely cha ged compounds, and hey also ha e no enes a ions (small anscellula
po es ha allow ee di usion), hus p e en ing as exchange o molecules. Endo helial
cells also ha e e y low le els o leucocy e adhesion molecules, es ic ing he numbe o
immune cells ha can indeed en e he CNS [52].
4.2. T anspo ac oss he BBB
The BBB plays a ole no only as a ba ie o cells and solu es, bu also as a ca ie
o selec i e d ug molecules. Po en ial ou es o he anspo and pe mea ion o small
molecules and biomac omolecules ac oss he BBB do exis (Figu e 4), p ima ily h ough
ei he pa acellula o anscellula anspo [
57
]. On he one hand, small hyd ophilic
molecules can c oss he BBB and each he b ain h ough an aqueous pa hway ia pa a-
cellula anspo . On he o he hand, small lipophilic compounds en e he b ain issue
h ough anscellula di usion, a nonsa u able pa hway, which could be op imized by
modi ying he physicochemical p ope ies o he d ug.
The e is a co ela ion be ween he lipid solubili y o a d ug and he a e a which i
en e s he CNS. Fac o s such as molecula weigh (<400–500 Da) and hyd ogen bonding
capaci y (<8–10 hyd ogen bonds) comp omise d ug access o he b ain [
58
]. Howe e ,
he e a e se e al o he examples o d ugs en e ing he CNS ha a e no a ec ed by hese
p ope ies [50].
Mo eo e , igh junc ions limi ing pa acellula pe meabili y po en ially isola e he
b ain om many ionic nu ien s, such as glucose and amino acids which a e needed o
b ain me abolism and, he e o e, he BBB endo helium also con ains many speci ic solu e
anspo e s o allow ca ie -media ed anspo (CMT) o hese subs ances. Indeed, he
endo helial cells p esen in he BBB exp ess anspo p o eins on hei su ace o a wide
ange o molecules, he eby media ing hei b ain in lux and e lux [42].
Rega ding la ge molecula weigh solu es such as selec i e pep ides, p o eins and
la ge mac omolecules, he mechanisms o c ossing he BBB and en e ing he CNS consis
o binding o speci ic ecep o s on he cell su ace o endo helial cells ia endocy osis.
This p ocess o endocy osis can be ei he h ough ecep o -media ed anscy osis (RMT),
p o iding he main ou e o which hese la ge molecula weigh solu es c oss he BBB and
en e he b ain, o h ough adso p i e-media ed endocy osis (AMT) o pinocy osis [57].
In summa y, he mo emen o molecules and d ugs h ough he BBB is ei he passi e
o ac i e. The o me is d i en by a concen a ion g adien om plasma o b ain, wi h
mo e lipophilic compounds en e ing mo e easily; he la e being acili a ed by ac i e
anspo e s in he endo helial cell memb anes [
42
]. Howe e , he BBB is an obs acle o
d ug deli e y o he b ain. The e o e, inc easing e o s a e cu en ly ongoing o o e come
he limi a ions encoun e ed in he BBB o deli e y o he apeu ics [52].
Appl. Sci. 2021,11, 4305 8 o 27
Figu e 4.
Schema ic ep esen a ion o po en ial ou es o anspo and pe mea ion ac oss he BBB
(based on [47]).
5. S a egies o Enhance he Deli e y o The apeu ic Agen s ac oss he BBB
The deli e y o d ugs o he b ain is manda o y o he ea men o b ain-associa ed
diseases, bu i is comp omised by he p esence o he BBB [59].
Despi e he mul iple BBB c ossing pa hways, app oxima ely 98% o small molecules,
and mos la ge molecules (e.g., an ibodies, ecombinan p o eins and pep ides, i al ec-
o s), a e unable o each he b ain h ough he BBB [
60
,
61
], esul ing in a e y low bioa ail-
abili y in he b ain [62].
All his has slowed down he exploi a ion o immuno he apy in b ain diseases. In
ac , in a enously adminis e ed an ibodies apidly en e he b ain and subsequen ly a e
quickly expelled om i . Thus, only abou 0.1% o he apeu ic an ibodies each he a ge ing
si e, esul ing in a demand o signi ican ly highe an ibody concen a ions in sys emic
ci cula ion, which, in u n, is associa ed wi h an inc eased isk o sys emic oxici y [63].
A common nonin asi e s a egy o enhance he BBB pe mea ion o small d ugs is o
inc ease he lipophilic cha ac e o he molecule by chemical modi ica ion [
45
]. Howe e ,
his app oach may p omo e a as e clea ance o he d ug om he ci cula o y sys em
h ough e lux anspo e s, he eby comp omising he d ug dis ibu ion and e ec i eness.
Thus, s uc u al modi ica ion o he d ug o inc ease i s a ini y o endogenous anspo
p o eins on he ce ebella endo helium has been p oposed [64].
In addi ion o d ug modi ica ion, inc ease o lipophilici y, o educ ion o he molecula
size, may also con ibu e o inc ease BBB pe mea ion by ocusing on he educ ion o e lux
anspo , hus enhancing he anscellula di usion pe meabili y o dis up ing he igh
junc ion complexes [
47
]. Fu he mo e, he use o nanopa icles and o he molecula T ojan
ho ses may also be exploi ed o enhance he deli e y o d ug molecules ac oss he BBB [
65
].
5.1. Nano echnological Tools o O e come he BBB
Mul idisciplina y e o s a e being made combining chemis y, physics, enginee ing,
and biology o c ea e e ec i e deli e y sys ems able o c oss he BBB wi h he aim o
diagnose and/o ea b ain diseases [66].
This is especially ele an o o e come he limi a ions encoun e ed wi h cu en ly
a ailable s a egies o deli e d ugs in o he CNS h ough he BBB [
47
], in pa icula o
Appl. Sci. 2021,11, 4305 9 o 27
he deli e y o pep ides, ecombinan p o eins, accines and nucleo ides [
67
,
68
]. The
mos commonly used deli e y sys ems a e liposomes, micelles, dend ime s and mic o
and nanopa icles [
69
], which can be designed o educed size, biodeg adabili y and
biocompa ibili y, p olonged blood hal -li e and no oxici y, making hese d ug deli e y
sys ems e y a ac i e [
70
]. These p ope ies ha e been associa ed wi h educed side
e ec s, imp o ed si e-speci ic a ge ing capaci y and be e pa ien compliance [71].
5.2. Polyme ic Nanopa icles
Polyme ic nanopa icles (NPs) a e pa icles o nanome ic size (1–1000 nm) composed
o a solid co e, and ha e been widely exploi ed o c oss he BBB due o hei p ope ies o
d ug deli e y, such as high loading capaci y, high s abili y, con olled d ug elease and
a ge ing e iciency [5].
Polyme ic NPs can be p oduced using ei he syn he ic o na u al polyme s (mo e
limi ed in e ms o hei syn hesis and p ocessing). Acco ding o hei mo phology, poly-
me ic NPs a e classi ied in wo dis inc ca ego ies, namely, nanosphe es and nanocapsules
(Figu e 5). In nanosphe es, he d ug is molecula ly dispe sed h oughou he polyme ic
ne wo k o is placed on o he su ace o he polyme ic co e, while in he case o nanocap-
sules, he d ug molecules a e solubilized in an oil o aqueous co e which is su ounded by
a polyme ic laye [59].
Figu e 5.
Schema ic ep esen a ion o nanosphe es and nanocapsules wi h he d ug en apped o
adso bed on o he su ace o nanopa icles (based on [72]).
Mo eo e , he p ope ies o hese NPs can be ailo ed by he in oduc ion o hi d
pa y componen s [
73
] in o de o inc ease hei hal -li e, o each he BBB mo e easily, and
o inc ease d ug bioa ailabili y in o he b ain o he ea men o neu ological diso de s
such as AD [69].
The selec ion o he ype o polyme o he p oduc ion o such NPs is based on se e al
c i e ia and ac o s, namely, he desi ed size o a pa icula applica ion, physicochemical
p ope ies o he d ug o be loaded wi hin he polyme ic co e, su ace cha ac e is ics and
equi ed unc ionali y, deg ee o biodeg adabili y and biocompa ibili y, and d ug elease
p o ile o he inal o mula ion [
74
]. Se e al na u al and syn he ic polyme s ha e been used
o p epa e NPs o b ain deli e y [75].
Poly (bu yl cyanoac yla e) (PBCA) NPs we e he i s polyme -based DDS used o
deli e d ugs o he CNS [
76
]. Un o una ely, despi e many ad an ages hey possess, such
as biocompa ibili y and biodeg adabili y, PBCA NPs ha e no ye been launched in clinical
use. One o he majo limi a ions o hese pa icles is hei poo d ug loading capaci y, in
pa icula o hyd ophobic molecules. Besides, he bu s elease o he d ug om PBCA-
NPs has also been poin ed ou as a sho coming in mos o he
in i o
elease s udies
desc ibing he use o PBCA-NPs [
77
]. Mo eo e , i has been seen ecen ly ha PBCA NPs
could p esen po en ial oxici y, which could be a ibu ed o as e deg ada ion and a mo e
apid elease o deg ada ion p oduc s [
78
]. Howe e , o he au ho s ha e demons a ed
ha hey can induce oxida i e s ess, e op osis and nec osis [79].
Al e na i ely, se e al ypes o polyme ic NPs wi h high posi i e cha ge ha e been
epo ed o c oss he BBB due o hei elec os a ic in e ac ion wi h b ain endo helial cells
(nega i ely cha ged). Chi osan (CS) is a na u ally occu ing polysaccha ide ha possesses
Appl. Sci. 2021,11, 4305 16 o 27
compa ed o o he PLGA NPs, CRT pep ide-modi ied PLGA NPs codeli e ing S1 and
cu cumin showed po en ial ad ances o he ea men o AD mice [107].
Following he same line, B6 pep ide (CGHKAKGPRK) is also conside ed as a p omis-
ing candida e o enhancing d ug deli e y in o he CNS due o i s abili y o a ge T R as a
subs i u e o he ans e in p o ein [
154
–
156
]. In ac , i is de i ed om a phage display
lib a y, and has p e iously shown high pe meabili y ac oss he BBB [
157
] and highe
accumula ion in b ain capilla y endo helial cells [
158
]. Thus, i is sugges ed ha i would
also imp o e cu cumin bioa ailabili y in he b ain. The e o e, Fan e al. [
106
] p epa ed
PLGA-PEG NPs loaded wi h cu cumin and conjuga ed wi h he B6 pep ide, ob aining
NPs wi h a size less han 150 nm. These PLGA-PEG-B6/Cu NPs signi ican ly inc eased
cu cumin cellula up ake
in i o
and could ema kably imp o e cogni i e impai men
in APP/PS1 mice, indica ing ha hese NPs can p o oundly imp o e cu cumin deli e y
e iciency o he b ain. Mo eo e , ex i o s udies demons a ed ha hey could educe
hippocampal
β
-amyloid o ma ion and deposi s, as well as au hype phospho yla ion.
Thus, hese NPs may se e as an in e es ing s a egy o he ea men o AD [106].
Ano he s a egy o o e come he hyd ophobic na u e and nonsolubili y in wa e
o cu cumin is conjuga ing PLGA NPs wi h a a ge ing Te -1 pep ide moie y. Te -1 is a
12- amino acid pep ide (HLNILSTLWKYR) iden i ied h ough phage display, which has
he binding ea u es o e anus oxin [
159
], hus p esen ing a ini y o neu ons, and could
a ge ca gos o he b ain, bypassing he BBB [
160
]. Fo his eason, Ma hew e al. [
104
]
syn hesized wa e -soluble PLGA coa ed-cu cumin NPs and coupled hese NPs wi h Te -1,
esul ing in NPs wi h a size be ween 150-200 nm. Su ace modi ica ion wi h Te -1 pep ide
inc eased neu onal a ge ing e iciency
in i o
. Indeed, enhanced neu onal up ake o
cu cumin-PLGA NPs was obse ed when compa ed o non a ge ed cu cumin-PLGA NPs.
The e o e, hese esul s indica e ha Te -1- a ge ed PLGA-coa ed cu cumin NPs can be
addi ional ools o he ea men o neu ological diseases, in pa icula AD, wi h espec
o i s an iamyloid and an ioxidan ac i i ies [
104
]. Howe e , his is a p elimina y
in i o
s udy ha needs mo e de ailed in i o in es iga ions o d aw u he conclusions.
Li e al. [
101
] employed ano he phage display pep ide lib a y wi h he pu pose
o isola ing pep ides ha may be exploi ed o a ge deli e y sys ems o he BBB and
inally selec ed a 12-amino-acid-pep ide (deno ed as Pep TGN). They co alen ly conju-
ga ed Pep TGN (TGNYKALHPHNG) on o he su ace o PEG-PLGA based NPs. The
su ace-modi ied PLGA NPs wi h Pep TGN had sizes abou 100 nm and esul ed in an
imp o ed deli e y o NPs ac oss he BBB and b ain a ge ing. This led o signi ican highe
cellula up ake
in i o
and enhanced
in i o
b ain accumula ion, a he han li e and
spleen accumula ion, showing powe ul b ain selec i i y o Pep TGN. The e o e, Pep TGN
modi ied NPs migh be a good s a egy o a ge ed d ug deli e y ac oss he BBB [
101
].
Indeed, he abili y o TGN o acili a e he deli e y o NPs o he b ain has been u he
demons a ed [
161
,
162
], con i ming ha signi ican ly highe cellula up ake and b ain
dis ibu ion occu ed wi h TGN-modi ied NPs compa ed o naked NPs.
Mo eo e , pep ides such as g7, ha a e simila o syn he ic opioid pep ides [
163
], can
also be employed o deli e d ugs in o he CNS. In ac , i was p e iously demons a ed ha
PLGA-NPs conjuga ed wi h g7 a e able o e icien ly c oss he BBB wi hou damage [
164
].
The e o e, Ba ba a e al. [
83
] designed and enginee ed cu cumin-encapsula ed PLGA NPs
bound o g7 (Cu -NP-g7). The esul ing NPs had a pa icle size a ound 200–250 nm,
a ou able o sys emic adminis a ion. The au ho s demons a ed ha Cu -NP-g7 could
inc ease he cellula a ini y o he ac i e neu onal cells and be in e nalized by hippocampal
neu ons. Besides, hey de e mined he e ec o Cu -NP-g7 on he agg ega ion o A
β
, which
showed an impo an dec ease o A
β
. Thus, b ain deli e y o cu cumin using BBB-c ossing
PLGA-g7 NPs is a p omising al e na i e in he ea men o AD. Howe e , his s udy has
been e i ied by an
in i o
cellula model and would need a comple e
in i o
s udy in AD
animal models so ha u he conclusions could be d awn.

Appl. Sci. 2021,11, 4305 17 o 27
6.2.2. Recep o -Media ed T anscy osis
CNS endo helial cells exp ess ecep o s, such as T R, low-densi y lipop o ein ecep o
(LDLR), insulin-like g ow h ac o ecep o , insulin ecep o , diph he ia oxin ecep o ,
sca enge ecep o class B ype and nico inic ace ylcholine ecep o (nAChR), on o hei
su aces. Thus, deli e y sys ems can be deco a ed wi h a ge ing ligands ha speci ically
ecognise hese ecep o s o media e d ug pene a ion o he b ain [165].
Polyso ba e 80 (P80, also known as Tween 80) is pa icula ly in e es ing o b ain
deli e y, since PBCA NPs coa ed wi h P80 ha e al eady acili a ed b ain deli e y o se e al
d ugs ha we e unable o c oss he BBB in a ee o m [
166
]. Poloxame 188 (P188, also
known as Plu onic F-68) was also ound o be e ec i e as an NP coa ing ma e ial o
b ain a ge ing [
97
]. This e ec is a ibu ed o he enhanced adso p ion o ce ain plasma
p o eins (especially he apolipop o eins E, A-I and B) on o he NPs.
Indeed, a e being exposed o se um o plasma, a ious p o eins quickly adso b on o
o eign NPs [
167
]. This e ec is known as di e en ial p o ein adso p ion, and was i s
desc ibed in 1989 [
168
]. The pos ula ed hypo hesis is ha he adso p ion o apolipop o-
eins on o P80/P188-coa ed NPs is esponsible o he subsequen in e ac ion wi h hei
espec i e ecep o s exp essed by he endo helial cells o ming he BBB, and hus p o-
mo es ecep o -media ed endocy osis o NPs, acili a ing hei deli e y in o he b ain [
169
].
The e o e, all hese nanopa icle DDS appea o ac like T ojan ho ses ha would anspo
he d ugs in o he b ain endo helial cells and, in his way, ep esen a no el pla o m
echnology o he ea men o neu odegene a i e diseases [170].
Mo eo e , he coa ing o pa icles wi h P80 causes a ea angemen o he p o eins
composing he igh junc ions a he BBB which esul s in he inc ease o pa acellula
c ossing o NPs in o he b ain [
171
,
172
]. Ano he eason is a ibu ed o he ole o P80 in
blocking he e lux sys em, educing he pump-o e ec o he P-glycop o ein, and he eby
achie ing a high d ug concen a ion in he b ain [173].
Taha a e al. [
102
] s udied di e en su ace-modi ied PLGA NPs o mula ions based
on P80, P188 and CS o a ge ing CNS diseases. The esul ing PLGA NPs had sizes anging
om 250 o 400 nm depending on he ype o su ace modi ie used, and a e sys emic
adminis a ion, NP concen a ion in he b ain inc eased wi h he su ace modi ica ion
o he pa icles, in pa icula , CS and P80 PLGA NP. Howe e , CS-PLGA NPs we e only
adso bed on endo helial cells and no ans e ed in o b ain issue, whe eas a highe b ain
dis ibu ion was seen wi h P80-PLGA NPs, which we e seen in he pa enchyma beyond he
ce eb al blood essel endo helial cells. This sugges ed ha P80-PLGA NPs could no only
adso b o he endo helial memb ane o ce eb al blood essels bu could also be in e nalized
by endo helial cells and c oss he BBB. Mo eo e , P80-PLGA NPs exhibi ed p olonged
ci cula ion in he blood compa ed o he o he NPs e alua ed, which migh be a eason
o he inc eased b ain dis ibu ion by a oiding up ake by RES. The e o e, P80-PLGA NPs
ha e high po en ial as e ec i e d ug ca ie s o CNS deli e y [102].
This was u he con i med by Fo nague a e al. [
174
]. Indeed, hey demons a ed he
capabili y o galan amine-PLGA NPs o c oss he BBB because o he pe meabilizing and
a ge ing e ec o P80, leading o a o mula ion wi h in e es ing p ope ies o be used as
ad anced DDS o he symp oma ic ea men o AD.
As al eady men ioned, ecep o s ha a e highly exp essed on CNS endo helial cells
include T R. Lac o e in (L ) is a na u ally occu ing i on-binding glycop o ein belonging
o he ans e in amily. I s ecep o (L R) is highly exp essed in b ain endo helial cells
and in neu ons, being especially o e exp essed in capilla ies and neu ons associa ed wi h
age- ela ed neu odegene a i e diseases [
175
,
176
]. This ac makes L a p omising a ge ing
molecule o he ea men o AD.
The e o e, Meng e al. [
108
] p epa ed L -PLGA NPs loaded wi h Hupe zine A (HupA),
a e e sible AChE inhibi o which enhances memo y in animal models [
177
,
178
]. The
esul ing NPs had an a e age size below 200 nm and L -su ace modi ica ion inc eased
cellula up ake o NPs h ough RMT, leading o imp o ed b ain deli e y. The e o e,
b ain accumula ion o L -TMC NPs was highe han non a ge ed analogues, especially in
Appl. Sci. 2021,11, 4305 18 o 27
he memo y- ela ed hippocampus. This ou come sugges s ha L -PLGA NPs may be a
p omising app oach o he deli e y o HupA in AD [
108
]. Howe e , u u e s udies a e
equi ed o con inue e alua ing hei he apeu ic e icacy in animal models o AD, and
i should be no ed ha he use o la ge p o eins such as lac o e in p o ein can esul in
p oblems like syn hesis p ocedu e, s abili y and immunological esponse [157].
6.2.3. Ca ie -Media ed T anspo
Besides ecep o s, ac i e anspo in he BBB may also be exploi ed o b ain a ge ing.
The glu a hione (GSH) anspo e is highly exp essed a he BBB [
97
]. This endogenous
ipep ide hiol ac s as an an ioxidan and helps o p o ec cells om ROS [179].
Since he e is a la ge numbe o GSH anspo e s a he BBB, GSH conjuga ed on o
he PLGA NP su ace is expec ed o bind o hese anspo e s and inc ease he numbe o
NPs a he BBB in e ace [
179
]. Howe e , al hough he mechanism o GSH anspo a ion
h ough he b ain cells was p o en o be pe o med h ough a speci ic mechanism [
180
],
he exac molecula mechanism emains o be elucida ed.
Paka e al. [
105
] de eloped GSH- unc ionalized PLGA-PEG NPs o be loaded wi h
cu cumin. The esul ing NPs, o mean size be ween 149 o 180 nm and coa ed wi h bo h
PEG and GSH, inc eased imp o ed d ug up ake
in i o
. Mo eo e , he in e nalized
cu cumin was ound localized in almos e e y cell and hei componen s, meaning ha
he GSH su ace-modi ica ion allowed be e cellula a icking o he o mula ion. No el
insigh s in o he de elopmen o e ec i e deli e y sys ems able o escape lysosomal
deg ada ion we e desc ibed, he e o e inc easing he he apeu ic e ec o d ugs use ul o
he ea men o AD [
105
]. Howe e ,
in i o
expe imen s a e s ill equi ed o d aw mo e
gene al conclusions.
6.2.4. Adso p ion-Media ed T anscy osis
In addi ion o pa icle size, su ace cha ge (i.e., ze a po en ial) is also expec ed o a ec
NP cellula up ake and cy o oxici y. The e o e, nanopa icles wi h a posi i e su ace cha ge
a e mo e sui able o cellula up ake. The su ace o CNS endo helial cells shows a nega i e
cha ge and hus, a ac s posi i ely cha ged nanopa icles o in e ac wi h he BBB h ough
adso p ion-media ed endocy osis [181].
In ac , while ecep o -media ed anscy osis equi es he ini ial binding o a ligand
o he memb ane o he BBB endo helial cells, abso p i e-media ed anscy osis elies on
nonspeci ic cha ge-based in e ac ions [
100
]. Consequen ly, poo selec i i y o abso p i e-
media ed anscy osis is p edominan , since i can be easily ini ia ed by polyca ionic
compounds binding he nega i e cha ges on o he memb ane.
Ca ionic su ac an coa ing is belie ed o ende a posi i e cha ge o NPs, hus im-
p o ing hei in e ac ion wi h cells and issues [
97
]. Fo ins ance, dioc adecyldime hylam-
monium b omide (DODAB), a qua e na y ammonium su ac an , can d as ically al e he
nega i e cha ge o PLGA NPs by p e e en ial adso p ion [
182
]. In he same way, didode-
cyldime hylammonium b omide (DMAB), ano he qua e na y ammonium compound, is
also used o nanopa icle s abiliza ion. Pee la e al. [
183
] epo ed ha DMAB enabled
he in e ac ion o NPs wi h a cell memb ane model in a p opo ional ashion o hei
cellula up ake
in i o
. The e o e, Xu e al. [
103
] p epa ed DMAB-PLGA NPs loaded wi h
couma in-6 and obse ed ha su ace modi ica ion wi h DMAB no ably imp o ed cellula
up ake
in i o
, which was size-dependen wi h an op imal pa icle size o 100 nm. Indeed,
DMAB-modi ied NPs showed smalle sizes and highe ze a po en ials han he PVA-coa ed
NPs, meaning ha he DMAB-coa ed nanopa icles could be en apped by he cells mo e
easily, inc easing cellula up ake.
In addi ion o ca ionic su ac an s, ca ionic polyme s such as chi osan (CS) can be em-
ployed. As p e iously men ioned, CS is a na u al ca ionic polyme which has been demon-
s a ed o p omo e AMT, he eby enhancing NP cellula up ake. Indeed, Taha a e al. [
102
]
in es iga ed CS as a su ace-modi ying agen o imp o e PLGA NPs b ain deli e y. NP
su ace modi ica ion wi h CS inc eased NP concen a ions in he b ain compa ed o un-
Appl. Sci. 2021,11, 4305 19 o 27
modi ied NPs. Mo eo e , CS-PLGA NPs we e abso bed on o he ce eb al blood essel by
adhesion o endo helial cells by means o elec os a ic in e ac ion wi h cell memb anes,
he eby enhancing cellula up ake o CS-PLGA NPs, whe eas unabso bed pa icles we e
elimina ed apidly om blood ci cula ion due o up ake by he RES. The e o e, PLGA NPs
su ace-modi ied wi h CS may play an in e es ing ole o CNS d ug deli e y.
T ime hyla ed chi osan (TMC) is a qua e nized CS de i a i e ha is posi i ely cha ged
unde physiological condi ions [
184
]. As a ca ionic ligand, TMC acili a es NP ac i e ans-
po ia abso p i e-media ed anscy osis. Thus, TMC-modi ied NPs can be exploi ed o
deli e y o he b ain [185,186]. Wang e al. [100] p epa ed PLGA-NPs and hen employed
co alen binding o a ach TMC o he su ace o PLGA–NPs and o m TMC/PLGA-NPs.
The ob ained pa icles showed a mean diame e o 150 nm and we e dis ibu ed in he
pe i en icula egion o he co ex and he hi d en icle ex ensi ely, while no b ain
up ake o unmodi ied PLGA–NPs was seen, showing ha posi i ely cha ged TMC con-
ibu ed o he elec os a ic in e ac ion wi h he anionic binding si es o he b an capilla ies.
This igge ed he abso p i e-media ed anscy osis pa hway, ollowed by he up ake o
NPs h ough he BBB, eaching he b ain pa enchyma. The inc eased cellula up ake and
anspo in o he b ain a e su ace modi ica ion wi h TMC was u he demons a ed
by Meng e al. [
108
]. Mo eo e , TMC o med a hyd ophilic su ounding, which also
con ibu ed o his enhancemen and a oided up ake by he mononuclea phagocy ic
sys em. As a esul , beha iou al es s conduc ed in mice showed ha hese NPs g ea ly
educed memo y impai men by es o ing i o a no mal le el. Besides, he senile plaque
and biochemical pa ame e es s con i med he b ain- a ge ed e ec s o TMC/PLGA–NPs.
Taken oge he , hese esul s indica e ha TMC su ace-modi ied NPs a e able o c oss he
BBB and could be a p omising s a egy o b ain a ge ing wi h low oxici y [100].
6.3. Pos -T anscy osis NP-B ain In e ac ion
As PLGA NPs a e able o each he b ain, a ge ed deli e y sys ems a e needed so
ha NPs can en e he b ain cells [
97
]. As al eady men ioned, CNS endo helial cells
o e exp ess se e al ecep o s, including T Rs, and hus, ano he p omising s a egy o
imp o e d ug anspo o he b ain is using monoclonal an ibodies (mAbs) o a ge T Rs.
Indeed, T Rs a e o e exp essed in he b ain capilla y endo helium and ha e been demon-
s a ed o unde go endocy osis ( ecep o media ed anscy osis) h ough he BBB [
187
].
Thus, an i ans e in ecep o monoclonal an ibodies such as OX26 a e being used o
BBB c ossing.
In ac , OX26 abili y o ecognize and bind o cells ha exp ess he T R, such as he BBB
endo helial cells, has been well desc ibed [
188
]. Lou ei o e al. [
109
] p oposed PEG-PLGA
NPs unc ionalized wi h wo mAbs o deli e encapsula ed an iamyloid iA
β
5 pep ide in o
he b ain o AD ea men . On he one hand, PEG-PLGA NPs we e conjuga ed wi h OX26
mAb o bind o he T R and c oss he BBB; hey we e conjuga ed wi h DE2B4 mAb o bind
o he A
β
pep ide, he majo cons i uen o AD plaques, he eby ac ing as a a ge ing ligand.
The esul ing PLGA NPs, o mean size o 150–170 nm, we e compa ible wi h he
pa en e al ou e. The
in i o
up ake o PEGyla ed-PLGA NPs (wi hou mAbs a ached)
was signi ican ly lowe when compa ed wi h he up ake o he immune NPs, he eby
con i ming OX26 abili y o inc ease he cellula up ake o NPs. Fu he mo e, PLGA NP
cellula up ake inc eases wi h he densi y o su ace-immobilized an ibody [
189
], explaining
he inc eased cellula up ake o NPs om 8% (wi h OX26) o 14% (wi h OX26 and DE2B4).
Thus, he o mula ion o PLGA NPs conjuga ed wi h hese wo an ibodies is a p omising
sys em o p o ec an iamyloid pep ides om p o eoly ic deg ada ion and o inc ease hei
up ake in he b ain. Howe e , he mechanism o in e naliza ion o PLGA immune NPs
by b ain capilla y endo helial cells needs o be elucida ed, and u u e wo k is equi ed o
con i m ha hese NPs a e e icien o he ea men o AD in ansgenic models. Mo eo e ,
as al eady men ioned, he usage o la ge p o eins such as T R an ibodies can esul in
p oblems like syn hesis p ocedu e, s abili y and immunological esponse [157].
Appl. Sci. 2021,11, 4305 20 o 27
7. Conclusions
Al hough much p og ess has been made owa ds he unde s anding o AD pa hophys-
iology, he e is s ill no clinically accep ed ea men o cu e o hal i s p og ession. Mo eo e ,
he s uc u e o he BBB is a majo obs acle o he deli e y o d ugs in o he b ain o he
ea men o CNS diseases like AD. The e o e, nano echnology-based DDS such as PLGA
NPs ha e eme ged and a e unde in es iga ion. Indeed, he use o PLGA NPs appea s
o be a p omising di ec ion o he ea men o neu odegene a i e diseases, since se e al
s a egies o enhance he anspo o NPs h ough he BBB ha e been de eloped. Indeed,
some o he la es app oaches o PLGA NPs su ace modi ica ion we e discussed in his
e iew a icle, and in mos cases, a single unc ionaliza ion s a egy was no enough. PLGA
NPs composi ion needs o be op imized, choosing app op ia e componen s o ob ain PLGA
o mula ions able o achie e BBB c ossing and p ecise a ge ing, so ha hese o mula ions
can play a i al ole in AD he apy.
Au ho Con ibu ions:
Concep ualiza ion, L.D.A., A.C. (Amanda Cano), M.E. (Mi en E che o) and
E.S.-L.; w i ing—o iginal d a p epa a ion, L.D.A., A.C. (An oni Camins), and E.B.S.; w i ing—
e iew and edi ing, L.D.A., M.E. (Ma a Espina), A.C. (Amanda Cano), A.C. (An oni Camins), E.B.S.,
M.L.G., and E.S.-L.; isualiza ion, moni o ing and esou ces: L.D.A., M.L.G. and E.S.-L. All au ho s
ha e ead and ag eed o he published e sion o he manusc ip .
Funding: This esea ch ecei ed no ex e nal unding.
Acknowledgmen s:
A.C. [Amanda Cano] acknowledges he suppo o he Spanish Minis y o
Science, Inno a ion and Uni e si ies unde he g an Juan de la Cie a (FJC2018-036012-I). Au ho s
acknowledge he suppo o he Spanish Minis y o Economy and Compe i i eness unde he
p ojec SAF2017-84283-R; Biomedical Resea ch Ne wo king Cen e in Neu odegene a i e Diseases
(CIBERNED, CB06/05/0024) and Po uguese Science and Technology Founda ion (FCT) o he
s a egic und (UIDB/04469/2020).
Con lic s o In e es : The au ho s decla e no con lic o in e es .
Re e ences
1.
Se ano-Pozo, A.; F osch, M.P.; Masliah, E.; Hyman, B.T. Neu opa hological Al e a ions in Alzheime Disease. Cold Sp ing Ha b.
Pe spec . Med. 2011,1, a006189. [C ossRe ]
2.
Wong, K.H.; Riaz, M.K.; Xie, Y.; Zhang, X.; Liu, Q.; Chen, H.; Bian, Z.; Chen, X.; Lu, A.; Yang, Z. Re iew o Cu en S a egies o
Deli e ing Alzheime ’s Disease D ugs ac oss he Blood-B ain Ba ie . In . J. Mol. Sci. 2019,20, 318. [C ossRe ] [PubMed]
3.
He sh, D.; Wadajka , A.; Robe s, N.; Pe ez, J.; Connolly, N.; F enkel, V.; Winkles, J.A.; Woodwo h, G.F.; Kim, A.J. E ol ing D ug
Deli e y S a egies o O e come he Blood B ain Ba ie . Cu . Pha m. Des. 2016,22, 1177–1193. [C ossRe ] [PubMed]
4.
Khalin, I.; Alyau din, R.; Ismail, N.M.; Ha on, M.H.; Kuzne so , D.; Na eeza, M.I. Nanoscale d ug deli e y sys ems and he
blood–b ain ba ie . In . J. Nanomed. 2014,9, 795–811. [C ossRe ]
5.
Kuma i, A.; Yada , S.K.; Yada , S.C. Biodeg adable polyme ic nanopa icles based d ug deli e y sys ems. Colloids Su . B
Bioin e aces 2010,75, 1–18. [C ossRe ] [PubMed]
6.
C apa o, E.F.; Bondi’, M.L.; Pi a esi, G.; Ca alla o, G. Nanopa icula e Sys ems o D ug Deli e y and Ta ge ing o he Cen al
Ne ous Sys em. CNS Neu osci. The . 2011,17, 670–677. [C ossRe ] [PubMed]
7.
Li, J. Su ace-Modi ied PLGA Nanopa icles o Ta ge ed D ug Deli e y o Neu ons. In Su ace Modi ica ion o Nanopa icles o
Ta ge ed D ug Deli e y; Sp inge : Be lin/Heidelbe g, Ge many, 2012.
8.
Rip, J.; Schenk, G.J.; De Boe , A.G. Di e en ial ecep o -media ed d ug a ge ing o he diseased b ain. Expe Opin. D ug Deli .
2009,6, 227–237. [C ossRe ]
9.
Danhie , F.; Anso ena, E.; Sil a, J.M.; Coco, R.; Le B e on, A.; P éa , V. PLGA-based nanopa icles: An o e iew o biomedical
applica ions. J. Con ol. Release 2012,161, 505–522. [C ossRe ]
10.
Sha ma, K. Cholines e ase inhibi o s as Alzheime ’s he apeu ics (Re iew). Mol. Med. Rep.
2019
,20, 1479–1487. [C ossRe ]
[PubMed]
11.
Bek is, L.M.; Yu, C.E.; Bi d, T.D.; Tsuang, D.W. Gene ics o Alzheime ’s disease. J. Ge ia . Psychia y
2010
,23, 213–227. [C ossRe ]
[PubMed]
12. Jo m, A.F.; Jolley, D. The incidence o demen ia: A me a-analysis. Neu ology 1998,51, 728–733. [C ossRe ]
13.
Kukull, W.A.; Higdon, R.; Bowen, J.D.; McCo mick, W.C.; Te i, L.; Schellenbe g, G.D.; Van Belle, G.; Jolley, L.; La son, E.B.
Demen ia and Alzheime Disease Incidence. A ch. Neu ol. 2002,59, 1737–1746. [C ossRe ]
14.
Yiannopoulou, K.G.; Papageo giou, S.G. Cu en and u u e ea men s o Alzheime ’s disease. The . Ad . Neu ol. Diso d.
2013
,6,
19–33. [C ossRe ]
Appl. Sci. 2021,11, 4305 21 o 27
15.
Langa, K.M. Cogni i e Aging, Demen ia, and he Fu u e o an Aging Popula ion. In Fu u e Di ec ions o he Demog aphy o Aging;
Na ional Academies P ess: Washing on, DC, USA, 2018.
16.
Cummings, J.; Aisen, P.S.; Dubois, B.; F ölich, L.; Jack, C.R., J .; Jones, R.W.; Mo is, J.C.; Raskin, J.; Dowse , S.A.; Schel ens, P.
D ug de elopmen in Alzheime ’s disease: The pa h o 2025. Alzheime s Res. The . 2016,8, 1–12. [C ossRe ] [PubMed]
17.
Sil e man, W.; Wisniewski, H.M.; Bobinski, M.; Wegiel, J. F equency o s ages o Alzheime - ela ed lesions in di e en age
ca ego ies. Neu obiol. Aging 1997,18, 377–379. [C ossRe ]
18.
Iwa subo, T.; Odaka, A.; Suzuki, N.; Mizusawa, H.; Nukina, N.; Iha a, Y. Visualiza ion o A
β
42 and A
β
40 in senile plaques wi h
end-speci ic Aβmonoclonals: E idence ha an ini ially deposi ed species is Aβ42. Neu on 1994,13, 45–53. [C ossRe ]
19.
Ben ahi , M.; Nyabi, O.; Ve hamme, J.; Tolia, A.; Ho e, K.; Wil ang, J.; Esselmann, H.; De S oope , B. P esenilin clinical mu a ions
can a ec gamma-sec e ase ac i i y by di e en mechanisms. J. Neu ochem. 2006,96, 732–742. [C ossRe ] [PubMed]
20.
Gu, L.; Guo, Z. Alzheime ’s A
β
42 and A
β
40 pep ides o m in e laced amyloid ib ils. J. Neu ochem.
2013
,126, 305–311. [C ossRe ]
21.
Goa e, A.; Cha ie -Ha lin, M.-C.; Mullan, M.; B own, J.; C aw o d, F.; Fidani, L.; Giu a, L.; Haynes, A.; I ing, N.; James, L.;
e al. Seg ega ion o a missense mu a ion in he amyloid p ecu so p o ein gene wi h amilial Alzheime ’s disease. Na u e
1991
,
349, 704–706. [C ossRe ]
22. Zhang, Y.-W.; Thompson, R.; Zhang, H.; Xu, H. APP p ocessing in Alzheime ’s disease. Mol. B ain 2011,4, 3. [C ossRe ]
23. Lane, C.A.; Ha dy, J.; Scho , J.M. Alzheime ’s disease. Eu . J. Neu ol. 2018,25, 59–70. [C ossRe ]
24.
Xu, F.; Fu, Z.; Dass, S.; Ko a ba, A.E.; Da is, J.; Smi h, S.O.; Van Nos and, W.E. Ce eb al ascula amyloid seeds d i e amyloid
β-p o ein ib il assembly wi h a dis inc an i-pa allel s uc u e. Na . Commun. 2016,7, 13527. [C ossRe ]
25. Golde, T.E. The AβHypo hesis. B ain Pa hol. 2005,15, 84–87. [C ossRe ]
26.
Musiek, E.S.; Hol zman, D.M. Th ee dimensions o he amyloid hypo hesis: Time, space and ‘wingmen’. Na . Neu osci.
2015
,18,
800–806. [C ossRe ] [PubMed]
27. Du, X.; Wang, X.; Geng, M. Alzheime ’s disease hypo hesis and ela ed he apies. T ansl. Neu odegene . 2018,7, 1–7. [C ossRe ]
28.
Alonso, A.D.C.; G undke-Iqbal, I.; Ba a, H.S.; Iqbal, K. Abno mal phospho yla ion o au and he mechanism o Alzheime
neu o ib illa y degene a ion: Seques a ion o mic o ubule-associa ed p o eins 1 and 2 and he disassembly o mic o ubules by
he abno mal au. P oc. Na l. Acad. Sci. USA 1997,94, 298–303. [C ossRe ]
29.
Lippens, G.; Sillen, A.; Land ieu, I.; Amniai, L.; Sibille, N.; Ba bie , P.; Le oy, A.; Hanoulle, X.; Wie uszeski, J.-M. Tau Agg ega ion
in Alzheime ’s Disease. P ion 2007,1, 21–25. [C ossRe ]
30.
Iqbal, K.; Liu, F.; Gong, C.X.; G undke-Iqbal, I. Tau in Alzheime Disease and Rela ed Tauopa hies. Cu . Alzheime Res.
2010
,7,
656–664. [C ossRe ] [PubMed]
31.
Šimi´c, G.; Leko, M.B.; W ay, S.; Ha ing on, C.R.; Delalle, I.; Jo ano -Miloše i´c, N.; Bažadona, D.; Buée, L.; De Sil a, R.; Di
Gio anni, G.; e al. Tau P o ein Hype phospho yla ion and Agg ega ion in Alzheime ’s Disease and O he Tauopa hies, and
Possible Neu op o ec i e S a egies. Biomolecules 2016,6, 6. [C ossRe ] [PubMed]
32.
Gong, C.-X.; Iqbal, K. Hype phospho yla ion o Mic o ubule-Associa ed P o ein Tau: A P omising The apeu ic Ta ge o
Alzheime Disease. Cu . Med. Chem. 2008,15, 2321–2328. [C ossRe ]
33.
B ie , M.R.; Go don, B.; F ied ichsen, K.; Mcca hy, J.; S e n, A.; Owen, C.; Aldea, P.; Su, Y.; Hassens ab, J.; Cai ns, N.J.; e al. Tau
and Aβimaging, CSF measu es, and cogni ion in Alzheime ’s disease. Sci. T ansl. Med. 2016,8. [C ossRe ]
34.
Kinney, J.W.; BeMille , S.M.; Mu ishaw, A.S.; Leisgang, A.M.; Salaza , A.M.; Lamb, B.T. In lamma ion as a cen al mechanism in
Alzheime ’s disease. Alzheime ’s Demen . T ansl. Res. Clin. In e . 2018,4, 575–590. [C ossRe ] [PubMed]
35.
Cummings, J.L. Op imizing phase II o d ug de elopmen o disease-modi ying compounds. Alzheime ’s Demen .
2008
,4, 18–23.
[C ossRe ] [PubMed]
36.
Zhang, M.; Schmi -Ulms, G.; Sa o, C.; Xi, Z.; Zhang, Y.; Zhou, Y.; Geo ge-Hyslop, P.S.; Rogae a, E. D ug Reposi ioning o
Alzheime ’s Disease Based on Sys ema ic ‘omics’ Da a Mining. PLoS ONE 2016,11, e0168812. [C ossRe ]
37. Lleo, A. Cu en The apeu ic Op ions o Alzheime s Disease. Cu . Genom. 2008,8, 550–558. [C ossRe ] [PubMed]
38.
Balla d, C.; Co be , A. Managemen o Neu opsychia ic Symp oms in People wi h Demen ia. CNS D ugs
2010
,24, 729–739.
[C ossRe ]
39.
Kim, L.D.; Fac o a, R.M. Alzheime demen ia: S a ing, s opping d ug he apy. Cle el. Clin. J. Med.
2018
,85, 209–214. [C ossRe ]
40.
Raichle, M.E.; Gusna d, D.A. App aising he b ain’s ene gy budge . P oc. Na l. Acad. Sci. USA
2002
,99, 10237–10239. [C ossRe ]
[PubMed]
41.
Me gen hale , P.; Lindaue , U.; Dienel, G.A.; Meisel, A. Suga o he b ain: The ole o glucose in physiological and pa hological
b ain unc ion. T ends Neu osci. 2013,36, 14347–14357. [C ossRe ] [PubMed]
42.
Abbo , N.J.; Pa abendige, A.A.K.; Dolman, D.E.M.; Yuso , S.R.; Begley, D.J. S uc u e and unc ion o he blood-b ain ba ie .
Neu obiol. Dis. 2010,37, 13–25. [C ossRe ] [PubMed]
43.
Abbo , N.J.; Rönnbäck, L.; Hansson, E. As ocy e-endo helial in e ac ions a he blood-b ain ba ie . Na . Re . Neu osci.
2006
,7,
41–53. [C ossRe ] [PubMed]
44.
Jessell, T.M.; Siegelbaum, S.; Hudspe h, A.J. P inciples o Neu al Science; Kandel, E.R., Schwa z, J.H., Jessell, T.M., Eds.; McG aw-
Hill: New Yo k, NY, USA, 2000.
45.
Pandi , R.; Chen, L.; Gö z, J. The blood-b ain ba ie : Physiology and s a egies o d ug deli e y. Ad . D ug Deli . Re .
2019
.
[C ossRe ] [PubMed]

Appl. Sci. 2021,11, 4305 22 o 27
46.
Abbo , N.J. Dynamics o CNS Ba ie s: E olu ion, Di e en ia ion, and Modula ion. Cell. Mol. Neu obiol.
2005
,25, 5–23. [C ossRe ]
[PubMed]
47.
Teleanu, D.M.; Chi co , C.; G umezescu, A.M.; Volceano , A.; Teleanu, R.I. Blood-B ain Deli e y Me hods Using Nano echnology.
Pha maceu ics 2018,10, 269. [C ossRe ] [PubMed]
48.
Shimizu, F.; Sano, Y.; Maeda, T.; Abe, M.-A.; Nakayama, H.; Takahashi, R.-I.; Ueda, M.; Oh suki, S.; Te asaki, T.; Obina a, M.; e al.
Pe iphe al Ne e pe icy es o igina ing om he blood-ne e ba ie exp esses igh junc ional molecules and anspo e s as
ba ie - o ming cells. J. Cell. Physiol. 2008,217, 388–399. [C ossRe ]
49.
Nakagawa, S.; Deli, M.A.; Kawaguchi, H.; Shimizudani, T.; Shimono, T.; Ki el, A.; Tanaka, K.; Niwa, M. A new blood–b ain
ba ie model using p ima y a b ain endo helial cells, pe icy es and as ocy es. Neu ochem. In .
2009
,54, 253–263. [C ossRe ]
[PubMed]
50.
Abbo , N.J. Blood-b ain ba ie s uc u e and unc ion and he challenges o CNS d ug deli e y. J. Inhe i . Me ab. Dis.
2013
,36,
437–449. [C ossRe ]
51.
Hawkins, R.A.; O’Kane, R.L.; Simpson, I.A.; Viña, J.R. S uc u e o he blood-b ain ba ie and i s ole in he anspo o amino
acids. J. Nu . 2006,136, 218–226. [C ossRe ]
52. Daneman, R.; P a , A. The Blood-B ain Ba ie . Neu oimmune Pha macol. 2015, 21–38. [C ossRe ]
53.
Reese, T.S.; Ka no sky, M.J. Fine s uc u al localiza ion o a blood-b ain ba ie o exogenous pe oxidase. J. Cell Biol.
1967
,34,
207–217. [C ossRe ]
54.
B igh man, M.W.; Reese, T.S. Junc ions be ween in ima ely apposed cell memb anes in he e eb a e b ain. J. Cell Biol.
1969
,40,
648–677. [C ossRe ]
55.
Wes e gaa d, E.; B igh man, M.W. T anspo o p o eins ac oss no mal ce eb al a e ioles. J. Comp. Neu ol.
1973
,152, 17–44.
[C ossRe ] [PubMed]
56.
Coombe , B.L.; S ewa , P.A. Mo phome ic analysis o CNS mic o ascula endo helium. Mic o asc. Res.
1985
,30, 99–115.
[C ossRe ]
57.
Ba a , J.; Ra i, M.A.; Pou sei , M.M.; Omidi, Y. Blood-b ain ba ie anspo machine ies and a ge ed he apy o b ain diseases.
BioImpac s 2016,6, 225–248. [C ossRe ]
58. Pa d idge, W.M. D ug T anspo ac oss he Blood–B ain Ba ie . B . J. Pha macol. 2012,32, 1959–1972. [C ossRe ] [PubMed]
59.
Pa el, M.M.; Pa el, B.M. C ossing he Blood–B ain Ba ie : Recen Ad ances in D ug Deli e y o he B ain. CNS D ugs
2017
,31,
109–133. [C ossRe ]
60. Pa d idge, W.M. The blood-b ain ba ie : Bo leneck in b ain d ug de elopmen . Neu oRx 2005,2, 3–14. [C ossRe ] [PubMed]
61.
Neuwel , E.; Abbo , N.J.; Ab ey, L.; Banks, W.A.; Blakley, B.; Da is, T.; Engelha d , B.; G ammas, P.; Nede gaa d, M.; Nu , J.; e al.
S a egies o ad ance ansla ional esea ch in o b ain ba ie s. Lance Neu ol. 2008,7, 84–96. [C ossRe ]
62.
Begley, D.J. Deli e y o he apeu ic agen s o he cen al ne ous sys em: The p oblems and he possibili ies. Pha macol. The .
2004,104, 29–45. [C ossRe ] [PubMed]
63. Golde, T.E. Open ques ions o Alzheime ’s disease immuno he apy. Alzheime ’s Res. The . 2014,6, 3. [C ossRe ]
64.
Leeson, P.D.; Sp ing ho pe, B. The in luence o d ug-like concep s on decision-making in medicinal chemis y. Na . Re . D ug
Disco . 2007,6, 881–890. [C ossRe ] [PubMed]
65.
O’Kee e, E.; Campbell, M. Modula ing he pa acellula pa hway a he blood–b ain ba ie : Cu en and u u e app oaches o
d ug deli e y o he CNS. D ug Disco . Today Technol. 2016,20, 35–39. [C ossRe ]
66.
Ali, I.U.; Chen, X. Pene a ing he Blood B ain Ba ie : P omise o No el Nanopla o ms and Deli e y Vehicles. ACS Nano
2015
,9,
9470–9474. [C ossRe ]
67.
Me z, T.; Haque, T.; Chen, H.; P akash, S.; Am e, D.; Das, S.K. P epa a ion and In Vi o Analysis o Mic ocapsule Thalidomide
Fo mula ion o Ta ge ed Supp ession o TNF-α.D ug Deli . 2006,13, 331–337. [C ossRe ]
68.
Rawa , M.; Singh, D.; Sa a , S.; Sa a , S. Nanoca ie s: P omising Vehicle o Bioac i e D ugs. Biol. Pha m. Bull.
2006
,29, 1790–1798.
[C ossRe ]
69.
Fakhou y, M.; Takechi, R.; Al-Salami, H. D ug Pe mea ion ac oss he Blood-B ain Ba ie : Applica ions o Nano echnology. B . J.
Med. Med. Res. 2015,6, 547–556. [C ossRe ]
70.
Chen, Y.; Liu, L. Mode n me hods o deli e y o d ugs ac oss he blood-b ain ba ie . Ad . D ug Deli . Re .
2012
,64, 640–665.
[C ossRe ]
71.
Pandey, P.K.; Sha ma, A.K.; Gup a, U. Blood b ain ba ie : An o e iew on s a egies in d ug deli e y, ealis ic
in i o
modeling
and in i o li e acking. Tissue Ba ie s 2016,4, 1129476. [C ossRe ] [PubMed]
72.
Khalil, I.R.; Bu ns, A.T.H.; Radecka, I.; Kowalczuk, M.; Khala , T.; Adamus, G.; Johns on, B.; Khecha a, M.P. Bac e ial-De i ed Poly-
me Poly-y-Glu amic Acid (y-PGA)-Based Mic o/Nanopa icles as a Deli e y Sys em o An imic obials and O he Biomedical
Applica ions. In . J. Mol. Sci. 2017,18, 313. [C ossRe ]
73.
Rez an alab, S.; D ude, N.I.; Mo a eji, M.K.; Gü ene , N.; Koons, E.K.; Shi, Y.; Lamme s, T.; Kiessling, F. PLGA-Based
Nanopa icles in Cance T ea men . F on . Pha macol. 2018,9, 1260. [C ossRe ] [PubMed]
74.
Mahapa o, A.; Singh, D.K. Biodeg adable nanopa icles a e excellen ehicle o si e di ec ed in- i o deli e y o d ugs and
accines. J. Nanobio echnol. 2011,9, 55. [C ossRe ] [PubMed]
75.
Pa el, T.; Zhou, J.; Piepmeie , J.M.; Sal zman, W.M. Polyme ic nanopa icles o d ug deli e y o he cen al ne ous sys em. Ad .
D ug Deli . Re . 2012,64, 701–705. [C ossRe ] [PubMed]
Appl. Sci. 2021,11, 4305 23 o 27
76.
K eu e , J.; Alyau din, R.N.; Kha ke ich, D.A.; I ano , A.A. Passage o pep ides h ough he blood-b ain ba ie wi h colloidal
polyme pa icles (nanopa icles). B ain Res. 1995,674, 171–174. [C ossRe ]
77.
Gao, S.; Xu, Y.; Asgha , S.; Chen, M.; Zou, L.; El ayeb, S.; Huo, M.; Ping, Q.; Xiao, Y. Polybu ylcyanoac yla e nanoca ie s as
p omising a ge ed d ug deli e y sys ems. J. D ug Ta ge . 2015,23, 481–496. [C ossRe ] [PubMed]
78.
Sulheim, E.; I e sen, T.-G.; Naks ad, V.T.; Klinkenbe g, G.; Sle a, H.; Schmid, R.; Ha le ei , A.R.; Wågbø, A.M.; Sundan, A.;
Sko land, T.; e al. Cy o oxici y o Poly(Alkyl Cyanoac yla e) Nanopa icles. In . J. Mol. Sci.
2017
,18, 2454. [C ossRe ] [PubMed]
79.
Szwed, M.; Søns e old, T.; Ø e bye, A.; Engedal, N.; G alle , B.; Mø ch, Ý.; I e sen, T.-G.; Sko land, T.; Sand ig, K.; To ge sen,
M.L. The alkyl side chain o PACA nanopa icles dic a es he impac on cellula s ess esponses and he mode o pa icle-induced
cell dea h. BioRxi 2018, 304618. [C ossRe ]
80.
Nagpal, K.; Singh, S.K.; Mish a, D.N. Chi osan Nanopa icles: A P omising Sys em in No el D ug Deli e y. Chem. Pha m. Bull.
2010,58, 1423–1430. [C ossRe ]
81.
Mohammed, M.A.; Syeda, J.T.M.; Wasan, K.M.; Wasan, E.K. An O e iew o Chi osan Nanopa icles and I s Applica ion in
Non-Pa en e al D ug Deli e y. Pha maceu ics 2017,9, 53. [C ossRe ]
82.
Sha ma, S.; Pa ma , A.; Ko i, S.; Sandhi , R. PLGA-based nanopa icles: A new pa adigm in biomedical applica ions. T AC T ends
Anal. Chem. 2016,80, 30–40. [C ossRe ]
83.
Ba ba a, R.; Belle i, D.; Pede zoli, F.; Masoni, M.; Kelle , J.; Balles azzi, A.; Vandelli, M.A.; Tosi, G.; G ab ucke , A.M. No el
Cu cumin loaded nanopa icles enginee ed o Blood-B ain Ba ie c ossing and able o dis up Abe a agg ega es. In . J. Pha m.
2017,526, 413–424. [C ossRe ]
84.
Sil a, A.T.C.R.; Ca doso, B.C.O.; E Sil a, M.E.S.R.; F ei as, R.F.S.; Sousa, R.G. Syn hesis, Cha ac e iza ion, and S udy o PLGA
Copolyme in Vi o Deg ada ion. J. Bioma e . Nanobio echnol. 2015,6, 8–19. [C ossRe ]
85.
Pandey, A.; Jain, D.S. Poly Lac ic-Co-Glycolic Acid (PLGA) Copolyme and I s Pha maceu ical Applica ion. In Handbook o
Polyme s o Pha maceu ical Technologies; Sc i ene : Be e ly, MA, USA, 2015.
86.
Dechy-caba e , O.; Ma in- aca, B.; Bou issou, D. Con olled Ring-Opening Polyme iza ion o Lac ide and Glycolide. Chem. Re .
2004,104, 6147–6176. [C ossRe ]
87.
Enginee , C.; Pa ikh, J.; Ra al, A. Re iew on hyd oly ic deg ada ion beha io o biodeg adable polyme s om con olled d ug
deli e y sys em. T ends Bioma e . A i . O gans 2011,25, 79–85.
88.
Xu, Y.; Kim, C.-S.; Saylo , D.M.; Koo, D. Polyme deg ada ion and d ug deli e y in PLGA-based d ug-polyme applica ions: A
e iew o expe imen s and heo ies. J. Biomed. Ma e . Res. Pa B Appl. Bioma e . 2017,105, 1692–1716. [C ossRe ]
89. Je e y, H.; Da is, S.S.; O’Hagan, D.T. The P epa a ion and Cha ac e iza ion o Poly(lac ide-co-glycolide) Mic opa icles. II. The
En apmen o a Model P o ein Using a (Wa e -in-Oil)-in-Wa e Emulsion Sol en E apo a ion Technique. Pha m. Res. 1993,10,
362–368. [C ossRe ] [PubMed]
90.
F ank, A.; Ra h, S.K.; Venka aman, S.S. Con olled elease om bioe odible polyme s: E ec o d ug ype and polyme
composi ion. J. Con ol. Release 2005,102, 333–344. [C ossRe ] [PubMed]
91.
Lee, L.Y.; Rangana h, S.H.; Fu, Y.; Zheng, J.L.; Lee, H.S.; Wang, C.H.; Smi h, K.A. Pacli axel elease om mic o-po ous PLGA
disks. Chem. Eng. Sci. 2009,64, 4341–4349. [C ossRe ]
92.
Alonso, M.J.; Gup a, R.K.; Min, C.; Sibe , G.R.; Lange , R. Biodeg adable mic osphe es as con olled- elease e anus oxoid
deli e y sys ems. Vaccine 1994,12, 299–306. [C ossRe ]
93.
F edenbe g, S.; Wahlg en, M.; Reslow, M.; Axelsson, A. The mechanisms o d ug elease in poly(lac ic-co-glycolic acid)-based
d ug deli e y sys ems—A e iew. In . J. Pha m. 2011,415, 34–52. [C ossRe ]
94.
Lag eca, E.; Ones o, V.; Di Na ale, C.; La Manna, S.; Ne i, P.A.; Vecchione, R. Recen ad ances in he o mula ion o PLGA
mic opa icles o con olled d ug deli e y. P og. Bioma e . 2020,9, 153–174. [C ossRe ]
95.
Goyal, R.; Mac i, L.K.; Kaplan, H.M.; Kohn, J. Nanopa icles and nano ibe s o opical d ug deli e y. J. Con ol. Release
2016
,240,
77–92. [C ossRe ]
96.
He nández-Gio onini, K.Y.; Rod íguez-Có do a, R.J.; Gu ié ez-Valenzuela, C.A.; Peñuñu i-Mi anda, O.; Za ala-Ri e a, P.;
Gue e o-Ge mán, P.; Luce o-Acuña, A. PLGA nanopa icle p epa a ions by emulsi ica ion and nanop ecipi a ion echniques:
E ec s o o mula ion pa ame e s. RSC Ad . 2020,10, 4218–4231. [C ossRe ]
97.
Cai, Q.; Wang, L.; Deng, G.; Liu, J.; Chen, Q.; Chen, Z. Sys emic deli e y o cen al ne ous sys em by enginee ed PLGA
nanopa icles. Am. J. T ansl. Res. 2016,8, 749–764.
98.
Sah, H.; Thoma, L.A.; Desu, H.R.; Sah, E.; Wood, G.C. Concep s and p ac ices used o de elop unc ional PLGA-based nanopa ic-
ula e sys ems. In . J. Nanomed. 2013,8, 747–765. [C ossRe ] [PubMed]
99.
Hoyos-Ceballos, G.P.; Ruozi, B.; O onelli, I.; Da Ros, F.; Vandelli, M.A.; Fo ni, F.; Daini, E.; Vilella, A.; Zoli, M.; Tosi, G.;
e al. PLGA-PEG-ANG-2 Nanopa icles o Blood–B ain Ba ie C ossing: P oo -o -Concep S udy. Pha maceu ics
2020
,12, 72.
[C ossRe ]
100.
Wang, Z.H.; Wang, Z.Y.; Sun, C.S.; Wang, C.Y.; Jiang, T.Y.; Wang, S.L. T ime hyla ed chi osan-conjuga ed PLGA nanopa icles o
he deli e y o d ugs o he b ain. Bioma e ials 2010,31, 908–915. [C ossRe ] [PubMed]
101.
Li, J.; Feng, L.; Fan, L.; Zha, Y.; Guo, L.; Zhang, Q.; Chen, J.; Pang, Z.; Wang, Y.; Jiang, X.; e al. Ta ge ing he b ain wi h PEG–PLGA
nanopa icles modi ied wi h phage-displayed pep ides. Bioma e ials 2011,32, 4943–4950. [C ossRe ] [PubMed]
102.
Taha a, K.; Miyazaki, Y.; Kawashima, Y.; K eu e , J.; Yamamo o, H. B ain a ge ing wi h su ace-modi ied poly(D,L-lac ic-co-
glycolic acid) nanopa icles deli e ed ia ca o id a e y adminis a ion. Eu . J. Pha m. Biopha m. 2011,77, 84–88. [C ossRe ]
Appl. Sci. 2021,11, 4305 24 o 27
103.
Jin, Y.; Xu, A.; Yao, M.; Li, B.; Ying, J.; Xu, G.; Ma, W. A physical model o he size-dependen cellula up ake o nanopa icles
modi ied wi h ca ionic su ac an s. In . J. Nanomed. 2012,7, 3547–3554. [C ossRe ]
104.
Ma hew, A.; Fukuda, T.; Nagaoka, Y.; Hasumu a, T.; Mo imo o, H.; Yoshida, Y.; Maekawa, T.; Venugopal, K.; Kuma , D.S.
Cu cumin Loaded-PLGA Nanopa icles Conjuga ed wi h Te -1 Pep ide o Po en ial Use in Alzheime ’s Disease. PLoS ONE
2012
,
7, e32616. [C ossRe ]
105.
Paka, G.D.; Ramassamy, C. Op imiza ion o Cu cumin-Loaded PEG-PLGA Nanopa icles by GSH Func ionaliza ion: In es iga ion
o he In e naliza ion Pa hway in Neu onal Cells. Mol. Pha m. 2017,14, 93–106. [C ossRe ]
106.
Fan, S.; Zheng, Y.; Liu, X.; Fang, W.; Chen, X.; Liao, W.; Jing, X.; Lei, M.; Tao, E.; Ma, Q.; e al. Cu cumin-loaded PLGA-PEG
nanopa icles conjuga ed wi h B6 pep ide o po en ial use in Alzheime ’s disease. D ug Deli . 2018,25, 1044–1055. [C ossRe ]
107.
Huang, N.; Lu, S.; Liu, X.; Zhu, J.; Wang, Y. PLGA nanopa icles modi ied wi h a BBB-pene a ing pep ide co-deli e ing A
β
gene a ion inhibi o and cu cumin a enua e memo y de ici s and neu opa hology in Alzheime ’s disease mice. Onco a ge
2017
,
8, 81001–81013. [C ossRe ] [PubMed]
108.
Meng, Q.; Hua, H.; Jiang, Y.; Wang, Y.; Mu, H.; Wu, Z. In anasal deli e y o Hupe zine A o he b ain using lac o e in-conjuga ed
N- ime hyla ed chi osan su ace-modi ied PLGA nanopa icles o ea men o alzheime ’s disease. In . J. Nanomed.
2018
,13,
705–718. [C ossRe ] [PubMed]
109.
Lou ei o, J.A.; Gomes, B.; F icke , G.; Coelho, M.A.; Rocha, S.; Pe ei a, M.C. Cellula up ake o PLGA nanopa icles a ge ed wi h
an i-amyloid and an i- ans e in ecep o an ibodies o Alzheime ’s disease ea men . Colloids Su . B Bioin e aces
2016
,145,
8–13. [C ossRe ]
110.
Sánchez-López, E.; E che o, M.; Egea, M.A.; Espina, M.; Cano, A.; Calpena, A.C.; Camins, A.; Ca mona, N.; Sil a, A.M.; Sou o,
E.B.; e al. Meman ine loaded PLGA PEGyla ed nanopa icles o Alzheime ’s disease:
In i o
and
in i o
cha ac e iza ion. J.
Nanobio echnol. 2018,16, 1–16. [C ossRe ] [PubMed]
111.
Behzadi, S.; Se pooshan, V.; Tao, W.; Hamaly, M.A.; Alkawa eek, M.Y.; D eaden, E.C.; B own, D.; Alkilany, A.M.; Fa okhzad, O.C.;
Mahmoudi, M. Cellula up ake o nanopa icles: Jou ney inside he cell. Chem. Soc. Re . 2017,46, 4218–4244. [C ossRe ]
112.
Jain, K.K. Nanobio echnology-based s a egies o c ossing he blood-b ain ba ie . Nanomedicine
2012
,7, 1225–1233. [C ossRe ]
113.
Owens, D.E.; Peppas, N.A. Opsoniza ion, biodis ibu ion, and pha macokine ics o polyme ic nanopa icles. In . J. Pha m.
2006
,
307, 93–102. [C ossRe ]
114.
Heinz, H.; P amanik, C.; Heinz, O.; Ding, Y.; Mish a, R.K.; Ma chon, D.; Fla , R.J.; Es ela-Lopis, I.; Llop, J.; Moya, S.; e al.
Nanopa icle deco a ion wi h su ac an s: Molecula in e ac ions, assembly, and applica ions. Su . Sci. Rep.
2017
,72, 1–58.
[C ossRe ]
115.
Swide , E.; Koshkina, O.; Tel, J.; C uz, L.J.; de V ies, I.J.M.; S ini as, M. Cus omizing poly(lac ic-co-glycolic acid) pa icles o
biomedical applica ions. Ac a Bioma e . 2018,73, 38–51. [C ossRe ]
116.
Song, K.C.; Lee, H.S.; Choung, I.Y.; Cho, K.I.; Ahn, Y.; Choi, E.J. The e ec o ype o o ganic phase sol en s on he pa icle size o
poly(D,L-lac ide-co-glycolide) nanopa icles. Colloids Su aces A Physicochem. Eng. Asp. 2006,276, 162–167. [C ossRe ]
117.
As e e, C.E.; Sablio , C.M. Syn hesis and cha ac e iza ion o PLGA nanopa icles. J. Bioma e . Sci. Polym. Ed.
2006
,17, 247–289.
[C ossRe ] [PubMed]
118.
Sah, E.; Sah, H. Recen T ends in P epa a ion o Poly(lac ide-co-glycolide) Nanopa icles by Mixing Polyme ic O ganic Solu ion
wi h An isol en . J. Nanoma e . 2015. [C ossRe ]
119.
Tang, N.; Du, G.; Wang, N.; Liu, C.; Hang, H.; Liang, W. Imp o ing Pene a ion in Tumo s Wi h Nanoassemblies o Phospholipids
and Doxo ubicin. J. Na l. Cance Ins . 2007,99, 1004–1015. [C ossRe ] [PubMed]
120.
K a z, F. Albumin as a d ug ca ie : Design o p od ugs, d ug conjuga es and nanopa icles. J. Con ol. Release
2008
,132, 171–183.
[C ossRe ]
121.
Es andya i-Manesh, M.; Mos a a i, S.H.; Majidi, R.F.; Koopaei, M.N.; Ra a i, N.S.; Amini, M.; Da ishi, B.; Os ad, S.N.; A yabi,
F.; Dina and, R. Imp o ed an icance deli e y o pacli axel by albumin su ace modi ica ion o PLGA nanopa icles. DARU J.
Pha m. Sci. 2015,23, 1–8. [C ossRe ] [PubMed]
122.
To chilin, V.P.; T ube skoy, V.S. Which polyme s can make nanopa icula e d ug ca ie s long-ci cula ing? Ad . D ug Deli . Re .
1995,16, 141–155. [C ossRe ]
123.
De Jaeghe e, F.; Allémann, E.; Le oux, J.; S e els, W.; Feijen, J.; Doelke , E.; Gu ny, R. Fo mula ion and Lyop o ec ion o Poly(Lac ic
Acid-Co-E hylene Oxide) Nanopa icles: In luence on Physical S abili y and In Vi o Cell Up ake. Pha m. Res.
1999
,16, 859–866.
[C ossRe ]
124.
Moghimi, S.; Hun e , A. Poloxame s and poloxamines in nanopa icle enginee ing and expe imen al medicine. T ends Bio echnol.
2000,18, 412–420. [C ossRe ]
125.
Shubh a, Q.T.H.; Tó h, J.; Gyenis, J.; Feczkó, T. Poloxame s o Su ace Modi ica ion o Hyd ophobic D ug Ca ie s and Thei
E ec s on D ug Deli e y. Polym. Re . 2014,54, 112–138. [C ossRe ]
126.
Mi akabad, F.S.T.; Neja i-Koshki, K.; Akba zadeh, A.; Yamchi, M.R.; Milani, M.; Za ghami, N.; Zeighamian, V.; Rahimzadeh, A.;
Alimohammadi, S.; Hani ehpou , Y.; e al. PLGA-Based Nanopa icles as Cance D ug Deli e y Sys ems. Asian Pac. J. Cance P e .
2014,15, 517–535. [C ossRe ]
127.
Yang, Q.; Lai, S.K. An i-PEG immuni y: Eme gence, cha ac e is ics, and unadd essed ques ions. In Nanomedicine and Nanobio ech-
nology; Wiley: Hoboken, NJ, USA, 2015.
Appl. Sci. 2021,11, 4305 25 o 27
128.
Suk, J.S.; Xu, Q.; Kim, N.; Hanes, J.; Ensign, L.M. PEGyla ion as a s a egy o imp o ing nanopa icle-based d ug and gene
deli e y. Ad . D ug Deli . Re . 2017,99, 28–51. [C ossRe ]
129.
Liu, L.; Guo, K.; Lu, J.; Venka aman, S.S.; Luo, D.; Ng, K.C.; Ling, E.-A.; Moochhala, S.; Yang, Y.-Y. Biologically ac i e co e/shell
nanopa icles sel -assembled om choles e ol- e mina ed PEG–TAT o d ug deli e y ac oss he blood–b ain ba ie . Bioma e ials
2008,29, 1509–1517. [C ossRe ] [PubMed]
130.
Tobío, M.; Sánchez, A.; Vila, A.; So iano, I.; E o a, C.; Vila-Ja o, J.; Alonso, M. The ole o PEG on he s abili y in diges i e
luids and
in i o
a e o PEG-PLA nanopa icles ollowing o al adminis a ion. Colloids Su . B Bioin e aces
2000
,18, 315–323.
[C ossRe ]
131.
Ra iei, P.; Haddadi, A. Doce axel-loaded PLGA and PLGA-PEG nanopa icles o in a enous applica ion: Pha macokine ics and
biodis ibu ion p o ile. In . J. Nanomed. 2017,12, 935–947. [C ossRe ]
132.
Yan, L.; Wang, H.; Jiang, Y.; Liu, J.; Wang, Z.; Yang, Y.; Huang, S.; Huang, Y. Cell-pene a ing pep ide-modi ied PLGA nanopa icles
o enhanced nose- o-b ain mac omolecula deli e y. Mac omol. Res. 2013,21, 435–441. [C ossRe ]
133.
Fon aine, S.D.; Reid, R.; Robinson, L.; Ashley, G.W.; San i, D.V. Long-Te m S abiliza ion o Maleimide–Thiol Conjuga es.
Bioconjuga e Chem. 2015,26, 145–152. [C ossRe ]
134.
Ma ínez-Jo ha , L.; Doulke idou, S.; Schi ele s, R.M.; To ano, J.S.; Oli ei a, S.; an Nos um, C.F.; Hennink, W.E. Insigh s in o
maleimide- hiol conjuga ion chemis y: Condi ions o e icien su ace unc ionaliza ion o nanopa icles o ecep o a ge ing.
J. Con ol. Release 2018,282, 101–109. [C ossRe ]
135.
Vamise i, G.B.; Sa ish, G.; Sulkshane, P.; Mann, G.; Glickman, M.H.; B ik, A. On-Demand De achmen o Succinimides on
Cys eine o Facili a e (Semi) Syn hesis o Challenging P o eins. J. Am. Chem. Soc. 2020,142, 19558–19569. [C ossRe ] [PubMed]
136.
Nampalli, S.; McDougall, M.G.; La eno , K.; Xiao, H.; Kuma , S. U ili y o hiol-c oss-linked luo escen dye labeled e mina o s
o DNA sequencing. Bioconjuga e Chem. 2002,13, 468–473. [C ossRe ]
137.
Alley, S.C.; Benjamin, D.R.; Je ey, S.C.; Okeley, N.M.; Meye , D.L.; Sande son, R.J.; Sen e , P.D. Con ibu ion o Linke S abili y o
he Ac i i ies o An icance Immunoconjuga es. Bioconjuga e Chem. 2008,19, 759–765. [C ossRe ]
138.
Lin, D.; Saleh, S.; Lieble , D.C. Re e sibili y o Co alen Elec ophile
−
P o ein Adduc s and Chemical Toxici y. Chem. Res. Toxicol.
2008,21, 2361–2369. [C ossRe ] [PubMed]
139.
Smi h, M.E.B.; Caspe sen, M.B.; Robinson, E.; Mo ais, M.; Ma uani, A.; Nunes, J.P.M.; Nicholls, K.; Sax on, M.J.; Caddick, S.;
Bake , J.R.; e al. A pla o m o e icien , hiol-s able conjuga ion o albumin’s na i e single accessible cys eine. O g. Biomol. Chem.
2015,13, 7946–7949. [C ossRe ] [PubMed]
140. Sie e s, E.L.; Sen e , P.D. An ibody-D ug Conjuga es in Cance The apy. Annu. Re . Med. 2013,64. [C ossRe ] [PubMed]
141.
Sen e , P.D.; Sie e s, E.L. The disco e y and de elopmen o b en uximab edo in o use in elapsed Hodgkin lymphoma and
sys emic anaplas ic la ge cell lymphoma. Na . Bio echnol. 2012,30, 631–637. [C ossRe ]
142.
Shen, B.-Q.; Xu, K.; Liu, L.; Raab, H.; Bhak a, S.; Ken ick, M.; Pa sons-Repon e, K.L.; Tien, J.; Yu, S.-F.; Mai, E.; e al. Conjuga ion
si e modula es he
in i o
s abili y and he apeu ic ac i i y o an ibody-d ug conjuga es. Na . Bio echnol.
2012
,30, 184–189.
[C ossRe ] [PubMed]
143.
Jazaye i, M.H.; Amani, H.; Pou a ollah, A.A.; Pazoki-To oudi, H.; Sedighimoghaddam, B. Va ious me hods o gold nanopa icles
(GNPs) conjuga ion o an ibodies. Sens. BioSens. Res. 2016,9, 17–22. [C ossRe ]
144.
Zhou, Y.; Ande sson, O.; Lindbe g, P.; Liedbe g, B. Re e sible Hyd ophobic Ba ie s In oduced by Mic ocon ac P in ing:
Applica ion o P o ein Mic oa ays. Mic ochim. Ac a 2004,146, 193–205. [C ossRe ]
145.
Wu, R.H.; Nguyen, T.P.; Ma qua , G.W.; Miesen, T.J.; Mau, T.; Mackiewicz, M.R. A Facile Rou e o Tailo ing Pep ide-S abilized
Gold Nanopa icles Using Glu a hione as a Syn hon. Molecules 2014,19, 6754–6775. [C ossRe ]
146.
Demeule, M.; Régina, A.; Ché, C.; Poi ie , J.; Nguyen, T.; Gaba hule , R.; Cas aigne, J.-P.; Béli eau, R. Iden i ica ion and Design o
Pep ides as a New D ug Deli e y Sys em o he B ain. J. Pha macol. Exp. The . 2008,324, 1064–1072. [C ossRe ]
147.
Ma zolo, M.-P.; Yuse , M.I.; Re amal, C.; Donoso, M.; Ezque , F.; Fa án, P.; Li, Y.; Bu, G. Di e en ial Dis ibu ion o Low-Densi y
Lipop o ein-Recep o -Rela ed P o ein (LRP) and Megalin in Pola ized Epi helial Cells is De e mined by hei Cy oplasmic
Domains. T a ic 2003,4, 273–288. [C ossRe ]
148. Spuch, C.; O olano, S.; Na a o, C. LRP-1 and LRP-2 ecep o s unc ion in he memb ane neu on. T a icking mechanisms and
p o eoly ic p ocessing in alzheime ’s disease. F on . Physiol. 2012,3, 269. [C ossRe ] [PubMed]
149.
Tian, X.; Nybe g, S.; Sha p, P.S.; Madsen, J.; Daneshpou , N.; A mes, S.P.; Be wick, J.; Azzouz, M.; Shaw, P.; Abbo , N.J.; e al.
LRP-1-media ed in acellula an ibody deli e y o he Cen al Ne ous Sys em. Sci. Rep. 2015,5, 11990. [C ossRe ]
150.
Aude se , L.; Cullen, C.L.; Young, K.M. Low Densi y Lipop o ein-Recep o Rela ed P o ein 1 Is Di e en ially Exp essed by
Neu onal and Glial Popula ions in he De eloping and Ma u e Mouse Cen al Ne ous Sys em. PLoS ONE
2016
,11, e155878.
[C ossRe ]
151.
Wang, L.; Hao, Y.; Li, H.; Zhao, Y.; Meng, D.; Li, D.; Shi, J.; Zhang, H.; Zhang, Z.; Zhang, Y. Co-deli e y o doxo ubicin and siRNA
o glioma he apy by a b ain a ge ing sys em: Angiopep-2-modi ied poly(lac ic-co-glycolic acid) nanopa icles. J. D ug Ta ge .
2015,23, 832–846. [C ossRe ] [PubMed]
152.
Tiwa i, S.K.; Aga wal, S.; Se h, B.; Yada , A.; Nai , S.; Bha naga , P.; Ka maka , M.; Kuma i, M.; Chauhan, L.K.S.; Pa el, D.K.; e al.
Cu cumin-Loaded Nanopa icles Po en ly Induce Adul Neu ogenesis and Re e se Cogni i e De ici s in Alzheime ’s Disease
Model iaCanonical Wn /β-Ca enin Pa hway. ACS Nano 2014,8, 76–103. [C ossRe ]