

Ci a ion: Galind es, D.M.; Ci uen es,
D.; Tinoco, L.E.; Mu illo-Ace edo, Y.;
Rod igo, M.M.; Ribei o, A.C.F.;
Es eso, M.A. A Re iew o he
Applica ion o Reso cina enes and
SBA-15 in D ug Deli e y. P ocesses
2022,10, 684. h ps://doi.o g/
10.3390/p 10040684
Academic Edi o : Yi Lu
Recei ed: 7 Feb ua y 2022
Accep ed: 29 Ma ch 2022
Published: 31 Ma ch 2022
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4.0/).
p ocesses
Re iew
A Re iew o he Applica ion o Reso cina enes and SBA-15 in
D ug Deli e y
Diana M. Galind es 1,*, Diego Ci uen es 1, Luz Elena Tinoco 1, Yesid Mu illo-Ace edo 1, M. Melia Rod igo 2,
Ana C. F. Ribei o 3and Miguel A. Es eso 2,4,*
1G upo de Fisicoquímica y Análisis Ma emá ico, Facul ad de Ciencias y Humanidades,
Fundación Uni e sidad de Amé ica, Bogo á111321, Colombia;
diego.ci uen es@p o eso es.uame ica.edu.co (D.C.); luz. inoco@p o eso es.uame ica.edu.co (L.E.T.);
yesid.mu illo@p o eso es.uame ica.edu.co (Y.M.-A.)
2
Uni e sidad de Alcalá, U.D. Química Física, 28805 Alcaláde Hena es, Mad id, Spain; mmelia. [email p o ec ed]
3Cen o de Química, Depa amen o de Química, Uni e si y o Coimb a, 3004-535 Coimb a, Po ugal;
[email p o ec ed]
4Uni e sidad Ca ólica de Á ila, Calle Can e os s/n, 05005 Á ila, Spain
*Co espondence: diana.galind es@p o eso es.uame ica.edu.co (D.M.G.); [email p o ec ed] (M.A.E.)
Abs ac :
Due o he diseases ha people ace oday, scien is s dedica e a pa o hei esea ch o
he syn hesis, cha ac e iza ion, and s udy o unc ional compounds o con olled d ug deli e y. On
he one hand, eso cina enes a e mac ocycles ob ained by condensa ion eac ions o eso cinol and
aldehyde. They include an uppe and a lowe im unc ioning wi h di e en g oups ha con e solu-
bili y o he mac ocycle and a o in e ac ions wi h o he compounds, he e o e he hyd oxyl g oups
on he uppe im imp o e he o ma ion o hyd ogen bonds. Addi ionally, eso cina enes ea u e a
ca i y s udied o o ming hos -gues complexes. SBA-15, on he o he hand, is a mesopo ous silica
cha ac e ized by o de ed po es in i s s uc u e and a la ge su ace a ea. As a esul o i s p ope ies, i
has been used o se e al pu poses, including abso ben s, d ug deli e y, ca alysis, and en i onmen al
p ocesses. This e iew shows he ecen ad ances in syn hesis me hods, cha ac e iza ion, micelle
o ma ion, in e ac ion wi h o he compounds, and hos -gues p ocedu es, as well as echniques o
e alua ing oxici y, d ug e en ion, and hei p elimina y uses in pha macology o mac ocycles, such
as eso cin[4]a enes and SBA-15.
Keywo ds:
eso cin[4]a enes; SBA-15; mac ocycles; pha macology; d ug deli e y; mesopo ous silica;
adso ben s; hos -gues complex
1. In oduc ion
A con olled d ug deli e y sys em can be desc ibed as a he apeu ic o mula ion [
1
,
2
],
in which an ac i e p inciple is deli e ed o speci ic pa s o he body a a con olled a e and
ime [
3
]. I is specially designed o main ain he apeu ic le els o he d ug h oughou he
en i e ea men pe iod and no only du ing ce ain in e als o he ea men , as is egula ly
he case wi h adi ional he apy whe e he d ug is dis ibu ed h ough he ci cula o y
sys em [4,5].
As o he use o d ugs in he ea men o di e en diseases in humans, one o he
mos widely used me hods is con olled deli e y sys ems [
6
]. They ep esen a cons an ly
g owing ield, in which bo h he demand o new he apeu ic agen s and he imp o emen
o he mechanisms o adminis e hem a e inc easing. Comme cial p esen a ions o d ug
deli e y sys ems based on polyme echnology a e ela i ely success ul, co e ing a wide
ange o applica ions o a ious applica ion a eas ( o example, in he ea men o diabe es,
cance , os eopo osis, e c.) [
6
,
7
]. Howe e , hese sys ems end o lose hei pha macological
ac i i y as he ac i e p inciple deg ades be o e eaching he a ge issue [8].
P ocesses 2022,10, 684. h ps://doi.o g/10.3390/p 10040684 h ps://www.mdpi.com/jou nal/p ocesses
P ocesses 2022,10, 684 2 o 14
In ecen yea s, ad ances in he ield o nano echnology and sup amolecula sys-
ems ha e led o he de elopmen o new nanos uc u ed ma e ials o biomedical
applica ions [9,10]
. Two app oaches applied o d ug deli e y sys ems a e shown in his
e iew: The i s one is sup amolecula sys ems using syn he ic mac ocycles as d ug
ese oi s (micelles, hyd ogels, esicles, liposomes, and nanopa icles) which can espond
o di e en s imuli o elease he d ug in a di ec ed and con olled way, showing some
ad ances in design [
11
–
13
]. They a e sys ems based on calix[4] eso cina enes ha a e
conside ed a amily o syn he ic sup amolecula mac ocycles able o o m cone-shaped
s uc u es and acili a e he o ma ion o complexes wi h gues molecules [14,15]
The second one is sys ems based on mesopo ous ma ices ha allow he encapsula ion
o he ac i e p inciples, p o iding a longe ci cula ion ime and a oiding in oxica ion
caused by high d ug concen a ions in he body. These sys ems ha e a high speci ic su ace
a ea, an o de ed s uc u e, and a la ge olume o po es, which allows a high adso p ion
po en ial and be e con ol o e he loading and elease o he ac i e p inciples. SBA-15 is
a mesopo ous ma e ial ha has an o de ed ne wo k o po es wi h homogeneous size and a
la ge po e olume o accommoda e he equi ed amoun s o d ugs [16–18].
These unique p ope ies o bo h calix[4] eso cina enes and SBA-15 make hese ma e i-
als excellen compounds o use in con olled d ug deli e y sys ems, as summa ized in
Table 1:
Table 1. Summa ize: Uses o Reso cin[4]a enes and SBA-15 in d ug deli e y.
Ac i e P inciple/
Diso de Ca ie Func ional G oup * Topic. Au ho /Yea
Hype glycemia
Insulin Reso cina ene Sul onyl
Diazonium
The modynamics
Solubili ies in wa e
Insulin ib illa ion
Nano anspo e s
Nanocapsules.
Galind es Jimenez e al., 2019.
Han, Tian, e al., 2017.
Maldonado e al., 2017.
Ziganshina e al., 2019.
An ibio ic
Doxo ubicin
Cla i h omycin
Chlo amphenicol
Amoxicillin
Reso cina ene
Guanidine
Acylhid azone
N-me hyl-glucamine
E hylene glycol
N-alkyl, N-A yl
Micelles
Nano anspo e s
Albaya i e al., 2019.
Ali e al., 2020.
Pang e al., 2013
Se gee a e al., 2020.
Se imli & Yılmaz, 2012.
Shuma bae a e al., 2019–2020.
SBA-15 Amine
Polye hyleneimine Adso p ion/Deso p ion
An i-in lamma o y
Indome hacinI
bup o en
Nap oxen
Reso cina ene
PEG
N-alkyl, N-a yl
E hylene glycol
Micelles
Nanoca ie s
Dend ime s
Gao e al., 2014.
Ahmadi e al., 2014.
Ped o-He nández e al., 2017.
Shuma bae a e al., 2019.
Mal ai e al., 2020.
SBA-15 Amine Adso p ion/Deso p ion
An icance
Chlo ambucil
Gemci abine
Reso cina ene Polyamidoamine Dend ime s Mendoza-Ca dozo e al., 2019.
Ra al e al., 2021.
Se imli & Yılmaz, 2012.
SBA-15 Amine Adso p ion/Deso p ion
* I e e s o he unc ional g oup used in he syn hesis o Reso cina ene o he SBA-15 ma e ial.
2. Syn hesis o calix[4] eso cina enes and Po ous Ma e ials (SBA15)
2.1. Syn hesis o calix[4] eso cina enes
Con olled d ug deli e y is a echnique ha aims o achie e op imal he apeu ic e ec s
by deli e ing a d ug in o he body in a con olled and p ecise manne
1
. The app oach o his
managemen sys em comp ises h ee main ac ions: (1) choice o he ou e o adminis a ion
and imp o emen o abso p ion, (2) con olled elease o he o mula ion, and (3) o ien a ion
owa d he si e o ac ion [
19
]. Acco ding o hese app oaches, he encapsula ion o he
di e en ac i e p inciples inside p o ec i e s uc u es is a e y a ac i e al e na i e. These
sys ems seek, among o he s, o educe possible physicochemical o enzyma ic al e a ions o
he ac i e compound. They also aim o inc ease he bioa ailabili y o he ac i e compound
and educe he undesi able side e ec s o i s non-speci ic dis ibu ion [20].
Pha maceu ical o mula ions o ac i e ing edien s wi h low o no aqueous solubili y
o en ha e poo bioa ailabili y when adminis e ed in o he body and he e o e low e icacy.
Among he compounds ha appea as sui able ehicles o he adminis a ion o d ugs wi h
P ocesses 2022,10, 684 3 o 14
low solubili y a e he calix[4] eso cina enes [
21
], These and hei wa e -soluble de i a i es
show good biocompa ibili y and no cy o oxici y, aspec s ele an o hei applica ion in any
p ac ical d ug deli e y sys em [22].
The syn hesis o calix[4] eso cina enes usually in ol es condensa ion o ei he alipha ic
o a oma ic aldehydes wi h eso cinol (Figu e 1); he eac ion is ca alyzed by an acid and is
ca ied ou using e hanol as sol en [23,24].
Figu e 1. The condensa ion eac ion be ween eso cinol and aldehyde.
The abili y o calix[4] eso cina enes o o m hos -gues complexes is based on hei
s uc u e. These molecules consis o ou phenolic esidues linked o me hylene g oups,
allowing he con o ma ion o i e s uc u es (Figu e 2), he mos common o which is he
c own con o ma ion used o hos -gues p ocesses [21].
Figu e 2.
Con o ma ions o calix[4] eso cina enes: (
a
). C own; (
b
). Boa ; (
c
). Chai ; (
d
). Diamond;
(e). Saddle.
Compa ed o o he mac omolecula sys ems ha ha e been s udied o d ug deli e y,
he sys ems like calix[4] eso cina enes ha e ewe epo s in e ms o biomedical appli-
ca ions, due o hei hyd ophobic p ope ies [
9
]. In an a emp o sol e his p oblem,
no el al e na i es a ise in he syn hesis o calix[4] eso cina enes ha a o he hyd ophilic
cha ac e is ics and inc ease he solubili y o hese compounds in wa e . Func ionaliza ion
by a oma ic nucleophilic subs i u ion in posi ion 2 o he a oma ic ings o by nucleonic
subs i u ion on he hyd oxyl g oups [
25
], opens he possibili y o gene a ing unc ionalized
calix[4] eso cina enes sys ems wi h g oups ha allow hem o imp o e hei solubili y.
The in e ac ions wi h o he molecules, selec i e complexa ion, he abili y o eac wi h
a ious molecules, he endency o o m sel -associa ions, and su ace ac i i y, ha e been
s udied [26].
N-me hyl-D-glucamine- eso cin[4]a ene, a de i a i e wi h highe wa e solubili y
han i s p ecu so , can be ob ained by a Mannich eac ion be ween decyl eso cin[4]a ene
P ocesses 2022,10, 684 4 o 14
and N-me hyl-D-glucamine. The syn hesized compound showed an imic obial ac i i y
only agains G am-posi i e bac e ia. E alua ing i s cy o oxic e ec on human e y h ocy es,
i is ound ha his mac ocycle does no cause comple e hemolysis, unlike o he de i a i es
o he calixa enes amily [27].
Me hyl (C1), pen yl (C5), and undecyl (C11) we e used as sys emic subs i uen s on
each ing o he unc ionalized amido(dime hyl)amino-calix[4] eso cina ene as hey ac
as educing and s abilizing agen s in he syn hesis o colloidal gold nanopa icles wi h
sphe ical shape (4–8 nm). In he syn hesis o nanopa icles, inc easing he concen a ion o
he mac ocycle in he solu ion and using mac ocycles wi h unc ional g oups wi h g ea e
hyd ophobici y leads o a dec ease in he size o he pa icles o med. The syn hesized
pa icles end o o m a mac ocycle bilaye on he su ace, which gi es s abili y and g ea e
wa e solubili y o he colloidal sys em. The binding capaci y o colloidal sys ems wi h
a non-s e oidal an i-in lamma o y molecule (Nap oxen) was s udied. Modi ying gold
nanopa icles wi h mac ocycles esul s in a signi ican inc ease in he d ug’s binding
p ope ies, wi h agg ega ions be ween 85% and 98%. [26].
2.2. Syn hesis o SBA-15
A coope a i e sel -assembly p ocess is used o he syn hesis o SBA-15. Fo his pu -
pose, a non-ionic iblock copolyme (Plu onic P123) is used as a empla e, which consis s
o e hylene oxide (EO) and p opylene oxide (PO). On he o he hand, e ame hoxysilane
(TMOS) o e ae hoxysilane (TEOS) a e used as silica sou ces. The hyd ophobic pa is
made o p opylene oxide, while he hyd ophilic pa is made o e hylene oxide. The p ocess
occu s in an acidic medium in wo s eps: (1) he o ma ion o micelles wi h hyd opho-
bic g oups inwa d and hyd ophilic g oups ou wa d; (2) he in e ac ion be ween wa e
molecules and alkylene oxides as a esul o hyd ogen bonds [28,29].
A e iew o he syn hesis p ocedu e o his mesopo ous compound can be ound
in he li e a u e [
30
]. B ie ly, his syn hesis in ol es he ollowing s eps: (a) he ini ial
solu ion is hea ed a 30–40
◦
C o 20–24 h; (b) hen he empe a u e is aised o 80–120
◦
C
o
24–48 h
; (c) a oom empe a u e o e nigh , he solid ob ained is il e ed, washed and
d ied; (d) nex , he solid is d ied a 80
◦
C o 5–6 h, and (e) inally, he sample is calcined a
550
◦
C o 4–6 h. The calcina ion p ocess is key because i emo es he empla e (Figu e 3).
Likewise, depending on he syn hesis condi ions, he size o he mesopo ous can a y ( om
5 o
30 nm
) as well as hei mo phology, hexagonal o cubic (a low EO: PO a io a o s
hexagonal mo phology) [
28
]. As a esul , he po ous solid ob ained will ha e di e en
p ope ies ela ed o a high su ace a ea and mechanical and chemical esis ance.
P ocesses 2021, 9, x FOR PEER REVIEW 5 o 15
+
Figu e 3. Gene al scheme o he p epa a ion o SBA-15.
3. Reso cina enes and hei Applica ions in D ug Deli e y
Sup amolecula chemis y is a discipline o chemis y ha s udies he in e ac ions
be ween molecules om which he o ma ion o in e molecula bonds is de i ed and con-
sequen ly he o ma ion o sup amolecula agg ega es. I s udies he chemical, physico-
chemical and biological p ope ies o hese species ha possess non-co alen in e molec-
ula o ces [31]. Among he compounds o in e es a e he eso cin[4]a enes, which ha e
a ca i y, an uppe im, and a lowe im. These mac ocycles can be unc ionalized: he
lowe im wi h hyd oca bon chains, which allow he hyd ophobici y o he mac ocycle o
a y, and he uppe im, wi h a ious unc ional g oups, such as he sul ona e g oup, he
amino g oup, and o he s ha gi e hem he p ope y o being soluble in wa e , which is
necessa y o p ocesses ela ed o d ug deli e y [32–34].
S udies ha e been ca ied ou on he he modynamic p ope ies o eso cin[4]a enes
showing he beha io o hese mac ocycles in solu ion. Diazo ed eso cin[4]a ene has been
cha ac e ized and syn hesized by spec oscopic echniques [35]. The iscosi ies and den-
si ies o hei solu ions in dime hyl sul oxide (DMSO) we e measu ed a empe a u es
anging om 293.15 K o 313.15 K, in a concen a ion ange o (0.0058 o 0.023) (mol kg−1).
Based on hese da a, he modynamic unc ions a e conside ed, which con ibu e o
unde s anding in e molecula in e ac ions in solu ion. Fo example, he s udy o iscosi-
ies sugges s he exis ence o s ong solu e-sol en in e ac ions, while ha o olumes in-
dica es he p esence o s ong solu e-solu e in e ac ions. On he o he hand, sul ona ed
eso cin[4]a enes ha e been syn hesized and s udies on hei mu ual di usion coe icien s
and mola ionic conduc i i ies in aqueous solu ion a 298.15 K, a concen a ions lowe
han 0.010 mol dm-3 ha e been epo ed. The esul s a e discussed in e ms o in e ac ions
in solu ion, he e ec o he leng h o he chain loca ed a he lowe im o he eso -
cin[4]a ene, and he hyd odynamic adii as compa ed be ween he wo echniques [36].
The di usion coe icien s o bo ine se um albumin in wa e and in he p esence o sul-
ona ed eso cin[4]a enes we e also e alua ed; he alues ob ained om he di usion co-
e icien s we e analyzed in e ms o in e ac ions and as he p esence o eso cin[4]a ene
a o s he in e ac ion be ween p o ein and wa e ; he sal ing-in e ec was also e alua ed
[37]. The anspo p ope ies we e used o model di usion in pha maceu ical and medi-
cal applica ions.
Wa e -soluble eso cina enes ha e been shown o be non- oxic and exhibi p ope
biocompa ibili y, and biodeg adabili y, making hem impo an and use ul molecules o
d ug deli e y p ocesses [38–40]. Menon e al. conduc ed s udies on inclusion complexes
o sulphona ocalix[4] eso cina ene and mycophenola e mo e il, in i o es s pe o med
on animals, showing no oxic e ec s o he complex and moni o ing hei weigh , espi -
a o y sys em, ci cula ion, and sleep. Mycophenola e mo e il was ound o ha e an o al
LD50 o 352 mg kg-1 in a s, 1000 mg kg-1 in mice, and 6000 mg kg-1 in abbi s, bu complex
o ma ion wi h eso cina ene does no cause mo ali y up o 2200 mg kg-1 [41].
Dawn e al. pe o med in i o cy o oxici y assays o calixa enes unc ionalized wi h
di e en g oups and a me allosup amolecula complex, cell iabili y s udies we e pe -
o med using CellTi e -Glo cell and MTT. The compound e icacy was e alua ed in a
C6G cells and human HEK293 cells, wi h oxici y a ying om low o mode a e. This
s udy shows ha he CC50 alues indica e ha he p esence o phosphona e g oups and
Figu e 3. Gene al scheme o he p epa a ion o SBA-15.
3. Reso cina enes and hei Applica ions in D ug Deli e y
Sup amolecula chemis y is a discipline o chemis y ha s udies he in e ac ions
be ween molecules om which he o ma ion o in e molecula bonds is de i ed and
consequen ly he o ma ion o sup amolecula agg ega es. I s udies he chemical, physico-
chemical and biological p ope ies o hese species ha possess non-co alen in e molecula
o ces [
31
]. Among he compounds o in e es a e he eso cin[4]a enes, which ha e a ca i y,
an uppe im, and a lowe im. These mac ocycles can be unc ionalized: he lowe im
wi h hyd oca bon chains, which allow he hyd ophobici y o he mac ocycle o a y, and
he uppe im, wi h a ious unc ional g oups, such as he sul ona e g oup, he amino
P ocesses 2022,10, 684 5 o 14
g oup, and o he s ha gi e hem he p ope y o being soluble in wa e , which is necessa y
o p ocesses ela ed o d ug deli e y [32–34].
S udies ha e been ca ied ou on he he modynamic p ope ies o eso cin[4]a enes
showing he beha io o hese mac ocycles in solu ion. Diazo ed eso cin[4]a ene has
been cha ac e ized and syn hesized by spec oscopic echniques [
35
]. The iscosi ies and
densi ies o hei solu ions in dime hyl sul oxide (DMSO) we e measu ed a empe a u es
anging om 293.15 K o 313.15 K, in a concen a ion ange o (0.0058 o 0.023) (mol kg
−1
).
Based on hese da a, he modynamic unc ions a e conside ed, which con ibu e o
unde s anding in e molecula in e ac ions in solu ion. Fo example, he s udy o iscosi ies
sugges s he exis ence o s ong solu e-sol en in e ac ions, while ha o olumes indica es
he p esence o s ong solu e-solu e in e ac ions. On he o he hand, sul ona ed eso -
cin[4]a enes ha e been syn hesized and s udies on hei mu ual di usion coe icien s and
mola ionic conduc i i ies in aqueous solu ion a 298.15 K, a concen a ions lowe han
0.010 mol dm
−3
ha e been epo ed. The esul s a e discussed in e ms o in e ac ions in
solu ion, he e ec o he leng h o he chain loca ed a he lowe im o he eso cin[4]a ene,
and he hyd odynamic adii as compa ed be ween he wo echniques [
36
]. The di usion
coe icien s o bo ine se um albumin in wa e and in he p esence o sul ona ed eso -
cin[4]a enes we e also e alua ed; he alues ob ained om he di usion coe icien s we e
analyzed in e ms o in e ac ions and as he p esence o eso cin[4]a ene a o s he in e ac-
ion be ween p o ein and wa e ; he sal ing-in e ec was also e alua ed [
37
]. The anspo
p ope ies we e used o model di usion in pha maceu ical and medical applica ions.
Wa e -soluble eso cina enes ha e been shown o be non- oxic and exhibi p ope
biocompa ibili y, and biodeg adabili y, making hem impo an and use ul molecules o
d ug deli e y p ocesses [
38
–
40
]. Menon e al. conduc ed s udies on inclusion complexes o
sulphona ocalix[4] eso cina ene and mycophenola e mo e il,
in i o
es s pe o med on
animals, showing no oxic e ec s o he complex and moni o ing hei weigh , espi a o y
sys em, ci cula ion, and sleep. Mycophenola e mo e il was ound o ha e an o al LD50
o 352 mg kg
−1
in a s, 1000 mg kg
−1
in mice, and 6000 mg kg
−1
in abbi s, bu complex
o ma ion wi h eso cina ene does no cause mo ali y up o 2200 mg kg−1[41].
Dawn e al. pe o med
in i o
cy o oxici y assays o calixa enes unc ionalized wi h
di e en g oups and a me allosup amolecula complex, cell iabili y s udies we e pe -
o med using CellTi e -Glo cell and MTT. The compound e icacy was e alua ed in a C6G
cells and human HEK293 cells, wi h oxici y a ying om low o mode a e. This s udy
shows ha he CC50 alues indica e ha he p esence o phosphona e g oups and he
supp ession o he coo dina ion capaci y educe he cy o oxici y o mac ocycles, he e o e i
is e iden ha he use o calixa enes o eso cina enes as d ug ca ie s is app op ia e [42].
Se e al s udies ha e shown ha a a ie y o molecula hos s a e accommoda ed in e-
so cina ene ca i ands. These a e e sa ile molecula hos s ha e en manage o empo a ily
isola e hem om hei en i onmen [
43
]. Wa e -soluble ca i ands syn hesized by adding
pola g oups a he uppe im o a he lowe im ha e been s udied. These compounds
ha e shown a g ea abili y o accep gues s in aqueous solu ions and ha e also been shown
o ac as hos s when used in micelles and lipid bilaye s.
Insulin is a ho mone eleased by he panc eas due o he p esence o glucose in
he blood. This ho mone ensu es ha glucose en e s he cells o be used as an ene gy
sou ce. Howe e , when insulin does no wo k p ope ly, glucose accumula es in he blood
and causes a ious diseases [
44
,
45
]. Fo his eason, some au ho s ha e dedica ed hei
s udies o e alua ing compounds ha can se e as insulin anspo e s in he body [
46
,
47
].
Xu Han e al.
in es iga ed he ole o eso cina enes in inhibi ing o p omo ing Insulin
Fib illa ion. In his s udy, modi ied eso cina enes wi h a sul ona e g oup a he uppe
im and wi h modi ica ions o hyd oca bon chains a he lowe im we e used o analyze
he e ec o he p esence o hese eso cina enes in he insulin ib illa ion p ocess h ough
expe imen al and compu a ional s udies. ThT assay, CD spec a, and AFM images we e
ca ied ou expe imen ally. Among he esul s ob ained, i is highligh ed ha he p esence
o he hyd oca bon chain o he eso cina ene e ec i ely inhibi s insulin ib illa ion; hese

P ocesses 2022,10, 684 6 o 14
esul s a e p omising o possible he apeu ic s a egies. The expe imen al condi ions used
by he au ho s we e: Thio la in T (ThT) luo escence in ensi y a 485 nm as a unc ion o
incuba ion ime a 65
◦
C in 0.1 M NaCl; ib illa ion kine ics o 0.2 mg / mL human insulin;
pH 1.6 wi h he a io o insulin and eso cina ene a 1: 0, 1: 0.02, 1: 0.05, 1: 0.1 and 1: 0.2,
espec i ely [48].
In he same way, Se gee a e al. epo ed he s udy o sul ona ed eso cina enes as
insulin anspo e s and hei elease in he p esence o glucose, Reso cina enes we e de-
sc ibed as nanoca ie s consis ing o a polyme sphe e con aining sul ona ed eso cina ene
molecules linked by phenylbo ona e b idges, wi h insulin encapsula ed in he ca i y. I was
ound ha depending on he glucose concen a ion, he nanoca ie also ac s; o example,
a a low glucose le el (5 mM), insulin elease is no mo e han 10%, bu an inc ease in glucose
concen a ion up o 10 mM leads o nanoca ie dissocia ion and he subsequen massi e
insulin elease. Dialysa e composi ion, pa icles s abili y, and insulin e en ion abili y we e
e alua ed by NMR. The amoun o unencapsula ed insulin was calcula ed om he a io
o he in eg al o he s anda d insulin solu ion (0.35 mg) in 0.04% DMF o he in eg al o
he insulin signals a 3.47–3.55 ppm and he DMF signal a 7.92. On he o he hand, he
amoun o encapsula ed insulin was calcula ed as he di e ence be ween he amoun s o
o al and non-encapsula ed insulin. In his s udy, he beha io wi h di e en concen a ions
o glucose was also e alua ed by NMR using he UV-Vis echnique, complemen ed by
insulin abso p ion s udies. In he wo p e ious s udies, an impo an ac o men ioned
is ha eso cina enes a e no oxic. In addi ion, because hey possess a ca i y, hey can
e ec i ely encapsula e o he molecules such as insulin and depending on he g oups wi h
which hey a e unc ionalized, hey can become e y soluble in wa e and in blood plasma
a no mal pH le els [49].
P o eins end o be s uc u ally damaged du ing ex ac ion and pu i ica ion p o-
cesses. Fo his eason, s udies ha e ocused on sys ems designed o imp o e p o ein
s abili y [50–52]
. Reso cin[4]a enes ha e been used no only o insulin ib illa ion bu also
o inhibi ion o A
β
- ib illa ion. S udies we e pe o med using echniques such as ThT
assays, a omic o ce mic oscopy, ci cula dich oism, and complemen ing he expe imen al
measu emen s wi h compu a ional me hods. Among he main indings, i was ound ha
hey a e compounds wi h low oxici y and ha in addi ion o blocking A
β
agg ega ion, i
delays he o ma ion o oxic species [53].
Zoled ona e is a d ug ha belongs o he bisphosphona e g oup and is used o ea
os eopo osis. Nine mac ocycles based on calix[4]a enes and calix[4] eso cina enes we e
s udied as hos s o he zoled ona e molecule by ab ini io densi y unc ional heo y calcula-
ions o he ene gies o eigh een hos -sla e complexes and o he s uc u es. Phosphona ed
and sul ona ed calix[4]a enes and calix[4] eso cina enes we e used, and he geome y o
he in e nal ca i ies was conside ed and compa ed wi h hose o he hos -gues complexes.
Calcula ions o he binding ene gy in he gaseous and aqueous s a es, and he limi ing
molecula o bi als including HOMO and LUMO we e made o he quan i a i e e alua ion
o he o ma ions o he hos -gues complexes, showing ha hey a e s able in aqueous so-
lu ions, while in he gaseous s a e some a e s able bu o he s a e no . The no m-conse ing
pseudo-po en ial pseudo-a omic o bi al me hod was adop ed wi h he s anda d DZP basis
se s and he BLYP + dW (G imme) GGA unc ional. Acco ding o he ob ained esul s,
calix[4] eso cina enes allow a be e hos -gues coupling han calix[4]a enes due o he
hyd ogen bonds o med wi h he op edge OH g oups, while sul ona e-calix[4]a enes a e
he mos app op ia e hos o ZOD gues on 1:1 s oichiome y [54].
In wa e and in dodecyl phosphocholine (DPC) micelles, Ja o e al. s udied he hos
capaci y o molecules con aining wa e -soluble eso cina enes and a guanidine g oup a
he lowe im, using NMR spec oscopy echniques. Ini ially, he ca i and syn hesis was
ca ied ou and la e he au ho s simula ed bo h molecula dynamics and op imiza ion
p og amming using he PM3 semiempi ical me hod in he Spa an 04 so wa e, con e ed
o GROMOS (gmx53a6 o ce ield) opology h ough he Topolbuild 1.3 p og am. He e, he
P ocesses 2022,10, 684 7 o 14
spon aneous inco po a ion o he ca i and in o he micelle is e idenced, hus e alua ing
hei beha io as ca ie s o biological compounds and hei u u e applica ions [43].
New molecules o calix[4] eso cina enes and me hoxy-PEG (mPEG) conjuga ed h ough
acylhyd azone bonds we e syn hesized. The e ec o hese compounds on he o ma ion o
sup amolecula d ug deli e y sys ems was s udied. The calix[4] eso cina enes we e syn he-
sized in boa and chai con o ma ions o ob ain amphiphilic conjuga es as sup amolecula
nanocon aine s and dend ime ic. The s uc u es o he conjuga es we e wo ked om
1H, 13C, FT-IR spec oscopy and NMR, Maldi-TOF mass spec oscopy, and SLS me hod.
The cy o oxici y o he compounds and he abili y o encapsula e d ugs such as Dox and
Me hylene Blue we e e alua ed and
in i o
s udies wi h M-Hela cells and Chang li e
cells we e ca ied ou . The esul s show ha he Dox-conjuga e has a be e e ec agains
umo cells han ha o he ee d ug. S udies con i med he hemolysis es wi h he lowes
hemo oxici y o he conjuga es: only 2.2% o cells s ain in he p esence o 9 mg
·
mL
−1
o
C11-mPEG and 8.7% in he p esence o 4.5 mg·mL−1o C1Ph-mPEG [55].
Doxo ubicin (DOX) is a well-known d ug ha has an imi o ic and an ip oli e a i e
ac i i y. Se gee a e al. syn hesized a polyme ic nanoca ie o he doxo ubicin deli e y:
basically, consis s o N-me hyl-glucamine eso cina enes co alen ly bound o phenyl-
bo onic acid. The nanoca ie was ound o be non- oxic and hemoly ically inac i e in he
concen a ion ange in which he au ho s wo ked. In addi ion, i was concluded ha he
nanoca ie is s able a no mal pH bu hyd olyzes a pH below 6. S udies used echniques
such as TEM, NMR, luo escence, and cy o oxici y, inding ha he nanoca ie a o s i s
pene a ion in o he cance cells and inc eases he cy o oxici y o DOX owa ds cells [56].
Mendoza-Ca dozo e al. used ou eso cina ene-polyamidoamine (PAMAM) conju-
ga es o chlo ambucil dend ime s wi h di e en g oups a he lowe pa o he mac ocycle;
he dend i ic a ms o di e en leng hs gene a ed good s abili y o he chemical bond be-
ween he ca ie and he d ug. The an icance ac i i y o eso cina ene conjuga es wi h
chlo ambucil was es ed.
in i o
es s we e pe o med agains six human cance cell lines:
U-251, PC3, K-562, HCT-15, MCF-7, and SKLU-1. S udies conduc ed wi h K-562, human
ch onic myelogenous leukemia cells showed ha chlo ambucil was less e ec i e han he
conjuga e as an an ip oli e a i e agen [57].
Calix[
4
] eso cina ene nano esicles wi h a diame e o 210 nm we e syn hesized. The
mac ocycles we e cha ac e ized by echniques such as Dynamic Ligh Sca e ing (DLS),
Fou ie T ans o m In a ed Spec oscopy (FTIR), Mass Spec oscopy, Di e en ial Scanning
Calo ime y (DSC), and X-Ray Di ac ion (XRD). The esul s show ha in he p esence o
chlo o o m, he syn hesized mac ocycles exhibi good monodispe si y o d ug and calixa s
and show a loading capaci y o 85%. The sphe ical shape o he esicle was e i ied using
echniques such as a omic o ce mic oscopy, which leads o a good elease o he d ug.
In i o
es s and hemolysis, es s we e ca ied ou , inding esul s ha can be ex apola ed
o a po en ial applica ion as a d ug anspo e agains cance [58].
Reso cina ene-cen e ed amphiphilic eigh -a med s a block copolyme s (SPCL-b-PEG)
we e syn hesized. The compounds we e ob ained wi h a de ined a chi ec u e and con olled
molecula weigh . Thei sui abili y as nanoca ie s o indome hacin and o he d ugs was
e alua ed as hey sel -assembled in he o m o micelles. A s ong hyd ophobic in e ac ion
be ween he d ugs and he PCL blocks was ound, showing a high e iciency o encapsula e
he d ug. The mac ocycles we e syn hesized by a se ies o eac ions and cha ac e ized by
H-NMR; subsequen ly, hei micelliza ion capaci y and he c i ical micella concen a ion
we e in es iga ed. Con olled elease and d ug loading we e e alua ed, inding ha
encapsula ion e iciency dec eased om 88.1% o 57.3% and d ug loading con en inc eased
om 8.8% o 17.2% when he heo e ical indome hacin loading inc eased om 10.0% o
30.0% [59].
The syn hesis o mul i- ailed eso cina ene (MTR) was pe o med h ough wo eac-
ions, he i s was he eac ion by O-alkyla ion o 4-hyd oxybenzaldehyde and he second
was he condensa ion wi h eso cinol. The mac ocycle was cha ac e ized by
1
H-NMR,
mass spec ome y, and FT-IR. F om he s udies, he sel -assembly and agg ega ion be-
P ocesses 2022,10, 684 8 o 14
ha io o he amphiphilic mac ocycle in an aqueous medium, and he esicles in e ms
o mo phology and c i ical micella concen a ion (CMC), CMC alues o 0.055 mM and
niosomal esicles wi h an a e age diame e o 210
±
2 nm we e de e mined. Hyd ophobic
d ugs such as cla i h omycin we e loaded due o he abili y o he MTR o sel -assemble.
D ug en apmen e iciency o 65.12
±
3.31% and maximum d ug elease a e 8 h we e
obse ed [33].
Reso cina ene-de i ed mac ocycles we e syn hesized o e alua e he e icacy o que c-
e in; he biocompa ibili y was assessed by hemolysis and cy o oxici y es s. The c i ical
concen a ion o associa ion (CCA) o cynna ene-based mac ocycle (Benzyloxy Mac ocycle,
BM) was de e mined by using a UV-Vis spec opho ome e . Que ce in-loaded esicles
e ealed a size o app oxima ely 225.5
±
16.31 nm wi h 88
±
1.52% QRT encapsula ion [
60
].
A he lowe edge o he mac ocycle, ibup o en conjuga es we e syn hesized wi h
eso cina ene dend ime s wi h alipha ic and a oma ic subs i uen s. Cellula in e naliza ion
o he eso cina ene-PAMAM-ibup o en dend ime s was e alua ed by cla h in-media ed
endocy osis. In his wo k, he au ho s ound ha he leng h o he dend i ic b anches
and hei chemical s uc u e di ec ly in luenced he hyd olysis o he d ug-conjuga ed
dend ime s. I is p o ed ha he syn hesized compounds ha e high po en ial an icance
ac i i y, especially in he p esence o 8- and 16- esidue subs i u ions o ibup o en in he den-
d i ic b anches compa ed wi h he e ec o ibup o en alone, his was p o ed by biological
ac i i y assays [61].
The syn hesis and cha ac e iza ion o he new conjuga e o e aphenylenexypen yl-
calix[4] eso cina ene and me hoxy-poly(e hylene glycol) was ca ied ou . The o ma ion o
micelles in an aqueous solu ion was s udied. The p esence o phenylene-oxy-g oups in he
hyd ophobic co e o he micelles p omo es he encapsula ion o d ugs such as nap oxen,
ibup o en, and doxo ubicin; he alues o encapsula ion e ec i eness we e 39.8%, 26.7%
and 28.9%, espec i ely [62].
4. Inclusion Complexes Based on SBA-15 and Thei Applica ions in D ug Deli e y
The con olled d ug deli e y p ocess is associa ed wi h he adso p ion p ocess, in
which he d ug is p e e en ially adso bed in he po osi y and a he han on he su ace.
Su ace adso p ion equi es examining di e en a iables o he medium, such as pH
changes o p e en c ys alliza ion. As a esul , i is de e mined ha he concen a ion o he
d ug has a as adso p ion kine ic and ha a sho ime in e al is needed o he deso p ion
kine ics o be eleased in he in ended o gan [63].
Ahmadi e al. epo ed ha modi ica ion o he su ace o SBA-15 wi h amino g oups
esul s in a dec ease in he a e o d ug deli e y bu also signi ican ly inc eases he in e ac-
ion wi h he unc ional ca boxyl g oup o ibup o en. In his s udy, SBA-15 modi ied wi h
(3-aminop opyl) ie hoxysilane
is used o he anspo o ibup o en. Using echniques
such as X- ay di ac ion (XRD), scanning elec on mic oscopy (SEM), N
2
adso p ion-
deso p ion iso he m, he mog a ime ic analysis (TGA), di e en ial he mal analysis and
Fou ie T ans o m In a ed Spec oscopy (FTIR), SBA-15-NH
2
was sa u a ed wi h ibup o en
in n-hexane solu ion a di e en imes, empe a u es, ibup o en/silica a ios and s i ing
a es. In his sense, he op imal expe imen al condi ions we e ound o be 40
◦
C, 35 h, wi h
a d ug/SBA-15 a io o 50:100 and a s i ing speed o 100 pm. The in e ac ion be ween he
amino g oups o SBA-15-NH
2
and he ca boxyl g oups o ibup o en conside ably inc eases
he d ug concen a ion on he su ace, so he unc ionaliza ion o mesopo ous ma e ials
wi h amino g oups has a high impac on bo h d ug anspo and adso p ion p ocess. Based
on he esul s o his s udy, we conclude ha ibup o en is anspo ed mo e e icien ly
on he modi ied su ace o SBA-15 wi h SBA-15 amino g oups; howe e , his implies a
dec eased elease a e [64].
The e ec o modi ying he su ace o SBA-15 wi h amino g oups, o be used as an
adso ben o an an ibio ic such as chlo amphenicol in aqueous solu ion, was s udied
using a pos -syn hesis p ocedu e. Expe imen s we e conduc ed analyzing a iables such
as con ac ime (0–72 h), mass (10–120 mg), and ini ial concen a ion (10–120 mg
·
L
−1
) o
P ocesses 2022,10, 684 9 o 14
de e mine he e ec s o he di e en a iables on he e iciency o he adso p ion p ocess.
Cha ac e iza ion echniques such as SEM, BET su ace a ea, FTIR, TGA and XRD, show
ha he ob ained ma e ials co espond o SBA-15 and NH
2
-SBA-15. The esul s ound
allowed o ob ain an adso p ion capaci y o 51% o a concen a ion highe han 20 mg
·
L
−1
.
On he o he hand, he d ug elease esul s show an op imal ime o hal an hou , wi h
a alue o 41.35%. Thus, i can also be deduced ha he adso p ion capaci y is di ec ly
p opo ional o bo h he NH
2
-SBA-15 dose and he con ac ime bu in e sely p opo ional
o he ini ial concen a ion [65].
Bah ami e al. epo ed ha he elease o gemci abine (a d ug used o cance ea -
men ) depends on pH; his was in he case o he modi ied samples con aining NH
2
g oups.
The ob ained esul s show a p omising u u e in e ms o applica ions o mesopo ous ma e-
ials in an icance d ug deli e y sys ems. They wo ked wi h NH
2
-SBA-15, N(OH)
2
-SBA-15,
and 3N-SBA-15 unc ionalized wi h APTES, HAPS, and AEPS, espec i ely. Cha ac e iza-
ion echniques such as TGA, N
2
adso p ion/deso p ion, SEM, TEM, small angle X- ay
sca e ing (SAXS), elemen al analysis, UV spec oscopies, and FTIR we e used. I was
concluded ha he o ma ion o ca ie s ha in e ac be e wi h he d ug may be due o
su ace modi ica ion. Fu he mo e, he ype and numbe o alkoxysilane g oups a ec he
adso p ion o gemci abine on he modi ied samples. The maximum amoun o adso bed
d ug (21.65 w %) is ela ed o he concen a ion o APTES on he su ace o NH
2
-SBA-15
(2.64 mmol
·
g
−1
). I can be concluded ha a modi ica ion o he su ace chemis y o SBA-15
makes he modi ied SBA-15 nano ods sui able ca ie s o gemci abine [16].
Mesopo ous silica SBA-15 was e alua ed as a ca ie o he anspo o he cy o oxic
na u al p oduc emodin (EO). A dose-dependen dec ease in cell iabili y is shown, s ic ly
ela ed o an inc easing amoun o EO in SBA-15 up o 27% EO. On he o he hand, a
cons an ac i i y was obse ed a 32% and 36% EO in SBA-15.
The p opo ion o SBA-15 and EO was a ied (SBA-15, always 100 mg; EO: 20, 30, 40,
50 o 60 mg; SBA-15|EO1
→
SBA-15|EO5, espec i ely) ob aining ma e ials wi h di e en
concen a ions. The EO con en in SBA-15 o hese ma e ials anged om 8.1 o 36.4 %
wi h an e iciency o 88.2–95.6% (in con as o SBA-15|EO whe e only 0.7% EO was ound
in mesopo ous silica nanopa icles (MSN)).
SBA-15|EOn (n = 1 o 5) was cha ac e ized by ni ogen adso p ion-deso p ion iso he-
ms, ene gy dispe si e X- ay spec oscopy (EDX), SEM, TEM, IR spec oscopy, and SAXS.
SBA-15 was ac i a ed unde he ollowing condi ions ( acuum, 150
◦
C, 16 h) and used
o ob ain di e en amoun s o EO. Fi s , EO loading ( a io: SBA-15, 100 mg; EO, 10 mg)
was pe o med a oom empe a u e (
→
SBA-15|EO1) and a 60
◦
C (
→
SBA-15|EO1a), o
check he empe a u e dependence o he concen a ion e iciency in SBA-15. High and
compa able d ug concen a ion e iciency in SBA-15 was demons a ed in he cases s udied
unde he speci ied condi ions (a oom empe a u e: 88.2%; a 60 ◦C: 90.4%).
Acco dingly, he au ho s de e mined ha a po ous ma e ial such as SBA-15 enhances
he ac i i y o EO
in i o
, and e en p o ec s he ac i e compound om spon aneous
inac i a ion by ligh o om deg ada ion by gas ic pH, whe e ex emely acidic condi ions
p e ail [66].
In Mal ai e al., a mill-based loading me hod (MAL) is used o concen a e a poo ly
wa e -soluble d ug (ibup o en, IBP) in he solid s a e wi hin he SBA-15 ma ix. F om he
esul ing TGA, Raman, di e en ial scanning calo ime y analysis, and X- ay di ac ion i
appea s ha he c ys alli es a e su ounded by a liquid monolaye and loca ed in he co e
o he channel. I is also e iden om he s udy ha he dec ease in mel ing empe a u e
o he con ined c ys alli es is a ec ed by he po e diame e and no by he size o he
c ys alli es along he channel di ec ion, which a e egula ly la ge han he po e diame e .
DSC expe imen s showed ha hese c ys alli es coexis wi h amo phous PPI loca ed in
he co e o he channel and su ounded by an amo phous su ace-in e ac ing laye , wi h a
hickness app oxima ely equal o one molecule o ibup o en (
∼
1 nm). As desc ibed, e y
high solubili y and as elease om SBA-15 (9 nm) ma ices o amo phous PPI can be
achie ed om PPI con inemen . The PPI elease can be p olonged by sligh ly manipula ion