1
o Alzheime 's and Pa kinson's diseases
Sa a He nando1,2,&, Oihane Ga ziandia1,2,&, Ena a He an1,2, Jose Luis Ped az1,2, Manoli
Iga ua1,2, Rosa Ma ia He nandez1,2,*
1NanoBioCel G oup, Labo a o y o Pha maceu ics, School o Pha macy, Uni e si y o he
Basque Coun y (UPV/EHU), Vi o ia-Gas eiz, 01006, Spain; 2Biomedical Resea ch Ne wo king
Cen e in Bioenginee ing, Bioma e ials and Nanomedicine (CIBER-BBN), Vi o ia-Gas eiz, 01006,
Spain.
*Co esponding au ho : R.M. He nández ( osa.he nande[email p o ec ed]s). NanoBioCel G oup,
Labo a o y o Pha maceu ics, School o Pha macy, Uni e si y o he Basque Coun y
(UPV/EHU), Paseo de la Uni e sidad 7, 01006 Vi o ia-Gas eiz, Spain. Tel: +34 945013095; Fax:
+34 945013040
&These wo au ho s con ibu ed equally o he wo k.
Ad ances in nanomedicine o he ea men
He nando, S., Ga ziandia, O., He an, E., Ped az, J. L., Iga ua, M., & He nandez, R. M. (2016). Ad ances in Nanomedicine o he T ea men o Alzheime ’s and Pa kinson’s
Diseases. Nanomedicine, 11(10), 1267–1285. . This is an Accep ed Manusc ip o an a icle published by Taylo & F ancis in Nanomedicine on 14 Ap 2016, a ailable a : h ps://
doi.o g/10.2217/nnm-2016-0019. I is deposi 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
2
ABSTRACT
Alzheime ‘s disease (AD) and Pa kinson’s disease (PD) a e he mos common
neu odegene a i e diseases (NDs) wo ldwide. Despi e all he e o s made by he scien i ic
communi y, cu en a ailable ea men s ha e limi ed e ec i eness, wi hou hal ing he
p og ession o he disease. Tha is why, new molecules such as g ow h ac o s (GF),
an ioxidan s and me al chela o s ha e been aised as new he apeu ical app oaches. Howe e ,
hese molecules ha e di icul ies o c oss he blood b ain ba ie (BBB) limi ing i s he apeu ic
e ec . The de elopmen o nanome ic d ug deli e y sys ems (DDS) may pe mi a a ge ed and
sus ained elease o old and new ea men s o e ing a no el s a egy o ea hese
neu odegene a i e diso de s. This e iew summa ized he main in es iga ed DDS as p omising
app oaches o ea AD and PD.
Keywo ds: Alzheime ’s disease, Pa kinson’s disease, nano echnology, nanomedicine, d ug
deli e y sys ems
3
INTRODUCTION
Neu odegene a i e diseases (NDs) a e cha ac e ized by a con inuous s uc u al and unc ional
neu onal loss, usually co ela ed wi h neu onal dea h. Due o his de e io a ion, some
cogni i e, mo o , emo ional and senso y unc ions o pa ien s a e a ec ed. Be ween di e en
NDs, Alzheime ’s disease (AD) and Pa kinson’s disease (PD) a e he i s and he second mos
common diso de s, espec i ely [1]. AD is caused by an i e e sible neu onal loss and ascula
oxici y due o amyloid be a (Aβ) pep ide ex acellula deposi ion in senile plaques, oge he
wi h neu o ib illa y angles o phospho yla ed au p o ein. The p og essi e loss o memo y,
de e io a ion o judgmen decision, o ien a ion o physical su ounding and language a e he
mos impo an clinical hallma ks o his disease [2-5]. Rega ding PD, i is pa hologically
cha ac e ized by he degene a ion o midb ain dopamine gic neu ons in he subs an ia nig a
(SN), ollowed by he dopamine dec ease in he s ia um (ST). The pa kinsonism is he se o
clinical symp oms ha cha ac e ize he disease, among which a e b adykinesia, es ing emo ,
igidi y and pos u al ins abili y [5,6]. As shown in Table 1, he app o ed and mos commonly
used ea men s o AD a e ace ylcholines ase inhibi o s ( ac ine, donepezil, i as igmine,
galan amine) and N-me hyl-D-aspa a e ecep o an agonis (meman ine). All o hem a e
adminis e ed by he o al ou e, and i as igmine can also be ansde mically adminis e ed
using pa ches. In ela ion o PD, cu en pha macological he apies a e based on dopamime ic
d ugs (Bense azide/Le odopa, Le odopa/Ca bidopa, Le odopa/Ca bidopa/En acapona)
adminis e ed by he o al ou e.
Table 1. Cu en pha macological ea men s o AD and PD.
ND
D ug
Mode o ac ion
AD
Tac ine
Ace ylcholines ase
inhibi o s
Donepezil
Ri as igmine
Galan amine
Meman ine
N-me hyl-D-
aspa a e ecep o
an agonis
PD
Bense azide/Le odopa
Dopamime ic
Le odopa/Ca bidopa
Le odopa/Ca bidopa/En acapona
Ne e heless, i is impo an o no e ha he ea men s men ioned abo e a e only
symp oma ic, wi h a empo a y e ec , and wi hou hal ing he p og ession o he disease [3].
The eby, he esea che s a e making big e o s sea ching new he apies o add ess he
neu odegene a i e p ocess.
NEW PROMISING MOLECULES FOR THE TREATMENT OF AD AND PD
Bea ing in mind ha nowadays he clinical ea men s o AD and PD a e mainly symp oma ic,
he de elopmen o new he apeu ic op ions o add ess he main causes o neu odegene a i e
diseases a e u gen ly needed. In his sense, in he las yea s new p omising molecules such as
neu o ophic ac o s (NTFs), an ioxidan molecules and me al chela o s ha e been conside ed
p omising app oaches o a ain his pu pose.
4
Acco dingly, g ow h ac o s (GFs) a e a g oup o p o eins which a e able o imp o e he
g ow h, p oli e a ion and di e en ia ion o neu onal cells, ha ing also a signi ican ole in
issue mo phogenesis, cell di e en ia ion, angiogenesis and neu i e ou g ow h [7-9]. Table 2
desc ibes he main neu o ophic ac o s (NTFs) used o de elop new he apies owa ds AD and
PD, in o de o add ess di ec ly he p og ession o he disease.
Table 2. Di e en g ow h ac o s and hei main unc ions in he cen al ne ous sys em (CNS).
G ow h ac o
Main unc ions
Re
Glial-de i ed neu o ophic
ac o (GDNF)
High speci ici y agains dopamine gic
neu ons.
P o ec i e and ophic e ec s on
no ad ene gic neu ons o he locus
coe uleus.
[10,11]
B ain-de i ed neu o ophic
ac o (BDNF)
Impo an ole in he no mal de elopmen
o he pe iphe al and CNS.
P omo es he synap ic plas ici y and
su i al o neu ons in adul b ains.
[12]
Ne e g ow h ac o (NGF)
P omo es he su i al, di e en ia ion and
main enance o sympa he ic and senso y
neu ons, ha ing neu op o ec i e and
epai unc ions.
[13]
Cilia y neu o ophic ac o
(CNTF)
Abili y o suppo he su i al and/o
di e en ia ion o sympa he ic, senso y, o
mo o neu ons.
[14]
Insulin g ow h ac o -I (IGF-I)
Helps in he su i al o neu ons and
escue om neu o oxici y, s imula ing
also he neu ogenesis and synap ogenesis.
[15]
Vascula endo helial g ow h
ac o (VEGF)
S imula es angiogenesis and he
de elopmen o endo helial cells.
Enhances neu onal g ow h and su i al,
and axonal ou g ow h.
[16,17]
Neu o ophin (NT-3)
Su i al and di e en ia ion o neu ons,
and in neu i e g ow h.
[18]
On he o he hand, i is commonly known ha oxida i e s ess plays an impo an ole in he
pa hophysiology o NDs such as AD and PD. Recen esea ch wo ks ha e demons a ed ha
he p oduc s gene a ed om ee- adical media ed eac ions a e inc eased in NDs, being
ela ed wi h he hallma ks o hese diseases [19-28]. Mo eo e , ansi ion me als ha e been
sugges ed o be esponsible o neu onal damage in AD [20]. In an a emp o ea o p e en
hese NDs, bo h an ioxidan s and me al chela o s ha e been aised as new ea men
app oaches. In he Table 3 i has been summa ized he s udied molecules and he ou come o
hei use in AD and PD.
Table 3. An ioxidan s and me al chela o s and hei he apeu ic unc ions in CNS
Molecule
Main unc ions
Re .
Res e a ol
Reduc ion in Aβ pa hway and a enua ion o cogni i e
decline. [21]
[22,23]
5
Up egula ion o he an ioxidan s a us and educ ion o
dopamine gic neu onal loss, imp o ing he o a ional
beha io .
Cu cumin
Inc ease o β-amyloid-deg ading enzymes;
P o ec ion agains oxida ion and imp o emen o
beha io al es s.
[24]
[25]
Ca echins
Dec ease in Aβ le els and plaques.
[24]
Me al chela o s
49% dec ease in Aβ deposi ion; inhibi ion o τ
phospho ila ion.
[26,27]
Coenzyme Q10
P o ec ion o he nig os ia al dopamine gic sys em;
Delay o he syn oma ology in PD pa ien s.
[28]
Ne e heless, wha e e he ea men , he clinical applica ion o all o hese new molecules is
limi ed. Some o hese d awbacks come a e hei in i o adminis a ion, due o hei sho
ci cula ion hal -li e and apid deg ada ion a e [29]. Hence, high doses a e equi ed o ob ain
he apeu ic le els in he b ain, wi h he isk o su e ing ad e se sys emic e ec s [30].
Howe e , he main obs acle o mos o he d ugs o access he b ain is he p esence o he
blood b ain-ba ie (BBB) (Figu e 1), ha ing big di icul ies o c oss i , due o hei unsui able
lipophili y, molecula weigh o cha ge. Thus, his ba ie es ic s he e ec i e deli e y and
di usion o he apeu ic molecules o he CNS [31], main aining CNS homeos asis and hinde ing
he ee pene a ion and di usion o o eign componen s om he bloods eam o he b ain
[32].
Figu e 1. Schema ic illus a ion o he BBB and i s igh junc ion s uc u e. The igu e shows an
i iga ed blood essel in he b ain which o ms he BBB. The BBB is o med by endo helial cells
wi h igh junc ions, su ounded by pe icy es and as ocy e end- ee .
The e o e, o e he yea s di e en s a egies o access he b ain ha e been de eloped, and
he di e en app oaches o c oss o by-pass he BBB can be di ided in o in asi e and non-
in asi e echniques (Figu es 2 and 3) [32]. As shown in Figu e 2, he in asi e echniques
enclose su gical me hods o adminis e d ugs di ec ly in o he b ain, and he dis up ion o he
6
BBB o in en ionally open i , while he non-in asi e echniques showed in Figu e 3 include non-
agg essi e app oaches o access in o he b ain, such as he in anasal adminis a ion o he
encapsula ion o d ugs wi hin nano echnological ca ie s.
Figu e 2. A schema ic ep esen a ion o he in asi e echniques used o deli e d ugs o he
b ain.
Figu e 3. A schema ic ep esen a ion o he non-in asi e echniques used o deli e d ugs o
he b ain.
All in all, g ea e o s a e being made by scien i ic communi y in he sea ch o adequa e
echnologies o b ain a ge ing, and in he las yea s, he nano echnology has appea ed as a
p omising solu ion o deal wi h his challenge [31].
NANOTECHNOLOGY SOLUTIONS FOR NEURODEGENERATIVE DISEASES
Nano echnology is an eme ging ield o science wi h p omising physiochemical p ope ies o
he ea men o neu odegene a i e diseases [33-35]. In his sec ion we ha e ocused on
desc ibing he ad ances made in nanomedicine o he ea men s o PD and AD, conc e ely.
7
Table 4 summa ized he d ug deli e y sys ems (DDS) mainly in es iga ed o he adminis a ion
o di e en d ugs o ea NDs (Table 4).
Table 4. Mainly used DDSs in he ea men o NDs.
AD and nano echnology.
DDSs o elease ace ylcholines ase inhibi o s and NMDA ecep o an agonis .
Ri as igmine (RT) is a e e sible inhibi o o bo h ace ylcholines ase (AchE) and
bu ylcholines ase (BuChE) which has low bioa ailabili y due o i s hid ophilic na u e. The
Nano echnology
de ice
Schema ic illus a ions Cha ac e is ics
Re .
Polyme ic
( unc ionalized)
nanopa icles
(NP)
Mic osphe es and nanosphe es a e
cons i u ed o biodeg adable and
biocompa ible ma e ials. The apeu ic
agen s a e en apped in he colloidal
ma ix o coa ed on he su ace by
adso p ion o conjuga ion. Mo eo e ,
ligands can be linked on he su ace
enhancing cell pene a ion.
Polyme m
ic ocapsules and
nanocapsules can be p oduced wi h
di e en syn he ic and na u al
monome s/polyme s and wi h
di e en p epa a ion me hods, hei
su ace can be also unc ionalized o
speci ic b ain a ge ing.
[36-39]
(Nano)liposomes
Vesicles composed by concen ic
bilaye s o phospolipid-based
memb anes. I s su ace may be
modi ied by a ge ing agen s achie ing
anspo ac oss BBB.
[40]
Solid lipid
nanopa icle
(SLN)
Lipid nanoca ie s o med by mono-di
and i glyce ides, a y acids, s e oids
and waxes and s abilized by a ious
classes o emulsi ie s.
[41]
Nanos uc u ed
lipid ca ie
(NLC)
Mix u e o solid and liquid lipids wi h
highe encapsula ion e iciency and
be e elease p ope ies.
[42]
Gene he apy:
i al and non
i al ec o s
Speci ic gene o DNA compac ed
ca ie s o a ge cells o issues,
en e ing o he nucleus o be
exp essed.
[43,44]
8
limi ed en y o he b ain makes necessa y equen dosing wo sening choline gic side e ec s
[41,45]. The applica ion o DDSs o o e come hese disad an ages could be sui able. Fo
example, Joshi e al. p epa ed RT loaded poly lac ide-co-gycolide (PLGA) and poly (n-
bu ylcyanoac yla e) NP coa ed wi h polyso ba e 80 (PBCA-80) o imp o e b ain a ge ing.
Mo eo e , hese NP p o ide sus ained elease, educing dosing equency and minimizing side
e ec s. The esul s om he Mo is Wa e Maze (MWM) Tes showed he sui abili y o hese
nano o mula ions egaining memo y as e han RT solu ion in a scopolamine-induced amnesic
mouse (Figu e 4) [46]. Fu he mo e, PBCA nanopa icles ha en been de eloped wi h he aim
o imp o ing diagnos ic imaging. Fo ins ance, Kulka ni e al. p epa ed PBCA loaded I-clioquinol
(CQ, 5-chlo o-7-iodo-8-hyd oxyquinoline)NPs, showing mo e e icien b ain en y and apid
clea ance, which a e he ideal cha ac e is ics o in i o imaging [47].
Figu e 4. Saline- ea ed mice: (a) Tes 1: lea ning and in ac e e ence memo y, (b) Tes 2:
sho - e m wo king memo y. (n = 4); scopolamine- ea ed mice: (c) Tes 1: lea ning and in ac
e e ence memo y, and (d) Tes 2: sho - e m wo king memo y. (n = 4). Abb e ia ions: RS, RT
solu ion; RNP, RT loaded PLGA NPs; RNPB, RT loaded PBCA NPs; ip, in ape i oneal; scop ip,
scopolamine in ape i oneal. Rep oduced wi h pe mission om [46].
On he o he hand, Wilson e al elabo a ed PBCA-80 NP o he a ge ed deli e y o RT in o he
b ain. They obse ed ha he up ake o RT a e in a enous adminis a ion o RT loaded
PBCA-80 NP was 3.82 old highe han he ee d ug [48]. Chi osan NP o RT ha e also been
de eloped by Naqpal e al. in an a emp o inc ease his d ug he apeu ic e icacy and
ole ance p o ile. The s udies demons a ed he educ ion o he oxici y as well as imp o ed
memo y ac i i y in RT chi osan NP ea ed mice compa ed wi h ee RT [49].
In addi ion o he in a enous ou e, he nasal ou e has also been in es iga ed o a oid i s
pass me abolism and dis ibu ion o non- a ge ed o gans hus, dec easing pe iphe al side
e ec s. The adminis a ion o RT chi osan NP ia in anasal ou e has showed an inc ease in
b ain AchE concen a ions, dec easing he le els a lungs o li e [45].
9
SLN ha e also been s udied as a new app oach o in anasal deli e y o RT. Despi e he
hid ophylic na u e o RT, he SLN sys em enhances i s di usion ac oss nasal memb ane due o
he lipidic na u e o hese nanosys ems [41].
Rega ding liposomal o mula ions, subcu aneous adminis a ion o RT loaded liposomes has
been in es iga ed. The pha macodynamic s udy in MWM Tes mani es ed o e coming e ec
o RT loaded liposomes o RT solu ion no malizing cogni i e le el [50].
Ano he comme cialized inhibi o o AchE is donepezil. In i o s udies o donepezil loaded
PLGA NP we e ca ied ou by Bha na e al. They e ealed ha he b ain accumula ion o
donepezil was highe when he d ug was encapsula ed in NP as i was con i med in he gamma
scin ig aphic image. This donepezil loaded NP we e coa ed wi h Tween 80 imp o ing he
opening o he igh junc ions in BBB and inhibi ing P-glycop o ein e lux sys em enhancing
d ug deli e y o he b ain [51].
Galan amine is also known o been a e e sible, compe i i e, AchE inhibi o used in he
ea men o AD. Ne e heless, i s poo b ain pene a ion esul s in lowe bioa ailabili y o he
a ge o gan. Wi h he aim o imp o e hese disad an ages, Mis a e al. elabo a ed SLN loaded
wi h galan amine. A e in i o adminis a ion, injec ed nano o mula ions p esen ed highe
bioa ailabili y han he ee d ug. In addi ion, he nano o mula ed galan amine imp o ed
beha io al de ici s p esen ed in ea ed a s when compa ed wi h he con ol g oup [52]. In
his case he DDSs can also be unc ionalized o imp o e b ain a ge ing. In an a emp o
ob ain i , Mu amadi e al. de eloped pegyla ed nanoliposomes o a ge ed deli e y o
galan amine. They s udied he cellula up ake o unc ionaliza ed galan amine loaded
nanoliposomes in cell cul u es, showing highe a ge ed deli e y han non- unc ionalized
liposomes [40].
Finally, Lase a e al. syn he ized a cod ug o he NMDA an agonis , meman ine, and (R)-α-
lipoic acid (LA-MEM) wi h neu op o ec i e p ope ies. This cod ug was loaded in SLN showing
lack o oxici y in bo h N2a neu oblas oma cells (NB) and p ima y whole blood (PHWB) a e
using MTT (3-(4,5-Dime hyl hiazol-2-yl)-2,5-Diphenyl e azolium B omide) and lac a e
dehyd ogenase (LDH) assays [53].
DDSs o elease GFs
Rega ding GFs, ou esea ch g oup de eloped VEGF loaded PLGA nanosphe es (NS)
adminis e ed by c anio omy as a no el he apeu ic app oach o AD. In i o s udies in co ical
neu onal cul u es showed hei e ec i eness inc easing cell iabili y and p o ec ing neu ons
om Aβ induced oxici y. Fu he mo e, hippocampal neu ogenesis was enhanced in APP/Ps1
mouse model ea ed g oup, which was con i med wi h an inc ease in B dU+cells, specially in
he den a e gy us. Beha io al s udies we e also ca ied ou o demons a e he he apeu ic
e ec o VEFG loaded NS. Mice ea ed wi h VEGF NS p esen ed be e esul s in T-maze es
and objec ecogni ion es , wi h highe explo a o y memo y and an imp o emen in sho -
e m memo y, espec i ely, as shown in Figu e 5 [54,55].
16
pha macodynamic ou comes as hey dec eased akinesias in 6-OHDA hemipa kinsonian a s
[83]. No only akinesia bu also ca alepsia and oxida i e s ess le els ha e been imp o ed in
he esea ch wo k de eloped by Shadab e al. Mo eo e , gamma scin ig aphy imaging has
demons a ed he capaci y o b omoc ip ine loaded chi osan NP o d ug a ge ed b ain
deli e y [37].
Finally, apomo phine is a non-na co ic de i a i e o mo phine which is used in he ea men
o pa ien s wi h ad anced PD. PLGA based NP we e used o he encapsula ion o his d ug,
imp o ing he physiochemical cha ac e is ics o he molecule and ob aining a sus ained
elease acco ding o in i o s udies [36]. Apomo phine loaded SLN we e de eloped by Tsai e .
al. o o al adminis a ion. This nanosys em enhanced he b ain up ake o he d ug in he
s ia um as well as i s bioa ailabili y [84].
DDSs o elease GFs
Jolli e e al. we e he i s ones o p opose DDSs o elease NTFs in o de o ea
neu odegene a i e diso de s. They designed PLGA MS o elease GDNF di ec ly in o he b ain
in a pa ial lesioned a model o PD. The ou comes o hese s udies e ealed he sui abili y o
his o mula ion a e in as ia al adminis a ion o s imula e he axonal egene a ion o
mesencephalic dopamine gic neu ons, which a e a ec ed in PD. Mo eo e , he b ain
implan a ion o GDNF-PLGA-MS inc eased TH+ ibe s (Figu e 8) and neu onal densi y in he
s ia um and subs an ia nig a which was accompanied by unc ional imp o emen in he
lesioned animals [85,86].
Figu e 8. Pho omic og aphs o s ia al TH-i ibe s. Fi e sec ions, which we e used o op ical
densi y (OD) measu emen s, a e shown. The wo-si es lesion induced an ex ensi e do sola e al
and caudal lesion in he non- ea ed a (A). Blank MS implan a ion induced an inc ease o he
ibe s densi y (B) whe eas GDNF-loaded MS induced a s onge einne a ion (C). Rep oduced
wi h pe mission om [85].
17
These esul s a e consis en wi h Ga bayo e al. published wo k, which con i med he
capabili y o PLGA MS o elease his biologically ac i e NTF in bo h in i o and in i o s udies.
Mo eo e , GDNF ea ed animals showed an imp o emen in amphe amine-induced o a ional
asymme y es and in inmunohis ochemical analysis wi h an inc ease in he densi y o TH+
ibe s a he s ia al le el. They could also con i m an inc ease in dopamine gic s ia al neu ons
and long- e m neu op o ec ion and neu o es o a ion by GDNF-MS [87,88].
Wi h he aim o egula ing he GDNF elease om MP, Guj al e al. de eloped PLGA/collagen
MS ha encapsula ed GDNF used wi h a collagen binding p o ein. Only when collagenase
pene a es in o he MS h ough i s po ous su ace, is he collagen phase deg aded. Then, he
GDNF should be de-link om he collagen and di use ou o he MS. In i o s udies a e PLGA
o mula ion adminis a ion, demons a ed he di e en ia ion o neu onal p ogeni o cells in o
ma u e neu ons, which a e p omising esul s o he ea men o PD [89].
The co-adminis a ion o GDNF wi h o he NTFs has also been s udied in o de o in es iga e
he syne gis ic e ec s o hese molecules a e he adminis a ion in o he b ain. Fo example,
Lampe e al. in es iga ed he b ain adminis a ion o BDNF and GDNF loaded PLGA MS wi hin a
deg adable PEG-based hyd ogel. This app oach allowed a di e en elease p o ile o bo h
g ow ac o s dec easing he mic oglial esponse ela ed wi h sham b ain su ge ies [90].
In a di e en s udy, ou esea ch g oup demons a ed he neu o egene a i e po en ial o
PLGA MS and NP encapsula ing VEGF, GDNF and hei combina ion on se e ely and pa ially
lesioned a models. The esul s o hese wo ks p o ed he biological ac i i ies o encapsula ed
NTFs in bo h in i o and in i o s udies. Beha io al and inmunohis ochemical es s we e
imp o ed in he ea ed 6-OHDA lesioned a s as shown in Figu e 9, due o he syne gis ic
e ec o NTF, pe mi ing a educ ion o he dose by a hal [91-93].
18
Figu e 9. His ological e alua ion o he ea men s in he SN.
No es: (A) Schema ic illus a ion o he SN wi h he “ex e nal SN” delimi ed. This a ea is
opologically ela ed o he lesioned a ea o s ia um and includes SNL, a pa o he SNR, and
hal o he SNC. (B) Pic u e o whole SN and delimi ed “ex e nal SN”. Scale ba =1 mm. (C)
Densi y o dopamine gic neu ons in “ex e nal SN”. The esul s a e exp essed as a pe cen age
o lesioned hemisphe e compa ed o he non-lesioned one (con ol). Da a a e shown as he
mean ± s anda d e o o he mean (n=6–8) (#P<0.05 GDNF NS g oup e sus sham g oup;
***P<0.001 VEGF NS and GDNF NS g oup e sus sham and emp y NS g oups). (D)
Pho omic og aphs o SN immunos ained o y osine hyd oxylase om a ep esen a i e in ac
hemisphe e (con ol) and 6-OHDA lesioned hemisphe es om he di e en expe imen al
g oups. Scale ba =1 mm. Abb e ia ions: 6-OHDA, 6-hyd oxydopamine; GDNF, glial cell line-
de i ed neu o ophic ac o ; NS, nanosphe es; SN, subs an ia nig a; SNC, SN pa s compac a;
SNL, SN la e al; SNR, SN pa s e icula a; SNE, SN ex e na; VEGF, ascula endo helial g ow h
ac o . Rep oduced wi h pe mission om [92].
Al hough GDNF is one o he mos s udied NTF o he ea men o PD, o he simila
molecules ha e also been encapsula ed o imp o e i s bioa ailabili y. NGF loaded PBCA NPs
we e able o educe he basic symp oms o PD in a MPTP (1-me hyl-4-phenyl-1,2,3,6-
e ahyd opy idine) a mode[94]. Besides his, gela in NLC encapsula ing bFGF has been
s udied as a no el app oach o a ge he b ain ia nasal adminis a ion. The in anasal NLCs
imp o ed o a ional beha io , monoamine neu o ansmi e le els and TH exp ession in in
i o and in i o s udies wi hou any ad e se e ec s on he in eg i y o nasal mucosa [95].
Finally, as in AD, gene he apy has also been conside ed as a po en ial app oach o he
ea men o PD [44]. In an a emp o ob ain his main goal, adeno i al-media ed GDNF gene
ans e has been s udied in a a model o PD. Kozlowski e al. esul s e ealed he sui abili y
o his nanosys em inc easing he numbe o dopamine gic neu ons in he subs an ia nig a and
main aining unc ional connec ions o he s ia um [96]. In addi ion, Chen e al. esea ch wo k
ein o ces hese ou comes since hey could demons a e he p o ec i e e ec o GDNF gene
ans e a e in ace eb al adminis a ion. Mo eo e , adeno i al (Ad) GDNF ea ed animals
showed an imp o emen in beha io al es s and an inc ease in he su i al o TH+ cells [97].
No only has been demons a ed he e ec i eness o Ad ec o s in mouse models, bu also,
s udies in non-human p ima e models o PD ha e been pe o med. Eslamboli e al and Ebe ling
e al. showed ha Ad-GDNF enhanced DA ac i i y in he s ia um, which was associa ed wi h
clinical imp o emen s wi hou ad e se e ec s in MPTP and 6-OHDA p ima e models o PD,
espec i ely [98,99]. Mo eo e , he in es iga ion led by Ko dowe e al. demons a ed ha he
deli e y o neu u in, a GDNF analogous, ia Ad ec o s p o ided s uc u al and unc ional
neu op o ec ion and neu o es o a ion in MPTP- ea ed monkeys wi hou his ological
pa hology [100].
Howe e , due o he isk o i al gene he apy associa ed wi h inmunogeneci y and sa e y,
sa e and e ec i e non i al gene deli e y ec o s ha e been de eloped [43]. A neu o ensin
polyplex ca ie was elabo a ed o deli e ing GDNF gene in o nig al dopamine neu ons o
hemipa kinsonian a s wi h s e eo axic p ocedu es. RT-PCR and wes e n blo analysis
con i med ha GDNF was co ec ly ans ec ed in he subs an ia nig a educing PD symp oms
19
[101]. In o de o imp o e ans ec ion e iciency o non i al gene ec o s, di e en
modi ica ions on hei su ace ha e been made. Fo ins ance, Chung-Fang e al. de eloped
in a enous GDNF plasmid DNA using T ojan ho se liposomes (THLs) a ge ed wi h a
monoclonal an ibody (MAb) o he a ans e ing ecep o (T R). They obse ed an inc ease
in he concen a ions o GDNF in he subs an ia nig a, which esul ed in a educ ion in
apomo phine-induced o a ions wi h di e en doses o encapsula ed GF (Figu e 10) and an
inc ease in s ia al TH enzyme ac i i y [102].
Figu e 10. Apomo phine-induced o a ion, measu ed in .p.m., in a s wi h expe imen al PD,
and ea ed in a enously wi h saline, o T RMAb- a ge ed THLs ca ying 2, 10 o 20 µg/ a o
encapsula ed pTHp o-GDNF plasmid DNA. The THLs we e gi en on day 0, and o a ion
beha iou was measu ed a 7, 14, 21, 28, 35 and 42 days a e he single in a enous injec ion
o THLs. The a s we e lesioned wi h in a-ce eb al 6-hyd oxydopamine 14 days be o e THL
adminis a ion. S a is is ical di e ences we e de e mined by ANOVA wi h Tukey's pos -hoc
co ec ion; di e ence om saline con ol: #p < 0.05; *p < 0. Rep oduced wi h pe mission om
[102].
Fu he mo e, Huang e al. p oposed a lac o e in-modi ied ec o which was demons a ed o
be e ec i e o b ain gene deli e y o GDNF. Neu op o ec i e e ec s o hese NPs we e
assayed in 6-OHDA lesioned a s and in o enone-induced ch onic PD model. In i o s udies
e ealed i s capabili y o imp o ing locomo o ac i i y, educing dopamine gic neu onal loss
and enhancing monoamine neu o ansmisso le els wi h mul iple in a enous adminis a ions
and wi hou b ain oxici y [103,104].
DDSs o elease o he molecules.
Al hough he e a e scien i ic s udies suppo ing he use o coenzyme Q10 o ea PD, he
esul s de i ed om clinical ials a e inconclusi e. I is may be due o he low solubili y,
bioa ailabili y and b ain pene a ion o his molecule. In an a emp o o e come hese all
d awbacks, Siko ska e al. de eloped a nanomicella o mula ion o coenzyme Q10 and es ed
i s e ec i eness in a mouse MPTP model. The ou comes o his in es iga ion e ealed he
he apeu ic e ec o coenzyme Q10 ia o al adminis a ion o se ing he neu o oxici y be o e
20
and a e MPTP injec ion. This was con i med by cell coun s, analyses o s ia al dopamine
le els and imp o ed animals’ mo o skills on beha io al es s [105].
The an ioxidan e ec o es e a ol has also been enhanced a e been loaded in liposomes.
The beha io s, TH+ cells, apop o ic cells, ROS le el and an ioxidan capaci y we e de e mined
in in i o s udies, showing es e a ol liposome mo e a o able e ec s han ee
es e a ol[106]. Res e a ol has also been loaded in Vi amin E nanoemulsion o imp o e i s
pha machological ac i i ies. Pha macokine ic s udies showed a highe concen a ion o he
d ug in he b ain wi h he nanoemulsion, which was consis en wi h highe an ioxidan ac i i y
e alua ed by DPPH (2,2-diphenyl-1-pic ylhyd azyl) assay [107].
CONCLUSIONS AND FUTURE OUTLOOK
Cu en a ailable he apies o ea AD and PD a e only symp oma ic wi hou modi ying he
p og ession o hese diseases. This ac , along wi h he di icul y o esea ching he pa hways
ha cause NDs, d i es he need o he de elopmen o new he apeu ic al e na i es o
add ess he p oblem o hese NDs.
Gi en his di icul si ua ion, in he las yea s, no only he s anda dized d ugs, bu also new
molecules such as g ow h ac o s, me al chela o s and an ioxidan s ha e been in es iga ed in
o de o s udy hei po en ial ac i i y in he es o a ion and p omo ion o neu onal p ocesses.
Howe e , he physicochemical p ope ies o hese molecules make di icul hei pass ac oss
he BBB o he b ain, limi ing hei e ec i eness and clinical applica ion in i o.
The e o e, he e is a c i ical need o de elop new DDSs o o e come hese d awbacks wi h he
aim o ob aining a ge ed d ug deli e y and a sus ained elease p o ile o he abo e men ioned
d ugs in o he b ain. The apid p og ession o he nanomedicine in he neu oscience a ea, is
gi ing ise o design di e en nanome ic o mula ions ha pe mi he encapsula ion o he
d ugs, p o ec ing hem agains he enzyma ic deg ada ion and helping o each he apeu ic
d ug concen a ions in o he CNS a e hei in i o adminis a ion.
The esul s p esen ed in his e iew suppo he use o nano echnology as a p omising
app oach o con ol he elease o old and new d ugs o he ea men o AD and PD.
Ne e heless, no only u he s udies o he p ope ies o hese nanoca ie s, bu also mo e
p eclinical es a e needed o assess he he apeu ic use and sa e y alues o his nanoca ie s
o u u e applica ions in human clinical ials.
21
EXECUTIVE SUMMARY
NEW PROMISING MOLECULES FOR THE TREATMENT OF AD AND PD
• In he las yea s new molecules such as neu o ophic
ac o s (NTFs), an ioxidan
molecules and me al chela o s ha e been conside ed p omising app oaches o
add ess he main causes o NDs.
•
G ow ac o s a e a g oup o p o eins which a e able o imp o e he g ow h,
p oli e a ion and di e en ia ion o neu onal cells.
• An ioxidan s ha e been aised as new ea men app oaches o add ess he oxida i e
s ess p oduced in AD and PD.
• The main obs acle o mos o hese d ugs o access in o he b ain is he p esence o
he BBB, he e o e, di e en s a egies ha e been de eloped o c oss o by-pass his
ba ie .
NANOTECHNOLOGY SOLUTIONS FOR NEURODEGENRATIVE DISEASES.
•
Nano echnology is an eme ging ield o science wi h p omising physiochemical
p ope ies o he ea men o neu odegene a i e diseases.
•
Di e en nano echnology de ices ha e been s udied such as, polyme ic
nanopa icles, liposomes, SLN, NLC o gene he apy.
• DDSs ha e been de eloped o elease cu en ly a ailable ea men s, g ow h ac o s,
an ioxidan s and me al chela o s o he ea men o AD and PD.
CONLUSIONS AND FUTURE OUTLOOK
• The e is a c i ical need o de elop new DDSs wi h he aim o ob aining a ge ed d ug
deli e y and a sus ained elease p o ile o he he apeu ic d ugs in o he b ain.
• The esul s p esen ed in his e iew suppo he use o nano echnology as a p omising
app oach o con ol he elease o old and new d ugs o he ea men o AD and PD.
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