Carbon-Based Nanostructures as Emerging Materials for Gene Delivery Applications

Ci a ion: Yazdani, S.; Moza a ian, M.;
Pazuki, G.; Hadidi, N.; Villa e-Bei ia,
I.; Zá a e, J.; Pu as, G.; Ped az, J.L.
Ca bon-Based Nanos uc u es as
Eme ging Ma e ials o Gene Deli e y
Applica ions. Pha maceu ics 2024,16,
288. h ps://doi.o g/10.3390/
pha maceu ics16020288
Academic Edi o : Anna Ho owy
Recei ed: 13 Decembe 2023
Re ised: 3 Feb ua y 2024
Accep ed: 14 Feb ua y 2024
Published: 18 Feb ua y 2024
Copy igh : © 2024 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
pha maceu ics
Re iew
Ca bon-Based Nanos uc u es as Eme ging Ma e ials o Gene
Deli e y Applica ions
Sa a Yazdani 1,2, Meh dad Moza a ian 1,*, Gholam eza Pazuki 1, Naghmeh Hadidi 3, Ilia Villa e-Bei ia 2,4,5 ,
Jon Zá a e 2,4,5 , Gus a o Pu as 2,4,5 and Jose Luis Ped az 2,4,5,*
1
Depa men o Chemical Enginee ing, Ami kabi Uni e si y o Technology, Teh an P.O. Box 15875-4413, I an;
[email p o ec ed] (S.Y.); [email p o ec ed] (G.P.)
2NanoBioCel Resea ch G oup, 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; [email p o ec ed] (I.V.-B.); [email p o ec ed] (J.Z.);
[email p o ec ed] (G.P.)
3Depa men o Clinical Resea ch and EM Mic oscope, Pas eu Ins i u e o I an (PII),
Teh an P.O. Box 131694-3551, I an; n_hadidi@pas eu .ac.i
4Ne wo king Resea ch Cen e o Bioenginee ing, Bioma e ials and Nanomedicine (CIBER-BBN),
Ins i u e o Heal h Ca los III, A Mon o e de Lemos 3-5, 28029 Mad id, Spain
5Bioa aba, NanoBioCel Resea ch G oup, Calle JoséAcho egui s/n, 01009 Vi o ia-Gas eiz, Spain
*Co espondence: [email p o ec ed] (M.M.); [email p o ec ed] (J.L.P.)
Abs ac : Gene he apeu ics a e p omising o ea ing diseases a he gene ic le el, wi h some al eady
alida ed o clinical use. Recen ly, nanos uc u es ha e eme ged o he a ge ed deli e y o gene ic
ma e ial. Nanoma e ials, exhibi ing ad an ageous p ope ies such as a high su ace- o- olume a io,
biocompa ibili y, acile unc ionaliza ion, subs an ial loading capaci y, and unable physicochemical
cha ac e is ics, a e ecognized as non- i al ec o s in gene he apy applica ions. Despi e p og ess,
cu en non- i al ec o s exhibi no ably low gene deli e y e iciency. P og ess in nano echnology is
essen ial o o e come ex acellula and in acellula ba ie s in gene deli e y. Speci ic nanos uc u es
such as ca bon nano ubes (CNTs), ca bon quan um do s (CQDs), nanodiamonds (NDs), and simila
ca bon-based s uc u es can accommoda e di e se gene ic ma e ials such as plasmid DNA (pDNA),
messenge RNA (mRNA), small in e e ence RNA (siRNA), mic o RNA (miRNA), and an isense
oligonucleo ides (AONs). To add ess challenges such as high oxici y and low ans ec ion e iciency,
ad ancemen s in he ea u es o ca bon-based nanos uc u es (CBNs) a e impe a i e. This o e iew
del es in o h ee ypes o CBNs employed as ec o s in d ug/gene deli e y sys ems, encompassing
hei syn hesis me hods, p ope ies, and biomedical applica ions. Ul ima ely, we p esen insigh s in o
he oppo uni ies and challenges wi hin he cap i a ing ealm o gene deli e y using CBNs.
Keywo ds: ca bon-based nanos uc u es; ca bon nano ubes; ca bon quan um do s; nano-diamonds;
gene he apy; non- i al ec o s
1. In oduc ion
The p omising and unique gene he apy me hod applies genes o p ohibi o melio a e
any illnesses such as cance , inhe i ed diso de s, and i al in ec ions. In he gene ea men
me hod, a se o ce ain genes ha may help emedy an illness is in oduced in o he
pa ien ’s cells ins ead o applying expensi e d ugs o complex su ge ies. Inac i a ing a
mu a ed gene, subs i u ing a mu a ed gene wi h a heal hy and s ong gene, and in oducing
sa e genes in o he cells o p ese e hem om any diso de s a e h ee app oaches in gene
he apy. Gene he apy is isky and has cu en ly been s udied only o special diso de s ha
ha e no o he e icien ea men s. Gene ic molecules a ain he hos cells’ nuclei o induce
gene exp ession [
1
,
2
]. A comp ehensi e unde s anding o he in e ac ion be ween a ge ing
cells and he gene deli e y sys em is a p e-p e equisi e s ep o achie ing a a o able and
e icien design o he gene deli e y sys ems. A plasmid-based gene exp ession sys em,
Pha maceu ics 2024,16, 288. h ps://doi.o g/10.3390/pha maceu ics16020288 h ps://www.mdpi.com/jou nal/pha maceu ics
Pha maceu ics 2024,16, 288 2 o 46
an e icien gene ha encodes a pa icula he apeu ic p o ein, and a gene deli e y ec o
a e h ee main componen s o gene deli e y sys ems [
3
,
4
]. The s abili y o ex e nal gene ic
molecules in he hos ’s cells is an impo an c i e ion o ha ing an e icien and s able
gene deli e y sys em [
5
–
7
]. The e a e ex acellula and in acellula ba ie s along he
gene deli e y pa h, which he ec o should be able o o e come. Unspeci ic molecula
in e ac ions, endo helial ba ie s, and he immune esponse a e he h ee main ex acellula
ba ie s. Limi a ions o cellula up ake, endosome–lysosome escape, in acellula a ick-
ing, and nuclea deli e y a e in acellula kinds o ba ie s [
8
]. So, he co ec choice o a
speci ic ec o o gene deli e y is an e ec i e pa ame e o he success o gene he apy.
On he o he hand, he ec o should be able o o e come he main challenges (blood ci cu-
la ion, issue p essu e, endosomal escape, gene exp ession du a ion, mechanism o cellula
up ake) be o e deg ada ion o adso p ion unde biological condi ions. Non- i al ec o s
a e classi ied in o wo majo g oups: o ganic and ino ganic nanos uc u es. Comp ising
ca bon-based nanoma e ials such as CNTs, CQDs, and ulle enes [
9
], NDs a e a subca ego y
o ino ganic ma e ial g oups [
10
]. In his wo k, CBNs ha ac as non- i al ec o s wi h
high capaci y in gene deli e y sys ems a e e iewed.
The desc ip ion o nanos uc u es consis s o highligh ing he design and ad ancemen
o ma e ials a he nanoscale. When hese nanos uc u es a e loca ed in he p esence o
speci ied s imuli, hey show pa icula esponses. The modi ica ion o su ace chemis y
and physics ia a ious me hods helps o modula e he applica ion o nanos uc u es wi h
p e e able biological p ope ies and imp o e hei pa icula ope a ion and solubili y unde
physiological condi ions [
11
]. Ca bon-based nanoma e ials wi h la ge su ace- o- olume
a ios, high biocompa ibili y, and easy unc ionaliza ion p ocess ha e a high capabili y o
pa icipa ion in gene he apy. These ma e ials can deli e di e en nucleic acid agmen s
such as plasmid DNA, siRNA, miRNA, and AONs o cell/ issue/o gan a ge s a e ha ing
been unc ionalized p ope ly wi h biocompa ible molecules [12–15].
In his e iew, we ocus on h ee impo an nanos uc u es including CNTs, CQDs, and
NDs. O he simila ca bon-based nanos uc u es such as g aphene oxides (GO), i s educed
o m ( GO), and ulle enes ha e shown p omising esul s as e icien and sa e gene ic
ma e ial deli e y sys ems [
16
–
18
]. In each pa , we explain he s uc u e and p ope ies o
he nanos uc u e and hen, in oduce hei syn hesis me hods. Finally, we desc ibe he
applica ions o each nanos uc u e in he biomedical ield, especially gene deli e y sys ems.
2. Ca bon-Based Nanos uc u es
2.1. Ca bon Nano ubes (CNTs)
2.1.1. S uc u e and P ope ies o CNTs
In ecen yea s, CNTs ha e a ac ed he a en ion o many esea che s. CNTs we e i s
disco e ed by Japanese scien is Iijima [
19
] in 1991, and hey a e one o he mos applicable
nanopa icles [
20
] in nano echnology. CNTs a e made om olled g aphi e shee s p oduced
om ca bon a oms o med in o hexagonal s uc u es. The leng hs o CNTs a y om
lowe han 100 nm o a ew cen ime e s ha span he molecula as well as mac oscopic
scales. CNTs a e classi ied in o wo g oups based on he numbe o g aphi e laye s:
Single-Wall Ca bon Nano ubes (SWCNTs) and Mul i-Wall Ca bon nano ubes (MWCNTs).
SWCNTs a e o med om only one laye o olled g aphene wi h a diame e ange o
0.4–3 nm. MWCNTs a e made om se e al laye s o olled g aphene shee s. The p esence
o mo e laye s makes CNT’s s uc u e mo e complex and subsequen ly mo e di icul o
e alua e. The diame e s o MWCNTs a e in a ange o 1–200 nm. One o he di e ences
be ween SWCNTs and MWCNTs is he necessi y o ca alys p esence in hei syn hesis [
21
].
MWCNTs can be p oduced wi hou ca alys s, bu SWCNTs equi e ca alys species such
as i on-g oup me al, palladium, pla inum [
22
], e c. ha play an impo an ole in hei
syn hesis. The o he di e ence is ha MWCNT accumula es in a li ing body [
21
] mo e
han SWCNT, which leads o SWCNT being p e e ed o pha maceu ical applica ions. In
addi ion o he classi ica ion o CNTs acco ding o he numbe o g aphi e laye s, hey can
also be di ided in o h ee di e en ypes o CNTs namely, a mchai , chi al, and zigzag
Pha maceu ics 2024,16, 288 3 o 46
CNTs. Each o hese ypes o CNTs is c ea ed om a di e en di ec ion o olling g aphi e
shee s. Chi al ec o (
→
C=n→
a1+m→
a2
) was a c i e ion o de e mine CNT’s con o ma ion
ype, and is ep esen ed wi h wo indices (n,m). Index n ep esen s he di ec ion o he
g aphi e shee , and m is ela ed o he diame e o CNT. When m = 0 and n = m, he
co esponding CNTs a e called zigzag and a mchai , espec i ely, and bo h s uc u es ha e
a mi o symme y. The es o CNT con igu a ion belongs o chi al s uc u e, which is
signi ied by chi al angle. Some cha ac e is ics o CNT such as me allic o semi-conduc ing
s uc u e, diame e (d) and chi al angel (
θ
) can be de e mined by he chi ali y o CNTs [
23
].
Figu e 1 ep esen s a mchai , zigzag, and chi al SWCNTs.
Pha maceu ics 2024, 16, x FOR PEER REVIEW 3 o 47
han SWCNT, which leads o SWCNT being p e e ed o pha maceu ical applica ions. In
addi ion o he classi ica ion o CNTs acco ding o he numbe o g aphi e laye s, hey can
also be di ided in o h ee diffe en ypes o CNTs namely, a mchai , chi al, and zigzag
CNTs. Each o hese ypes o CNTs is c ea ed om a diffe en di ec ion o olling g aphi e
shee s. Chi al ec o (C
󰇍

 na

󰇍
󰇍
󰇍

ma

󰇍
󰇍
󰇍

) was a c i e ion o de e mine CNT’s con o ma ion
ype, and is ep esen ed wi h wo indices (n,m). Index n ep esen s he di ec ion o he
g aphi e shee , and m is ela ed o he diame e o CNT. When m = 0 and n = m, he co e-
sponding CNTs a e called zigzag and a mchai , espec i ely, and bo h s uc u es ha e a
mi o symme y. The es o CNT con igu a ion belongs o chi al s uc u e, which is sig-
ni ied by chi al angle. Some cha ac e is ics o CNT such as me allic o semi-conduc ing
s uc u e, diame e (d) and chi al angel (𝜃) can be de e mined by he chi ali y o CNTs
[23]. Figu e 1 ep esen s a mchai , zigzag, and chi al SWCNTs.
Figu e 1. Schema ic diag am showing zigzag, a mchai , and chi al SWCNTs; he semi-conduc i e
and me allic SWCNTs a e labeled wi h blue and pink colo s, espec i ely.
In he las wo decades, CNTs ha e a ac ed he a en ion o many esea che s due
o hei ex ao dina y mechanical, op ical, he mal, and elec ical p ope ies. The la ge
su ace a ea o CNTs can conjuga e o a wide a ie y o he apeu ic molecules [24]. They
can be an excellen ehicle in d ug/gene deli e y sys ems wi h high loading capaci y o
ans e d ugs o genes o a ge cells wi hou des oying hem o causing me abolic
changes in he body [25]. The bioac i e d ugs and genes (chemo he apeu ic d ugs [26]
such as doxo ubicin and cispla in, an ibio ics [27], nucleic acids [28], and an ibodies [29])
can a ach o he su ace o CNT o encapsula e in he CNT s uc u e. In his way, he
oxici y and side effec s o hese ca goes will be educed [30]. The high lexibili y o CNTs
Figu e 1. Schema ic diag am showing zigzag, a mchai , and chi al SWCNTs; he semi-conduc i e
and me allic SWCNTs a e labeled wi h blue and pink colo s, espec i ely.
In he las wo decades, CNTs ha e a ac ed he a en ion o many esea che s due
o hei ex ao dina y mechanical, op ical, he mal, and elec ical p ope ies. The la ge
su ace a ea o CNTs can conjuga e o a wide a ie y o he apeu ic molecules [
24
]. They
can be an excellen ehicle in d ug/gene deli e y sys ems wi h high loading capaci y o
ans e d ugs o genes o a ge cells wi hou des oying hem o causing me abolic changes
in he body [
25
]. The bioac i e d ugs and genes (chemo he apeu ic d ugs [
26
] such as
doxo ubicin and cispla in, an ibio ics [
27
], nucleic acids [
28
], and an ibodies [
29
]) can a ach
o he su ace o CNT o encapsula e in he CNT s uc u e. In his way, he oxici y and
side e ec s o hese ca goes will be educed [
30
]. The high lexibili y o CNTs enables hem
o be ben conside ably wi hou sus aining any damage and hen e u n o he p e ious
shape. CNTs can easily pene a e deep h ough memb anes, and ans e ca go o a ge
Pha maceu ics 2024,16, 288 4 o 46
cells. In e naliza ion o CNT o a ge cells is a ec ed by he physicochemical p ope ies
o CNT o su ace unc ionaliza ion, cellula p ocesses, bio-dis ibu ion, and deg ada ion
kine ics. On he o he hand, he size, dimensions, and colloidal beha io o CNTs a e some
pa ame e s ha a ec he in e ac ion be ween he ma e ial ha conjuga es o he su ace o
CNT and memb ane. CNT up ake a cellula le el possesses di e en mechanisms called
endocy osis, phagocy osis, pinocy osis and memb ane adso p ion [
30
,
31
]. Ha ing high
densi y-no malized Young’s moduli and good ensile s eng h a e o he p ope ies o CNTs,
which can be applied in biomedical applica ions [
32
,
33
]. Al hough CNTs possess high
mechanical s eng h, hei weigh is ul a-ligh due o emp y spaces in hei s uc u es. The
chemical and he mal s abili y (in acuum up o 2800
◦
C and in ai up o 1000
◦
C [
30
]) o
CNTs a e conside able and a e chemically un eac i e [
34
–
36
]. Besides he ad an ages o
CNT, he e a e also some disad an ages such as low solubili y and oxici y ha should be
esol ed be o e any biomedical applica ions [
37
,
38
]. To o e come hese p oblems, CNTs
should be unc ionalized by biocompa ible and biodeg adable ma e ials o imp o e hei
dispe sibili y and educe hei oxici y. The unc ionaliza ion o CNTs is one solu ion
o o e coming hese undesi able p ope ies, and can be pe o med ia wo me hods
(co alen ly and non-co alen ly). The unc ionaliza ion o CNTs is a powe ul poin o hem
o ac as a sma d ug/gene deli e y agen , and ha can s imula e mul i- esponsi eness.
The unc ionaliza ion o CNTs is explained in de ail in he ollowing sec ion.
2.1.2. Syn hesis Me hods o CNTs
Some p e equisi es, including an ac i e ca alys , ca bon sou ce, and su icien ene gy
sou ce a e needed o he syn hesis o CNTs. The a c-discha ge me hod [
39
,
40
], lase
abla ion [
41
,
42
], and chemical apo deposi ion (CVD) [
39
] a e signi ican me hods o he
syn hesis o CNTs [
43
–
45
]. In he a c-discha ge me hod, he e a e wo g aphi e elec odes
e e ed o as he anode and ca hode, wi h he anode o be consumed so ha CNT is
o med on he ca hode du ing CNT gene a ion [
46
]. The sou ce o ene gy in his me hod is
p o ided by s able a c-discha ged elec ici y wi h a ol age ange o abou 15–25 V [
43
,
47
].
Helium gas en e s he eac ion en i onmen a low p essu e (100–500 To , since CNT
canno be o med a To unde 100) [
48
]. MWCNTs will be gene a ed wi h an inne
diame e o 1.3 nm and an ou e diame e o abou 10 nm only i unmodi ied g aphi e
elec odes a e used. SWCNTs wi h diame e s in he ange o 0.6–1.4 nm can be p oduced
by using g aphi e elec odes wi h me allic ca alys s such as Fe, Co, and Ni [
49
] a he
cen e pa o he posi i e elec ode [
43
,
48
,
50
,
51
]. Usually, CNT syn hesis h ough his
me hod needs a long pu i ica ion p ocess a e syn hesis o emo e impu i ies such as
amo phous ca bon, non ubula ulle enes, and ca alys pa icles. These impu i ies a e
p esen as pa o he syn hesis ou come [
47
,
52
,
53
]. Al hough some a iables such as he
empe a u e o he chambe , concen a ion, kind o ca alys , he p esence o hyd ogen, e c.
a ec he size and s uc u e o syn hesized CNT, his me hod is s ill chosen as he bes
me hod o p oducing CNT wi h a high deg ee o s uc u al pe ec ion [
44
,
54
]. Chaudha y
e al. syn hesized MWCNT by using he a c-discha ge me hod wi h hyd oca bon as a
eeds ock a 100, 300, and 500 To p essu es and h ee di e en a c cu en s [
55
]. A o a
e al. in es iga ed he e ec o empe a u e on he syn hesis o MWCNT om a ca bon
block as a p ecu so ia he a c-discha ge echnique in an a gon a mosphe e. Also, hey
shi ed he a c cu en om 25 o 40 A o s udy he mo phological changes du ing he
syn hesis p ocess and concluded ha ca bon black can con e o MWCNT e en a low
le els o cu en and when he a c empe a u e is kep cons an o longe pe iods [
56
].
Singh and cowo ke s p oduced MWCNT ia he AC a c-discha ge me hod om pu e
g aphi e elec odes o di e en shapes and epo ed he ange o nano ubes’ leng h o be
be ween
231 and 561 nm
, and i s ange diame e be ween 14 and 55 nm [
57
]. Sa i e al.
we e able o p oduce MWCNT ia he a c-discha ge me hod and in es iga ed he e ec o
liquid medium on he g ow h, size, and quali y o MWCNT s uc u e. They epo ed ha
NaCl concen a ion has a di ec ela ionship o he leng h o gene a ed nano ube, namely,
Pha maceu ics 2024,16, 288 5 o 46
as he NaCl concen a ion inc eases, he leng h o p oduced nano ube changes om a ew
mic ome e s o mo e han 150 µm [58].
Applying he lase abla ion me hod o CNT syn hesis was i s epo ed by Guo and
cowo ke s in 1995 [
41
]. The lase abla ion me hod is a physical apo deposi ion me hod
wi h a sligh ly mo e complica ed sys em han he a c-discha ge me hod. Solid g aphi e
i adia ed by a lase sou ce is in oduced as he ca bon sou ce in his me hod and apo ized
in o apo ca bon a oms a 800–1500
◦
C. High-in ensi y ligh om a CO
2
lase o pulsed
lase sou ce such as neodymium-doped y ium aluminum ga ne (Nd:YAG) is applied
as he ene gy sou ce [
48
]. A cons an low a e o a gon o ni ogen gas en e s he sys em
housing a 500 To and g aphi e unde high in ense lase pulses explodes, and inally,
CNT will be o med on wa e -cooled coppe [
43
,
47
]. The lase abla ion me hod is a good
me hod o la ge-scale p oduc ion o SWCNT (1–10 g ), bu i consumes a lo o ene gy
in addi ion o equi ing di e en pieces o equipmen [
59
]. So, om an economic poin
o iew, i is no sui able. SWCNT syn hesis h ough his me hod will p oduce diame e s
be ween 1 and 2 nm. MWCNT can also be p oduced h ough his me hod bu equi es
high expenses [
43
]. Syn hesizing SWCNT by his me hod will p o ide highe quali y
and yield han hose ob ained by he a c discha ge me hod. Also, a na owe SWCNT
dis ibu ion can be ob ained h ough lase abla ion [
47
]. Howe e , bo h me hods (a c
discha ge and lase abla ion) consume a lo o ene gy o con e ca bon a oms in o a CNT
s uc u e [
47
]. The ad an ages o hese me hods a e he capabili y o con ol some i al
pa ame e s such as pu i y o p oduced CNT, densi y, leng h and diame e o CNTs [
43
].
Ch zanowska and co-wo ke s in es iga ed he e ec o lase wa eleng h on p ope ies o
SWCNT and p oduc ion yield [
60
]. They concluded ha lase luence has a s onge e ec
on he p ope ies o syn hesized nano ubes han in a ed lase adia ion [
60
]. Das e al.
ied o op imize he a c-discha ge and lase abla ion me hods o CNT syn hesis [
61
]. Thei
a emp s p oduced a CNT yield wi h he desi ed diame e and chi ali y [
61
]. Alam o e al.
unc ionalized CNT wi h di e en amoun s o sil e nanopa icles h ough a lase -abla ion-
assis ed me hod o be used as an excellen adso p ion ma e ial agains naph halene [
62
].
They concluded ha loading sil e nanopa icles on he su ace o CNT p o ides an op ion
o wa e ea men applica ions [
62
]. Zhang and cowo ke s syn hesized SWCNT using he
lase abla ion me hod a oom empe a u e. Co and Ni as a ca alys and g aphi e powde
we e ans o med in o a a ge pla e by hea ea men [
63
]. Table 1indica es some esea ch
ela ed o CNTs syn hesized ia he lase abla ion me hod.
Table 1. Re iew o CNTs p epa a ion ia he lase abla ion me hod.
CNT Type Ine Gas Lase Sou ce Ca alys Re .
SWCNT A CO2lase Co, Co/Ni, Fe, Fe/Ni, Ni, and Ni/Y [64]
MWCNT A Nd:YAG lase No me al [65]
SWCNT A CO2lase Co/Ni [66]
SWCNT A Pulsed Nd:YAG Co/Ni [67]
SWCNT A Nd:YAG lase Ni and Co [60]
SWCNT A CO2lase Ni and Co [68]
SWCNT N2and B CO2lase Ca bon [69]
MWCNT A Nd:YAG lase - [70]
Chemical apo deposi ion (CVD) is ano he me hod o he syn hesis o ca bon
nano ubes. He e, he ca bon sou ce is one such as e hanol, ace ylene, p opylene, and
me hane ha en e s he p ocesso in he p esence o a me al ca alys (Ni, Fe, Co, e c.), and is
hea ed o 1000
◦
C [
44
,
71
,
72
]. The diame e o ca alys pa icles and he leng h o he eac ion
ime a ec he diame e o MWCNT p oduced by his me hod [73]. The CVD me hod can
be used o la ge-scale CNT p oduc ion. Good alignmen , con ol o e diame e and i s
wall numbe as well as con ol o nano ube g ow h a e some o he powe ul and posi i e
poin s o his me hod [
72
]. This me hod can be di ided in o se en di e en echniques (ho
ilm CVD, plasma-enhanced CVD (PECVD), adio equency PECVD, mic owa e PECVD,

Pha maceu ics 2024,16, 288 6 o 46
wa e -assis ed CVD, oxygen-/ca bon dioxide-assis ed CVD, and CVD wi h o gano-me allic
p ecu so s) [
74
]. Szymanski e al. de eloped a new app oach o CNT syn hesis in eac o s
ope a ing a a mosphe ic p essu e [
75
]. Zhang e al. ocused on upg ading he con olled
syn hesis o ul a-long CNT wi h pe ec s uc u es and excellen p ope ies [
76
]. Duc
Vu Quyen e al. syn hesized CNT om lique ied pe oleum gas on a Fe
2
O
3
/Al
2
O
3
p e-
ca alys ia a CVD me hod wi hou hyd ogen [
77
]. Yang and cowo ke s syn hesized CNT-
mic o ib ous composi es ia he he mal CVD me hod and s udied he e ec o di e en
pa ame e s such as deposi ion ime and empe a u e, acid p e ea men , and gas low a e
on he p ope ies and s uc u e o he ob ained composi es [
78
]. Ib ahimo e al. syn hesized
CNT ia CVD echnology and py olysis o na u al gas in he p esence o i on a he nano-
scale [
79
]. A unkuma and cowo ke s p oduced la ge-scale MWCNTs ia he he mal
ca aly ic CVD me hod by applying ace ylene and Fe/MgO as gas and ca alys , espec i ely.
The cha ac e iza ion esul s indica ed ha he pa icle size o MWCNT was in a ange o
20–30 nm [
80
]. Das e al. epo ed ha he size o ca alys nanopa icles plays an impo an
ole in he diame e size o MWCNTs when syn hesized h ough mic owa e plasma-CVD
a low- empe a u es [
81
]. Zhang e al. syn hesized and hen cha ac e ized MWCNTs ia
mic owa e-assis ed CVD and also s udied a ious pa ame e s (ca alys , ca bon sou ce, he
enewable ca bon subs a e, and he eac ion’s empe a u e) [
82
]. The esul s showed ha
600
◦
C was he op imum empe a u e o p oducing MWCNTs. The leng h o MWCNTs
was be ween 2600 and 3200 nm and he MWCNT’s diame e was 50 nm [
82
]. Smagulo a
and cowo ke s syn hesized CNT om high-densi y polye hylene was e in a one-s ep
CVD p ocess [
83
]. The esul s o he physicochemical analysis con i med he absence
o u bos a ic ca bon in he inal p oduc s [
83
]. Tang and cowo ke s nomina ed some
p ominen me hods in p og essing he quali y o CVD-g own 2D componen s [
84
]. Haque
e al. syn hesized MWCNT ia CVD p ocess and con e ed i o a diamond nanos uc u e
by nanosecond pulsed lase mel ing p ocedu e a oom empe a u e and wi hou using any
ca alys [
85
]. Table 2indica es some s udies ega ding CNTs syn hesized ia CVD me hod.
Table 2. Re iew o CNT p epa a ion ia he CVD me hod.
CNT Type Ine Gas Ca bon Sou ce
Technique Se up Ca alys Re .
Time (min)
Tempe a u e (
◦
C)
MWCNT A Benzene 5–240 750 Fe ocene [86]
MWCNT A Ace ylene 60 850 Fe ocene [87]
MWCNT H2Me hane 10–60 1000 MgMoO4[88]
MWCNT H2Cyclohexane 5 750 Co, Fe, and Alumina [89]
MWCNT N2Polyp opylene 40 500–800 NiO/hzsm-5 zeoli e [90]
MWCNT N2Ace ylene 15 750–900 NH3/Co [91]
MWCNT N2
Xylene & Cyclohexanol
- 750 Fe ocene [92]
SWCNT N2E hylene 10 550–750 Fe, Fe/Al, Fe/Al2O3,
and Co/Al2O3[93]
SWCNT A /N2Me hane - 1200 Fe ocene [94]
MWCNT A /N2E hanol - 350–750 Cobal nanopa icles [95]
SWCNT H2Ee hane - 550–950 Fe and Alumina [96]
CNT pu i ica ion is he nex s ep a e he CNT syn hesis p ocess. In his way, un a o -
able en i ies such as ca bon nanopa icles, esidual ca alys s, and o he g aphi ic impu i ies
a e sepa a ed [
97
]. Choosing an e icien and gen le pu i ica ion me hod is necessa y o
p e en he des uc ion o he CNT’s s uc u e. The pu i ica ion p ocess can be done by
bo h chemical and physical echniques [
97
]. Mos o he pu i ica ion me hods a e applied
simul aneously o elimina e he impu i ies and imp o e he pu i ica ion p ocess. Liquid
and gas phases a e pa o he chemical pu i ica ion ca ego y and il a ion, sonica ion,
and ch oma og aphy a e a subse o he physical pu i ica ion ca ego y. The oxida ion o
syn hesized CNTs is mo e applicable ia he chemical pu i ica ion p ocess a bo h d y and
we condi ions. Oxida ion a d y condi ions is p ocessed by ai and oxygen, and highly
Pha maceu ics 2024,16, 288 7 o 46
concen a ed acidic solu ions o s ong oxidan s a e chosen o he oxida ion p ocess a we
condi ions. The simplici y and high yield o chemical oxida ion ha e a ac ed ex ensi e
a en ion in liquid-phase echnology. Concen a ed acid can emo e he me al pa icles and
ca bon impu i ies om CNT. The oxida ion pe iod and e lux empe a u e a e wo pa ame-
e s o elimina ing ca alys pa icles [
97
,
98
]. The physical pu i ica ion p ocess is applied
o educe he damage ia non-con en ional me hods. The ul a-sonica ion p ocedu es a e
ca ied ou ia he seg ega ion o pa icles. High ene gy in he p esence o sol en s such as
o-dichlo obenzene and dichlo ome hane is applied o pu i ying CNT by ul a-sonica ion
me hods. Du ing hese pu i ica ion p ocedu es, he molecules can in e ac wi h CNTs and
c ea e solubiliza ion. Fil a ion is ano he me hod o physical pu i ica ion ha depends
on di e en p ope ies such as size (leng h and diame e ) and pa icle sepa a ion. On
he o he hand, ch oma og aphy is used o pu i ica ion and cu ing he leng h o CNTs.
High-pe o mance liquid ch oma og aphy (HPLC) and size exclusion ch oma og aphy
(SEC) a e wo popula me hods o leng h sepa a ion o CNTs. Chemical pu i ica ion is
supe io compa ed o physical pu i ica ion due o i s mode a e condi ions, which pu i ies
CNT weakly. Howe e , he posi i e cha ac e is ic o physical sepa a ion is he capabili y o
ejec impu i ies du ing p oduc ion [97,99].
2.1.3. Func ionalizing CNTs
As men ioned in he p e ious sec ion, CNTs ha e some unwan ed p ope ies ha
c ea e p oblems o biomedical applica ions. Two o he mos signi ican p oblems o
CNTs a e high oxici y and low solubili y. CNT’s solubili y is e y weak in mos sol en s
(bo h o ganic and ino ganic) due o possessing highly hyd ophobic su ace s uc u es. The
solubili y ac o o CNTs in aqueous solu ions should be se iously imp o ed be o e being
applied in biological sys ems [
74
]. Fu he mo e, he oxici y na u e o CNTs should also
be elimina ed. The eupon, he su ace o CNTs should be modi ied by ma e ials ha will
imp o e hei physicochemical p ope ies. So, unc ionalizing CNTs wi h o ganic and
ino ganic ma e ials will inc ease hei dispe sion and biocompa ibili y and educe hei
oxici y [
100
]. Gene ally, he e a e wo me hods o unc ionalizing CNTs: co alen and
non-co alen , which a e add essed in he nex sec ion.
Co alen unc ionaliza ion o CNTs: This me hod has been widely used o inc easing
dispe sion and easy conjuga ion o bio-molecules. In his me hod, he unc ional g oups
a ach o he su ace o CNT wi h co alen bonds [
74
]. The hyb idiza ion s uc u e o CNT
changes om sp
2
o sp
3
s a e by molecules wi h high chemical eac i i y used o his
p ocess [
101
]. Fluo ina ion o CNTs was he i s in es iga ion o co alen - unc ionaliza ion
o CNTs h ough his me hod [
101
]. C-F bonds on sidewalls o luo ina ed CNT a e weak
and, he e o e, c ea e si es o addi ional unc ionaliza ion such as amino and hyd oxy
g oups. In addi ion o he luo ina ion o CNTs, o he me hods such as ca bene and ni ene
addi ion, cycloaddi ion, chlo ina ion, and b omina ion can also be used [
101
]. Le e al. [
102
]
syn hesized poly(ionic liquid)s om poly (s y ene-al -maleic anhyd ide) (PSM) and u u yl
amine, which is called PSMF-IL. In he nex s ep, hey conjuga ed PSMF-IL o he su ace
o MWCNT o p oduce PSMF-IL-MWCNT nanoma e ial. They obse ed ou peaks in
C1s o MWCNT, which ela ed o C-C, C-O, C=O, and
π
-
π
* ansi ion le el. Also, hey
obse ed ha he in ensi y o O1s inc eased conside ably a e unc ionalizing MWCNT,
and wo new peaks o N1s appea ed a PSMF-IL-MWCNT, which ela e o C-N and C=N
bonds. He e al. epo ed an imp essi e me hod o co alen unc ionaliza ion o CNT. This
me hod includes dec easing ca bon nanoma e ials wi h sodium naph halide, and hen,
adding dia yliodonium sal s, a ene, and he e oa ene iodonium sal s [
103
]. Guzman and
cowo ke s unc ionalized CNT-COOH co alen ly wi h insulin as a p o ein model [
104
].
In his app oach, candida an a c ica lipase was used as an enzyme ha can help he
conjuga ion o ca boxylic g oups o hyd oxyl g oups [
104
]. Table 3indica es some s udies
ega ding co alen - unc ionalized CNTs.
Pha maceu ics 2024,16, 288 8 o 46
Table 3. Lis o co alen - unc ionalized ca bon nano ubes in some esea ch.
Type o CNT Type o Func ionaliza ion Func ionaliza ion Compound Re .
SWCNT co alen poly y osine [105]
SWCNT co alen Pho osensi ize e epo in [106]
MWCNT co alen Spi opy an-4’,6’-dica bonylazides [107]
Ca boxylic CNT co alen Hyd oxyl- e mina ed polydime hylsiloxane [108]
MWCNT co alen Imidazolium-based poly (ionic liquid)s [102]
MWCNT co alen Zinc and coppe complexes o meso- e a
(4-aminophenyl) po phy in [109]
SWCNT co alen Me hac yla e-co-po phy ins [110]
SWCNT co alen Ca boxyl, hyd oxyl, and amine chemical g oups [111]
MWCNT Co alen /non-co alen Alkaline solu ion o KMnO4[112]
SWCNT Co alen /non-co alen Fluo ina ed phosphona e analogs o phenylglycine [113]
SWCNT co alen Acyl chlo ide [114]
Non-co alen Func ionaliza ion o CNTs: In his me hod, unlike he co alen app oach,
i is p e e ed ha he s uc u e o he nano ube does no change due o unc ionaliza ion.
The non-co alen unc ionaliza ion o CNT gene ally includes h ee s eps: ul asonica ion
o CNTs in solu ion, cen i uga ion, and inally il a ion. These s eps a e ca ied ou in a
oom- empe a u e en i onmen . In non-co alen unc ionaliza ion, a wide a ie y o com-
pounds such as bio-molecules, polyme s (such as polye hylene glycol and i s de i a i es),
and su ac an s (like sodium dodecyl sulpha e) and polynuclea a oma ic compounds can
be a ached o he su ace o CNT h ough physical weak in e ac ion. On he o he hand,
di e en o ces such as
π
-
π
s acking in e ac ions, an de Waals o ces, hyd ogen bonds,
and elec os a ic o ces be ween CNT and molecules c ea e and help o modi y he ini ial
s uc u e o CNTs [
74
]. Siu e al. unc ionalized SWCNT non-co alen ly wi h succina e
polye hyleneimine, and applied i as a ca ie o siRNA deli e y in o melanoma [
115
].
Wang and cowo ke s unc ionalized MWCNT wi h po phy in-Sn ne wo ks o inc easing
p o ein adso p ion [
116
]. The inal p oduc was cha ac e ized, and he esul s showed
ha he unc ionalized CNT was capable o adso bing high le els o p o eins (cy och ome,
lysozyme, bo ine hemoglobin, and bo ine se um albumin) [
116
]. Yazdani e al. unc ional-
ized SWCNT non-co alen ly wi h DSPE-PEG-COOH and hen applied i as a ca ie o
ampho e icin B deli e y, and also in es iga ed he capabili y o unc ionalized CNT in gene
ma e ial deli e y [
117
]. Yazdani e al. also s udied he s abili y o he o e all ampho e icin
B deli e y sys em by he Flo y–Huggins model [
118
]. Hadidi e al. unc ionalized SWCNT
non-co alen ly wi h an amine de i a i e o phospholipid polye hylene glycol o dec ease
he in insic oxici y le el o pu e CNT [
119
]. The oxici y cells we e ca ied ou on he lung,
li e , and o a ian cance cell lines and indica ed he CNT unc ionalizing p ocess has an
e icien ole in applying he unc ionalized CNT in pho o he mal he apy [
119
]. Table 4
indica es some s udies ega ding non-co alen unc ionalized CNTs.
Table 4. Lis o non-co alen unc ionalized ca bon nano ubes in some esea ch.
Type o CNT Type o Func ionaliza ion Func ionaliza ion Compound Re .
SWCNT non-co alen Su ac an pep ides [120]
MWCNT non-co alen Lec in concana alin A [121]
MWCNT non-co alen Di e en deep eu ec ic sol en compounds [122]
SWCNT non-co alen Py ene pendan polyes e [123]
MWCNT non-co alen
P e unc ional polyes e s (py ene, py ene oge he wi h
-COOH, -OH, and -C≡CH) [124]
SWCNT/MWCNT non-co alen py ene-polye hylene glycol de i a i es [125]
SWCNT non-co alen Fmoc-amino-acid-bea ing polye hylene glycol chains [126]
Pha maceu ics 2024,16, 288 9 o 46
2.1.4. Applica ion o CNTs in Gene The apy
CNTs p o ide nume ous applica ions in a ious ields due o hei inhe en physico-
chemical p ope ies such as dis inc i e leng h- o-diame e a io, biocompa ibili y, nano ube
su ace a ea, and easy chemical unc ionaliza ion by di e en ma e ials. The pu e and
p is ine CNTs ha e a hyd ophobic s uc u e and dispe se wi h di icul y in aqueous media.
Func ionalizing CNTs (co alen ly o non-co alen ly) helps o inc ease hei solubili y and
imp o e biocompa ibili y by modi ying hei su ace wi h di e en molecules and c ea ing
unc ional g oups such as ca boxylic acid o amine g oups, which makes hem ideal o
deli e ing nucleic acid, plasmid DNA, siRNA, AONs, and ap ame s [
127
]. Rela ed o his,
shown in Table 5, he e a e a lo o wo ks whe e esea che s elabo a e on unc ionalized
CNTs o gene ic ma e ial deli e y. The ollowing a e he main examples o each ype
o nucleic acid. Pan a o o e al. [
128
] unc ionalized CNTs wi h ammonium and used o
plasmid deoxy ibonucleic acid (pDNA) deli e y. They obse ed he unc ionalized CNTs
ha e a low cy o oxici y and pene a e he cell easily [
128
]. K ajcik e al. [
129
] unc ionalized
SWCNT chemically wi h hexame hylenediamine (HMDA) and poly (diallyldime hylam-
monium) chlo ide (PDDA) o ob ain a nanoca ie o conjuga e o siRNA by elec os a ic
in e ac ions. They concluded ha PDDA-SWNT is an e ec i e ca ie sys em o in acellu-
la deli e y o siRNA [
129
]. In he wo k o Siu e al. [
130
], h ee di e en combina ions we e
made om a lipopolyme (DSPE-PEG-COOH) and polye hyleneimine (PEI) a di e en
a ios and called DGI. Nex , hey used h ee DGIs as a su ac an o unc ionalized ca bon
nano ubes. Finally, hey a ached he unc ionalized CNT o siRNA and cha ac e ized i a
in i o
and
in i o
scales. They concluded ha he combina ion o DGI wi h low amoun s
o PEI ac ed e ec i ely o complex siRNA-CNT, and he cy o oxici y o h ee di e en DGI
combina ions was low in
in i o
expe imen s [
130
]. Mohammadi e al. [
131
] syn hesized
ca boxyla ed SWCNT and hen conjuga ed i o polye hylenimine-pipe azine o be used
as a ec o o ab ica e ec o -ap ame o a ge ed deli e y o siRNA. Masso i e al. [
132
]
unc ionalized CNT wi h wo polyme s (polye hyleneimine (PEI) and polyamidoamine
dend ime (PAMAM)) and conjuga ed i o miR-503 oligonucleo ides. They epo ed ha
he oxici y o CNT was educed a e coa ing i wi h he wo polyme s, and i also helped
he e iciency o miR-503 oligonucleo ide deli e y o endo helial cells [
132
]. They concluded
ha hese o mula ions inc ease he s abili y o miRNA oligonucleo ides in se um [
132
].
Gu e al. [
133
] unc ionalized MWCNT wi h polye hylene glycol (MWCNT-PEG) and con-
juga ed i o an i-PSMA ap ame (MWCNT-PEG-Ap) o a ge p os a e cance cells and
in es iga e (MWCNT-PEG-Ap) a
in i o
and
in i o
scales. They obse ed he ul asound
signal in MWCNT-PEG-Ap was s onge han ha in MWCNT-PEG and no ul asound
signal was de ec ed in he hea . They concluded his o mula ion (MWCNT-PEG-Ap)
had a good e ec a
in i o
scale [
133
]. Table 5shows he exhaus i e o e iew o he
unc ionalized CNTs o deli e nucleic acid in bo h
in i o
and
in i o
cases. The s udies
in he ollowing able a e ca ego ized acco ding o he ype o nucleic acids deli e ed
(pDNA, siRNA and miRNA, AONs and ap ame s). Chen and cowo ke s [
134
] modi ied
he SWCNTs wi h amylose de i a i es con aining poly(L-lysine) dend ons (ADP@SWNT).
They s udied some pa ame e s such as aqueous dispe sion s abili y, cy o oxici y, gene ans-
ec ion e iciency, and pho o he mal e ec o he complex bo h
in i o
and
in i o
. Figu e 2
illus a es he umo -inhibi ing e ec s o ADP@SWNT/TNF
α
and ADP@SWNT/TNF
α
combined wi h lase i adia ion in a nude mouse model o human colo ec al cance [
134
].
In Figu e 2a, he absence o umo nec osis was e iden in he ADP g oup. Simila ly, he
ADP@SWNT/TNF
α
g oup displayed no signi ican damage, albei wi h obse able i egu-
la i ies in shape. In con as , he ADP@SWNT/TNF
α
+lase i adia ion g oup exhibi ed a
p onounced le el o inju y, coupled wi h a educ ion in umo size due o he mal combus-
ion on he skin. These indings unde sco e he e icacy o he nea -in a ed (NIR)- igge ed
pho o he mal e ec o ADP@SWNT/TNF
α
in selec i ely damaging umo cells, he eby
sugges ing i s po en ial u ili y in umo he apy [
134
]. As shown in Figu e 2b, ini ial umo
sizes we e compa able ac oss he h ee g oups. Subsequen ly, he ADP g oup exhibi ed
subs an ial umo de elopmen , dis inguishing i om he o he wo g oups a e 5 days.
Pha maceu ics 2024,16, 288 16 o 46
Bo om-Up Me hods
In his app oach, molecula p ecu so s change o ca bon quan um do s h ough
di e en me hods. In ac , he high ene gy o mic owa e, hyd o he mal, and ul asound
gene a e nanoscale-size CQDs om small o ganic molecules [
177
]. The p oduced CQDs
ha e high quan um yields and excellen op ical p ope ies. The ad an ages o hese
me hods a e simple ope a ing p ocesses and con ollable eac ion condi ions. Also, he
aw ma e ials a e inexpensi e [
177
]. Hyd o he mal ea men , elec ochemical me hods,
mic owa e syn hesis, and he mal decomposi ion a e subca ego ies o bo om–up me hods.
Hyd o he mal Me hod: In his app oach, small o ganic molecules such as glucose,
chi osan [
203
], ci ic acid [
204
], uc ose, amino acids, and o he na u al p oduc s p oduce
CQDs a high empe a u es and p essu es [
177
]. This me hod is cheap, non- oxic, and
en i onmen ally iendly. Meh a e al. [
164
] ab ica ed highly luo escen CQDs om
Saccha um o icina um
juice h ough a single-s ep hyd o he mal ope a ion a cons an em-
pe a u e (
T = 120 ◦C
). A e hea ing, ex ac ion, and cen i uga ion, highly blue luo escen
CQDs wi h uni o m size (~3 nm) we e p oduced. Bhunia e al. [
205
] syn hesized wo kinds
o CQDs. The i s one was hyd ophobic CQDs gene a ed om mixing di e en amoun s
o ca bohyd a es wi h ac adecylamine and oc adecene. The hyd ophilic ype o CQDs was
gene a ed om hea ing an aqueous solu ion o ca bohyd a es wi hin a wide pH ange. I he
aqueous solu ion o ca bohyd a es is mixed wi h concen a ed phospho ic acid, hyd ophilic
CQDs wi h ed and yellow emissions will be gene a ed.
Yang e al.
[
203
] syn hesized lu-
o escen CQDs by hyd o he mal ca boniza ion o chi osan ha was unc ionalized wi h
amine. These ypes o CQDs can be applied as new bio-imaging agen s. Zhu e al. [
206
]
used glucose and po assium phospha e as he ini ial ma e ials o p oducing CQDs by a
simple, e ec i e, and one-s ep hyd o he mal p ocess. The p oduced CQDs we e applied as
an elec oluminescence senso . The amoun o po assium phospha e a ec s he luo escen
colo s o gene a ed CQDs, and hey in es iga ed he op ical and elec onic p ope ies o
p oduced CQDs by densi y unc ional heo y [
206
].
Nammahachak e al.
[
207
] con olled
he a e age size o CQDs by applying di e en illing olume o suc ose solu ions in he
hyd o he mal eac o and epo ed ha he illing olume and a e age size o CQDs ha e
an in e se co ela ion. Kuma and cowo ke s [
208
] syn hesized CQDs composed o ca bon,
oxygen, and ni ogen om cow milk as a s a ing ma e ial ia hyd o he mal ea men . The
shape o p oduced CQDs was almos ci cula wi h a e age size o 7 nm. They concluded
his echnology is simple, and sa e o he en i onmen and does no need special chemical
ing edien s o equipmen [208].
Elec ochemical Me hod: The elec ochemical s a egy is a con enien and s aigh -
o wa d pa h o gene a ing CQDs a ambien empe a u e and p essu e [
209
]. Mos
o he syn hesized CQDs p oduced h ough his me hod possess high s abili y and
uni o m size dis ibu ion and a e applied in bio-imaging and senso applica ions [
209
].
Hou e al.
[
210
] syn hesized CQDs wi h size 2.4 nm om sodium ci a e and u ea in
de-ionized wa e ia his s a egy and epo ed ha i can be applied as an Hg
2+
de-
ec o . Tian and colleagues [
211
] epo ed ha ni a e solu ion is he bes choice o
p oducing CQDs ia he elec ochemical ex olia ion me hod due o he high simila i y
o pho oluminescence and a e age size o 3.5 nm. The XPS and FTIR esul s showed
some simple unc ional g oups on he su ace o ob ained CQDs du ing elec ochemical
ex olia ion, and he quan um yield o p oduced CQDs was 5.6% [
211
]. Niu and cowo k-
e s [
212
] syn hesized g een- luo escen N-doped CQDs ia a simple elec ochemical
s a egy, and he quan um yield was 30.6%. Py oca echol and e hylenediamine we e
used as p ecu so s and elec oly es, espec i ely. They concluded he o iginal ou pu o
he p ocess has a high po en ial in bo h
in i o
and
in i o
s ages o clinical diagnosis
applica ions [
212
]. Bo olami e al. [
213
] epo ed he syn hesis o L-p oline-based chi al
CDs and e hanol-de i ed L-p oline-based chi al CDs ia elec ochemical me hod. They
op imized he elec ochemical se up and s udied he e ec o eac ion condi ions on he
inal p oduc s, pho oluminescence, and ca aly ic ac i i y [213].

Pha maceu ics 2024,16, 288 17 o 46
Mic owa e I adia ion: One o he as es and lowes -cos me hods o p oducing
CQDs is mic owa e i adia ion echnology [
172
]. O iginally, Xu and colleagues [
214
]
u ilized a mix u e o calcium ci a e and u ea solu ion o gene a e CQDs h ough his
me hod. A high luminescence was emi ed (bo h in liquid and solid phases) by he
p oduc . Some esea che s ha e epo ed [
214
] ha g een luminescen CQDs can be
p oduced h ough mic owa e i adia ion by using suc ose as he ca bon sou ce and
die hylene glycol (DEG) as he eac ion media. The p oduced CQDs possessed good
dispe sibili y in wa e and hei appea ances we e anspa en . Also, his p oduc (DEG-
CQDs) was obse ed o ha e low cy o oxici y le el, and could hope ully be applied o
bio-imaging [
172
].
Liu e al.
[
215
] gene a ed pho oluminescen CDs om a solu ion o
bo ine se um albumin and u ea ia a mic owa e ea men p ocess and applied hem
as pH and empe a u e nanosenso s. The p o ein ca bon sou ce can be esponsi e o a
speci ic ype o me al ions [
215
].
Medei os e al
. [
216
] s udied he bo om–up me hods
o p oducing CQDs, by ocusing speci ically on mic owa e i adia ion echnology, and
in es iga ed di e en applica ions o hei ob ained CQDs. This p ocess can p oduce hy-
d ophilic, hyd ophobic, and amphiphilic CQDs [
216
].
Manioudakis e al.
[
217
] p oduced
hyd ophilic CQDs h ough a mic owa e-assis ed eac ion be ween ni ogen (passi a ing
molecules) and ci ic acid. They s udied he ole o N-doping on CQDs’s pho o-physical
p ope ies [
217
]. The size o he ob ained CQDs was 2.5 nm and he dis ibu ion was
na ow. The FTIR and XPS esul s indica ed he inal p oduc had good dispe sibili y
in wa e due o he p esence o unc ional g oups (ca boxylic acid, amine, e c.) on he
su ace o CQDs [
217
]. Ang and cowo ke s [
218
] used palm ke nel shell biomass as a
p ecu so o gene a e CDs ia a mic owa e i adia ion me hod and s udied di e en
pa ame e s such as i adia ion pe iod, p esence o chi osan, and eac ion medium. The
quan um yield o ob ained ca bon do om die hylene glycol wi h a 1 min i adia ion
pe iod was 44%. They concluded he inal CDs can be applied in cellula imaging and
o emo ing hea y me al ions [
218
]. Shejale and cowo ke s [
219
] syn hesized N-CQDs
ia mic owa e py olysis echnology, and applied hem as a co-pho oac i e laye wi h
an 8.75% pho o-con e sion e iciency. Also, he powe con e sion e iciencies we e 55%
and 99% o co-sensi ize and sensi ize , espec i ely [219].
The mal Decomposi ion: Ano he s anda d bo om–up me hod o he syn hesis o
CQDs om small o ganic molecules is he mal decomposi ion. In his me hod, smalle
ca bon uni s (o ganics) con e o semi-conduc o and magne ic nanoma e ials unde
ex e nal hea wi h sizes less han 10 nm which classi ies hem as CQDs. This s a egy o
decomposi ion eac ions is ei he i e e sible such as he decomposi ion o p o eins o
e e sible such as he decomposi ion o ammonium chlo ide [
220
]. The ad an ages o his
app oach a e simplici y o ope a ion, lesse ime consump ion, and inexpensi e and la ge
scalable p oduc ion capabili y [
185
,
221
]. Wang e al. [
222
] syn hesized CDs om ci ic acid
as he ca bon sou ce by using he mal decomposi ion. They passi a ed ci ic acid wi h
o ganosilane and N-(
β
-aminoe hyl)-
γ
-aminop opyl me hyl dime hoxy silane (AEAPMS)
du ing he p ocess. The eac ion mix u e was hea ed a 240
◦
C o 1 min. Finally, hey
syn hesized he CDs wi h diame e s o abou 0.9 nm. Wang e al. [
223
] used di e en
condi ions o syn hesis o CDs h ough he mal decomposi ion. In his app oach, hey
pu ci ic acid on a ho pla e a 200
◦
C o 30 min and hen, neu alized i wi h sodium
hyd oxide solu ion, and inally pu i ied i h ough dializa ion. This p oduc had a size
ange om 0.7 o 1 nm. Ma indale e al. [
224
] could syn hesize CQDs wi h an a e age size
o 6.8
±
2.3 nm and high yields o a ound 45% h ough py olysis o ci ic acid a 180
◦
C o
40 h. Ma e al. [
221
] could con e E hylene diamine e aace ic acid (EDTA) o N-doped
GQDs by using a sand ba h a 260~280
◦
C h ough di ec ca boniza ion. These p oduc s
ha e g aphene-like s uc u es. Table 6shows some esea ch ha has syn hesized CQDs
h ough di e en me hods, including he syn hesized me hod, p ecu so , a e age size o
CQDs, and c ys allini y.
Pha maceu ics 2024,16, 288 18 o 46
Table 6. Summa y o op–down and bo om–up CQDs’ syn hesis me hods.
Top–Down o
Bo om–Up
Syn hesized
Me hod P ecu so (s) A e age Size o CQDs
(nm) C ys allini y Re .
Top–down Lase abla ion G aphi e lakes 3.2 nm, 8.1 nm, 13.4 nm Yes [225]
Top–down Chemical
Oxida ion g-Bu y olac one 9 ±6 nm Yes [226]
Top–down Chemical
Oxida ion Pe oleum coke CQD: 5.0 nm
N-CQD: 2.7 nm No [227]
Bo om–up Hyd o he mal
Ci ic acid and
e hylenediamine o
N-e hyle hane-1,1-diamine
o N-(2-aminoe hyl)
ace amide
In he ange o 2–6 nm Yes/No [228]
Bo om–up Hyd o he mal
Ci ic acid, e hylenediamine
and ammonia wa e ~3.7 ±0.7 nm Yes [229]
Bo om–up Mic owa e
i adia ion
Ci ic acid, u ea and
o mic acid
G een: 0.5–2.0 nm
Red: 0.7–2.5 nm - [230]
Chemical apo
deposi ion Ace ylene In he ange o 2–7 nm Yes [231]
Bo om–up Hyd o he mal
o-Phenylenediamine o
4,5-di luo o-1,2-
benzenediamine
5.52 nm and 5.18 nm No [232]
Bo om–up Mic owa e
i adia ion
o-Phenylene-diamine and
ci ic acid 1.1 ±0.3 nm - [233]
Bo om–up Py olysis Fennel seeds 3.90 ±0.91 nm Yes [234]
Bo om–up Hyd o he mal Hyd o he mal ca bon
biomass
100 ◦C: 2.3 nm,
120 ◦C: 1.3 nm,
140 ◦C: 1.9 nm,
160 ◦C: 2.9 nm,
180 ◦C: 2.4 nm
No [235]
Top–down Elec ochemical
Ca boniza ion G aphi e od 6 nm - [236]
Bo om–up Mic owa e
i adia ion Ammonium ci a e ~4 nm - [237]
Bo om–up Hyd o he mal Chi osan powde s In he ange o 1.5–3 nm No [238]
Bo om–up Hyd o he mal Ci us Lemon Juice In he ange o 1–6 nm No [239]
Bo om–up Mic owa e
i adia ion Roas ed chickpeas
In he ange o 4.5–10.3 nm
No [240]
Bo om–up Hyd o he mal
Mic oc ys alline cellulose,
hyd oxyme hyl u u al, and
u u al
(6.36 ±0.54 nm),
(5.35 ±0.56 nm) and
(3.94 ±0.6 nm)
- [241]
Bo om–up Mic owa e
i adia ion Ci ic acid In he ange o 1.5–4.5 nm Yes [242]
2.2.3. Func ionalized CQDs
Low s abili y and biocompa ibili y o highe doses o CQDs a physiological condi ions
a e some o he main challenges o applying CQDs in biomedical applica ions. In his ega d,
unc ionalizing CQDs can be in oduced as a solu ion me hod o imp o e bac e icidal,
biocompa ibili y, and biodeg adabili y p ope ies [
243
]. The su ace o CQDs could be
unc ionalized wi h di e en su ace g oups. The p esence o some unc ional g oups
such as hyd oxyl and ca boxyl on CQDs’ su ace will esul in imp o ed wa e solubili y.
The unc ional g oups on CQDs’ su ace no only inc ease solubili y bu also cause he
o ma ion o s able colloids in aqueous/pola o ganic sol en s which is ad an ageous in
compa ing GQDs ha ha e a weak solubili y in o dina y sol en s [244].
Zhang e al. [
245
] unc ionalized CQDs wi h PEI and hyalu ona e (HA) o umo
a ge ing and gene deli e y. The syn hesized CQDs displayed excellen dispe sibili y
and desi able biocompa ibili y in aqueous solu ions and we e in e nalized easily in o he
cy oplasm o cance . This nanos uc u e was applied in in acellula imaging and gene
Pha maceu ics 2024,16, 288 19 o 46
deli e y sys ems due o i s ex ao dina y pho oluminescence ea u es. Xiang-Yi [
246
]
syn hesized CQDs by unc ionalizing hem wi h polye hyleneimine (PEI) h ough a single-
s ep hyd o he mal me hod and using biomass a as a ca bon p ecu so . The esul s
indica ed ha he inal s uc u e o CQDs consis ed o sphe es wi h uni o m sizes and
he dispe sibili y in aqueous solu ion had imp o ed due o he exis ence o unc ional
g oups on he su ace o unc ionalized CQDs. Also, he luo escence quan um yield o
CQDs was enhanced up o 27.3% a e being unc ionalized wi h PEI [
246
]. Ghosh and
cowo ke s [
247
] ab ica ed CQDs om swee lemon peel and a ached hem o a ious
gene a ions o polyamidoamine (PAMAM) dend ime s, hen conjuga ed hem o he RGDS
pep ide o a ge in eg in, which is o e -exp essed in T iple-nega i e b eas cance (TNBC).
he esul s o cellula cy o oxici y, DNase I assay, hemolysis assay, cellula up ake, and
in i o
ans ec ion con i med ha his nanoca ie is a p omising gene ca ie sys em o
TNBC gene he apy [247].
CQDs a e gene ally acknowledged o hei biocompa ibili y owing o hei ca bon-
based composi ion. Ne e heless, hei po en ial oxici y is subjec o mul i ace ed in lu-
ences such as size, su ace unc ionaliza ion, and concen a ion. No ably, smalle CQDs
may mani es heigh ened oxici y due o augmen ed su ace a ea, ampli ying in e ac ions
wi h biological sys ems [
248
]. The pi o al ole o su ace modi ica ions in dic a ing oxici y
is unde sco ed, wi h judicious unc ionaliza ion augmen ing biocompa ibili y and mi iga -
ing ad e se e ec s. Ele a ed concen a ions o CQDs pose he isk o inducing cy o oxici y,
necessi a ing op imiza ion o speci ic applica ions o mi iga e po en ial ha m.
In i o
s udies a e impe a i e o un a el he physiological esponse o CQDs, wi h a ocus on
o gan-speci ic oxici y and long- e m e ec s. S a egies encompassing su ace enginee ing,
size modula ion, and de elopmen o biodeg adable CQDs, along wi h me iculous
in i o
and
in i o
assessmen s, con ibu e o e ining oxici y p o iles [
249
]. Conjuga ing CQD
su aces wi h biocompa ible en i ies, such as polyme s o biomolecules, no only enhances
s abili y bu also mi iga es po en ial oxici y. The p ecision in con olling CQD size h ough
adep syn hesis echniques allows ailo ed applica ions, a o ing la ge CQDs o ce ain
pu poses o assuage oxici y conce ns. Pionee ing he ealm o biodeg adable CQDs as-
su es hei me abolic b eakdown and subsequen elimina ion om he body, add essing
long- e m oxici y app ehensions [250]. A holis ic e alua ion o oxici y, spanning in i o
cell s udies and
in i o
animal models, is impe a i e o gauge he sa e y pa ame e s o
CQDs. P og essing om p eclinical in es iga ions o clinical ials is pi o al, a o ding a
comp ehensi e unde s anding o CQD beha io in human sys ems and po en ial oxici y
issues [251].
2.2.4. Applica ion o CQDs in Gene The apy
As men ioned be o e, CQDs ha e a high po en ial o applica ion in cance imaging,
a cance diagnosis in ea ly s ages, i us sensing, and cance he apy due o hei la ge
su ace a ea o olume a io, pho oluminescence, low oxici y, eco- iendliness, good wa e
solubili y, e ec i e conjuga ion o o ganic/ino ganic ma e ials and biocompa ibili y [
252
].
Lo and cowo ke s [
253
] modi ied he s uc u e o GQDs wi h polye hyleneimine o im-
p o e GQDs’ biocompa ibili y and hei applica ion as ca go o g een luo escen p o ein
(GFP). Also, he new s uc u e o GQDs could a ach o colon cance cells and epide mal
g ow h ac o ecep o s o inc ease cell memb ane pene a ion and cell up ake o ca gos.
¸Sim¸sek e al.
[
254
] syn hesized CDs wi h 2.05 nm sizes om Ne ium Oleande ex ac ia
he mal me hod. Resul s showed ha he gene a ed CDs can pene a e cell nuclei o eac
wi h genes esul ing in DNA damage [
254
]. Ahn e al. [
255
] ab ica ed N-doped GQDs o
he ans ec ion o di e en genes such as mRNA, and pDNAs. Elec os a ic complexes
a e composed o N-doped GQDs (wi h a posi i e cha ge) and mRNA o pDNAs (wi h
a nega i e cha ge) and hey ac as a ehicle o e icien ans ec ion o genes in o a ge
cells. They [
255
] concluded hese N-doped GQDs wi h high s abili y and low oxici y can
be in oduced as a no el pla o m o gene deli e y in he u u e. Hasanzadeh e al. [
256
]
syn hesized zinc/ni ogen-doped ca bon do s ia a single-s ep mic owa e me hod. These
Pha maceu ics 2024,16, 288 20 o 46
nanoca ie s can ans e la ge plasmids wi h high yield and also, deli e mRNA in o
HEK-293 cells. The esul s indica ed ha he newly syn hesized CDs wi h no able pho o-
luminescence ea u es and high ans ec ion e iciency can be a p omising candida e o
he deli e y o bo h clus e ed egula ly in e spaced sho palind omic epea s (CRISPR)
complexes and mRNA [
256
]. Di e en unc ional g oups exis on he su ace o CQDs,
which make hem a ach o a ious biomolecules such as an igens, genes, and an ibodies.
Zhang e al. [
257
] syn hesized CDs om ci ic acid and pan eae hylenehexamine h ough
a single-s ep mic owa e-media ed pa h. Resul s showed he syn hesized CDs we e ull
o amine g oups and had a low oxici y. The e o e, he gene a ed CDs could conjuga e o
DNA non-co alen ly, and high ans ec ion e iciency could be obse ed [
257
]. Ala aj and
colleagues [
258
] syn hesized CQDs om Ci us lemon pe ica p ia hyd o he mal me hod
and a ached i o zinc oxide o de e mine cy oke a in-19 agmen an igene in human
se um [
258
]. P amanik e al. [
259
] syn hesized CQDs om mango and p une. In he nex
s ep, i was conjuga ed o an i-HER2 an ibodies o de ec he e ogenici y in b eas cance .
They concluded ha mul icolo nano-scale sys ems syn hesized om na u al ui s can be
used o de e mining cance he e ogenei y [
259
]. Wang e al. [
260
] syn hesized CDs om
ci ic acid and yp ophan ia a one-s ep mic owa e me hod. The ob ained CDs we e conju-
ga ed o polye hylenimine and used o siRNA deli e y o cell line MGC-803 [
260
]. Liu and
cowo ke s [
261
] unc ionalized GQDs wi h polye hylenimine and applied i in he miRNA
deli e y sys em. The esul s indica ed ha he new s uc u e o GQDs was able o deli e
i gin and unc ional mRNA o Huh-7 hepa oca cinoma cells [
261
]. Huang e al. [
262
]
syn hesized pho os able CQDs om deg aded p oduc s ia hyd o he mal ea men . The
size dis ibu ion o gene a ed CQDs was in he ange o 2–6 nm and he quan um yield was
13%. Huang e al. in es iga ed he op ical bio-imgaing capabili y o syn hesized CQDs a
in i o
scale [
262
]. Op ical ime elapsed imaging esul s o CQD-whea s aw dis ibu ion
in a umo -bea ing mouse and he esul s o op ical luo escence in ensi ies wi hin he
ha es ed o gans a e shown in Figu e 4a,b, espec i ely [
262
]. Finally, hey concluded he
inal CQDs could be applied in bio-imaging and pho o he apy [
262
]. Hua and cowo k-
e s [
263
] ab ica ed a se ies o nucleolus- a ge ed ed emissi e CDs. The esul s showed
Ni-pa a-phenyl-diamine CDs (Ni-pPCDs) a e he bes choice be ween all syn hesized CDs,
due o high pho o-s abili y, excellen wa e dispe sibili y, high quan um yield, and pola i y
dependen luo escence emission [
263
]. Figu e 4c,d shows he con ocal and STED images o
A549 cell, which indica e enla ged nucleoli wi h a high imaging esolu ion (146 nm) [263].
In addi ion, Ni-pPCDs we e used o
in i o
imaging in bo h zeb a- ish and mice models.
They concluded CDs ha e g ea po en ial o applica ion in bio-imaging [
263
]. Table 7
indica es some s udies ega ding applica ion o CNTs in gene he apy.
Table 7. P e ious esea ch on he applica ion o CDs in gene he apy.
CDs P ecu so s Syn hesis Me hods
Size (nm)/Quan um Yield
(%) Cell Line Re .
CD-PDMA-PMPD ci ic acid Mic owa e 50/41.5 COS-7 [264]
Cdo s-PEI yp ophan,
Ni ogen, CA Mic owa e py olysis 4.7 ±0.8/24.2 MGC-803 [265]
CDs Ci ic acid, PEI Mic owa e py olysis 12–13.2/31.5–48.1 A549 [266]
c- PEI-Cdo s Glyce ol and PEI Mic owa e py olysis 143.1/- H460; 3T3 [267]
CDs PEI and FA Hyd o he mal /42 293T; HeLa [268]
HP-CDs b anched PEI Hyd o he mal 2.25/12.4 HeLa [245]
CDs/pDNA Po phy a
polysaccha ide-EDA Hyd o he mal <10/56.3 EMSCs [269]
CDs/pSOX9 A ginine, glucose Mic owa e py olysis 10–30/12.7 MEFs [270]
Ca ionic CDs Pcyclen, p aea,
ci ic acid Hyd o he mal (1.8 ±0.4), (5.4 ±2)/- HeLa [271]
CDs Chi osan Hyd o he mal 6–11/- AGS [272]
Pha maceu ics 2024,16, 288 21 o 46
1
Figu e 4. (a)
In i o
luo escence imaging o nude mice a e in a enous injec ion o he ca bon
quan um do -whea s aw solu ion; (b) ep esen a i e luo escence images o dissec ed o gans o a
mouse a e in a enous injec ion o ca bon quan um do -whea s aw solu ion o 24 h. Rep in ed
wi h pe mission om Huang e al. [262]. (c) STED image and (d) con ocal image o a ep esen a i e
A549 cell s ained by (Ni-pPCDs). (I1, II1, and III1) Enla ged STED images o he nucleoli o he A549
cell in (c), and (I2, II 2, and III2) co esponding luo escence in ensi y analysis esul s o he ma ked
lines in I1, II 1, and III1. (IV1, V1, and VI1) Enla ged con ocal images o he nucleoli o he A549 cell
in (d) and (IV2, V2, and VI2) co esponding luo escence in ensi y analysis esul s o he ma ked lines
in IV1, V1, and VI1. (c,d) Rep oduced wi h pe mission om e . [
263
]. Copy igh 2019, Ame ican
Chemical Socie y.
Wu e al. [
273
] in es iga ed he unwan ed e ec s o in ahippocampal injec ions o
3-me cap op opionic acid (MPA)- unc ionalized CdTe QDs, ul a-s uc u e o neu ons,
hippocampus, and synapses in a s. T ansc ip ome sequencing was applied o disco e

Pha maceu ics 2024,16, 288 22 o 46
he unde lying mechanisms [
273
]. The esul s o his ological analyses o he hippocampus
o a s ea ed wi h 2.2 nm and 3.5 nm MPA-capped CdTe QDs showed an i egula
a angemen o neu ons and cellula swelling [
273
]. Wang e al. [
274
] syn hesized polyme -
coa ed ni ogen-doped ca bon nanodo s (pN-CNDs) wi h pa icle sizes be ween
5 o 15 nm
h ough a sol o- he mal eac ion. The o iginal p oduc showed high wa e solubili y and
adjus able luo escence. Figu e 5b (A–E) shows he luo escen imaging a di e en imes o
pos -injec ion o pN-CNDs [
274
]. Figu e 5b (F,G) shows co onal imaging o he main o gans
90 min a e pN-CND adminis a ion. The esul s showed glioma possesses a high and
conside able accumula ion o pN-CNDs [
274
]. Liu e al. [
275
] epo ed ha he p oduced
CDs i adia ed wi h ligh will con e o oxic molecules ei he o no mal (HEK-293)
o cance ous (HeLa and HepG2) human cells. Figu e 5c–j shows he e ec o di e en
pa ame e s such as ligh in ensi y, pH, wa eleng h, empe a u e, and ionic s eng h [
275
].
The esul s showed CD deg ada ion inc eased as ligh in ensi y inc eased (Figu e 5c) and
he wa eleng h dec eased (Figu e 5d). Also, mo e CDs deg aded a highe empe a u e
o pH (Figu e 5e, ) [
275
]. Ionic s eng h (Figu e 5g) and size (Figu e 5h) did no play an
impo an ole in CD deg ada ion. Liu e al. epo ed [
275
] ha when CDs we e i adia ed
wi h whi e luo escen o 10 min, alkyl and hyd oxyl adicals we e o ganized (Figu e 5i).
Figu e 5j indica es he main ole o isop opanol in dec easing deg ada ion o CDs [275].
Pha maceu ics 2024, 16, x FOR PEER REVIEW 24 o 47
Figu e 5. (a) His ological analysis o hippocampus ea men o a s ea ed wi h 2.2 nm and 3.5 nm
MPa-capped CdTe QDs; ep oduced wi h pe mission om ”In e na ional Jou nal o Nanomedicine
2016, 11, 2737–2755” O iginally published by
[273]
and used wi h pe mission om Do e Medical
P ess L d. Foamy cells a e deno ed by black a ows, neu ophils a e highligh ed by ed a ows,
accumula ed quan um do s (QDs) a e indica ed by blue a ows, nec o ic cells a e ep esen ed by
g een a ows, and swollen blood essels a e ma ked by yellow a ows. (b) In− and ex− i o imaging
o glioma−bea ing mice in a enously adminis e ed wi h he polyme -coa ed ni ogen−doped ca -
bon nanodo s (pN−CNDs). ((b), A–E) Whole-body imaging o he pN−CNDs a a ious ime poin s
pos −injec ion. ((b), F) Ex- i o imaging o majo o gans 90 min a e pN−CNDs adminis a ion. ((b),
G) Co onal imaging o he b ain 90 min a e pN-CNDs adminis a ion. The black a ow ep esen s
he signal in ensi y ( adian efficiency) om weak ( ed) o s ong (yellow). Rep oduced wi h pe -
mission om e
[274]
. Copy igh 2015, John Wiley and Sons. Pho odeg ada ion o labo a o y-syn-
hesized CDs. (c– ) Mo e CDs deg aded a highe ligh in ensi y (0, 15, 30, 60, and 90 µmol pho-
ons/m
2
/s) (c), sho e ligh wa eleng h (390, 450, 520, and 620 nm) (d), highe empe a u e (18, 30,
35, and 40 °C) (e), and pH (5, 6, 7, 8, and 9) ( ). (g) Ionic s eng h (0, 4.6, 13.8, 41.5, and 124.4 mM)
had no effec s on CD deg ada ion. (h) CDs wi h diffe en sizes (2.5 and 4.8 nm) show simila deg a-
da ion kine ics. (i) F ee hyd oxyl and alkyl adicals we e p oduced when CDs we e i adia ed by
whi e luo escen ligh (60 µmol pho ons/m
2
/s). (j) When he hyd oxyl adicals we e sca enged by
10 mM isop opanol, ewe CDs deg aded compa ed o he con ol ea men wi hou any addi ion
o isop opanol. Da a a e p esen ed as he mean ± s.d. (n = 3 independen expe imen s). Sou ce da a
a e p o ided as a sou ce da a ile. Rep oduced wi h pe mission om e
[275]
Copy igh 2021,
Sp inge Na u e.
Figu e 5. (a) His ological analysis o hippocampus ea men o a s ea ed wi h 2.2 nm and 3.5 nm
MPa-capped CdTe QDs; ep oduced wi h pe mission om ”In e na ional Jou nal o Nanomedicine 2016,
Pha maceu ics 2024,16, 288 23 o 46
11, 2737–2755” O iginally published by [
273
] and used wi h pe mission om Do e Medical P ess
L d. Foamy cells a e deno ed by black a ows, neu ophils a e highligh ed by ed a ows, accu-
mula ed quan um do s (QDs) a e indica ed by blue a ows, nec o ic cells a e ep esen ed by g een
a ows, and swollen blood essels a e ma ked by yellow a ows. (b) In
−
and ex
−
i o imaging o
glioma
−
bea ing mice in a enously adminis e ed wi h he polyme -coa ed ni ogen
−
doped ca bon
nanodo s (pN
−
CNDs). ((b), A–E) Whole-body imaging o he pN
−
CNDs a a ious ime poin s
pos
−
injec ion. ((b), F) Ex- i o imaging o majo o gans 90 min a e pN
−
CNDs adminis a ion.
((b), G)
Co onal imaging o he b ain 90 min a e pN-CNDs adminis a ion. The black a ow ep e-
sen s he signal in ensi y ( adian e iciency) om weak ( ed) o s ong (yellow). Rep oduced wi h
pe mission om e . [
274
]. Copy igh 2015, John Wiley and Sons. Pho odeg ada ion o labo a o y-
syn hesized CDs. (c– ) Mo e CDs deg aded a highe ligh in ensi y (0, 15, 30, 60, and 90
µ
mol
pho ons/m
2
/s) (c), sho e ligh wa eleng h (390, 450, 520, and 620 nm) (d), highe empe a u e
(18, 30, 35, and 40
◦
C) (e), and pH (5, 6, 7, 8, and 9) ( ). (g) Ionic s eng h (0, 4.6, 13.8, 41.5, and
124.4 mM
) had no e ec s on CD deg ada ion. (h) CDs wi h di e en sizes (2.5 and 4.8 nm) show
simila deg ada ion kine ics.
(i) F ee
hyd oxyl and alkyl adicals we e p oduced when CDs we e
i adia ed by whi e luo escen ligh (60
µ
mol pho ons/m
2
/s). (j) When he hyd oxyl adicals we e
sca enged by 10 mM isop opanol, ewe CDs deg aded compa ed o he con ol ea men wi hou
any addi ion o isop opanol. Da a a e p esen ed as he mean
±
s.d. (n = 3 independen expe imen s).
Sou ce da a a e p o ided as a sou ce da a ile. Rep oduced wi h pe mission om e . [
275
] Copy igh
2021, Sp inge Na u e.
2.3. Nanodiamonds (NDs)
2.3.1. S uc u e and p ope ies o NDs
Diamond nanopa icles we e i s syn hesized ia he de ona ion echnique in 1960 [
276
].
NDs a e based on ca bon building blocks wi h a sp
3
-hyb idiza ion cen e co e ed by sp
2
ca bon a oms [
277
]. In o he wo ds, i is made om a diamond co e and amo phous ca bon
laye s. High su ace a ea, sp
3
ca bon ma ix, and he p esence o unc ional g oups on
hei su aces. These ea u es enable nanodiamonds o adso b biomolecules, ac as d ug
ca ie s, and modula e cellula signaling pa hways. Fu he mo e, he diamond co e can
se e as a biocompa ible sca old o a ious he apeu ic molecules, making nanodiamonds
a e sa ile pla o m o d ug deli e y and imaging applica ions [
278
]. Thei diame e is
usually less han 20 nm [
277
]. NDs and syn he ic diamonds a e ela i ely cheap. Thei
unique and inhe en p ope ies such as supe io ha dness and Young’s modulus, op ical
p ope ies and luo escence, esis ance o ha sh en i onmen s, high he mal conduc i i y,
and elec ical esis i i y ha e a ac ed ema kable scien i ic a en ion o a ious applica-
ions [
279
]. NDs a e also in insically biocompa ible wi h low oxici y, s able luo escence,
high he mal conduc i i y, and la ge su ace a eas, which makes hem sui able o biomedi-
cal applica ions such as d ug/gene deli e y [
280
], bio-imaging, and biosenso s [
281
]. As
deli e y sys ems, NDs a e capable o ans e ing a b oad ange o he apeu ic ma e ials
such as p o eins, small molecule inhibi o s, pep ides, and chemo he apy d ugs. NDs can
wi hs and high dosages in a ious anges o cell lines and animal models ha con i ms
hei low oxici y. Biodis ibu ion s udies ha e indica ed ha NDs do no accumula e
in i o
o a long pe iod o ime [
282
]. The high su ace a ea o NDs is sui able o he
conjuga ion o molecules. Va ious pu i ica ion p ocesses and su ace modi ica ion a ec
he biocompa ibili y o NDs, and ex ensi e s udies ha e also been pe o med on he oxi-
ci y o NDs [
283
,
284
]. Unde s anding he mechanisms by which nanodiamonds in e ac
wi h biological en i ies is c ucial o ha nessing hei ull po en ial in a ious biomedical
applica ions. The nano-bio in e ace se es as he c i ical in e ace whe e nanodiamonds
in e ace wi h biological en i ies, including cells, p o eins, and nucleic acids. The in e play
a his in e ace is go e ned by complex physical and chemical in e ac ions, such as elec o-
s a ic o ces, an de Waals in e ac ions, and hyd ogen bonding. Su ace modi ica ions o
nanodiamonds play a pi o al ole in modula ing hese in e ac ions, allowing o ailo ed
bio- unc ionaliza ion and imp o ed speci ici y in a ge ing biological componen s [
285
].
The dynamics o nanodiamond in e ac ions wi h cells in ol e in ica e physico-kine ic
Pha maceu ics 2024,16, 288 24 o 46
p ocesses. Cellula up ake mechanisms, in acellula a icking, and e en ual a e wi hin
he cellula milieu a e in luenced by ac o s such as nanodiamond size, su ace cha ge, and
unc ionaliza ion. Unde s anding hese physico-kine ic aspec s is pa amoun o op imiz-
ing nanodiamond-based echnologies, including d ug deli e y sys ems and diagnos ic
p obes [
286
]. Sch and e al. s udied he cy o oxici y o NDs by de ec ing he unc ion o
mi ochond ia and he yield o adenosine 5
′
iphospha e [
287
]. They epo ed ha he cell
ac i i y was mo e han 95% and NDs did no show any conside able oxici y in di e en
cell ypes [
287
]. F ye and cowo ke s [
288
] e alua ed he cy o oxici y and luo escence
imaging capaci y o ni ogen- acancy NDs wi h sizes in he ange o
40 o 90 nm
. Resul s
showed ha as he size o NDs inc eased, he cy o oxici y o NDs dec eased and NDs
wi h size 90 nm indica ed high cellula up ake and luo escence in ensi y [
288
]. Ka pe a
e al. [
289
] in es iga ed he cy o oxici y o NDs in di e en cell lines and s udied NDs’
biological ac i i ies such as cell iabili y, lipid pe oxida ion, and le el o eac i e oxy-
gen species. Resul s showed he accumula ion o NDs in skin issue was mo e han ha
in o he o gans in C57 mouse. They concluded ha NDs can play a signi ican ole in
diagnosis o skin cance [
289
]. NDs ha e a high endency o agglome a e in aqueous
solu ions. Sonica ion and mechanical g inding echnology a e wo solu ion me hods o
o e coming his issue. Howe e , su ace modi ica ion wi h biocompa ible polyme and
biological molecules has been in oduced as an e ec i e me hod o change he biological
and physicochemical p ope ies o NDs [
290
]. NDs agglome a e easily and dispe se weakly
in aqueous solu ions. Dispe sion o NDs is possible h ough mechanical and sonica ion
p ocesses. Mai a e al. [
291
] in es iga ed he e ec o di e en su ac an s such as Sodium
bis(2-e hylhexyl) sul osuccina e, T i on X-100, Ce yl ime hylammonium b omide, e -
oc ylphenoxy poly(oxye hylene) e hanol, and poly inyl alcohol on dispe sion p ope y
o NDs. Resul s indica ed ha e -oc ylphenoxy poly(oxye hylene) e hanol has he bes
dispe sion in wa e a a minimum concen a ion o su ac an [
291
]. The su ace o NDs can
be unc ionalized/modi ied wi h a ious ing edien s and di e en unc ional g oups such
as a hyd oxyl g oup (-OH), ca boxylic acid g oup (-COOH), sul u g oup, amino and es e
g oups c ea ed in NDs’ s uc u es; among hem, ca boxylic acid g oups (-COOH) a e he
mos widesp ead. Func ionalizing NDs will imp o e hei dispe sibili y, biocompa ibili y,
and make hem o conjuga e o o he ma e ials/biological molecules o o m nanos uc u es
wi h speci ied physicochemical p ope ies o di e en selec i e applica ions [292].
2.3.2. Syn hesis Me hods o NDs
NDs can be syn hesized by di e en me hods wi h each o he syn hesis echniques
a ec ing hei physical and chemical p ope ies. The size, shape, su ace s uc u e, and
quali y o p is ine NDs a e a unc ion o syn he ic me hods. NDs’ syn hesizing me hods
a e la ge abla ion, high-p essu e high empe a u e (HPHT) [
279
], plasma-assis ed chemical
apo deposi ion (CVD) [
279
], au ocla e syn hesis om supe c i ical luids, ion i adia ion
o g aphi e, elec on i adia ion o ca bon anions and ul asound ca i a ion [
293
,
294
]. Two
comme cial-scale NDs exis in he ma ke oday. Fi s , NDs a e syn hesized h ough
de ona ion p ocesses wi h a size ange o 4 o 5 nm called de ona ion NDs, and hen NDs
a e syn hesized h ough he HPHT op ion wi h an a e age size o mo e han 30 nm. In he
ollowing, CVD, HPHT? and de ona ion echniques a e discussed in de ail.
Chemical Vapo Deposi ion Me hod (CVD): CVD is a p ocedu e o p oducing in-
o ganic ma e ials, and applies one o mo e gas-phase combina ions including he main
p oduc compound o accomplish a chemical eac ion on he subs a um su ace ha
p oduces he o iginal p oduc s. Applying his echnology o gene a e diamonds s a ed
o iginally in 1970 [
295
]. By applying his me hod, la ge-size diamonds wi h high pu i y
can be syn hesized. NDs syn hesized ia he CVD me hod do no equi e a supplemen a y
pu i ica ion s age, and he densi y o he luminescen cen e s can be selec ed which is use ul
o op ical esea ch. Besides he posi i e a ibu es o he CVD me hod o syn hesizing
NDs, he e a e some disad an ages such as high cos , low deposi ion a e, being oxic and
lammabili y o eac ion sou ces and esidues ha limi using his me hod [
292
]. The CVD
Pha maceu ics 2024,16, 288 25 o 46
me hod is one o he mos classic me hods o he syn hesis o ND ilms [
279
]. ND ilms
a e classi ied in o wo ca ego ies based on hei mic os uc u e and g ow h en i onmen :
he Ul a-nanoc ys al diamond (UNCD) and nanoc ys alline-diamond (NCD) [
296
]. Ul a-
nanoc ys al diamond (UNCD) ilms a e usually g own in a CVD en i onmen ha is a gon-
ich and hyd ogen-poo . Thei mic os uc u es look like c ys alline g ains (
2–5 nm size
)
wi h a laye o ND ca bon a ound hem. This mic os uc u e con ains up o 2–5% sp
2
-
bonded ca bon con en [
296
,
297
]. Hexane/ni ogen-based CVD is applied o p oduce NCD.
Ini ial nuclea ion si es o gene a ing his ype o ilm a e no needed. This ype o ilm
was g own on Ni subs a es in a mic owa e plasma eac o a a empe a u e ange o
400–600 ◦C
[
297
]. Some o ms o NCD can be gene a ed om he decomposi ion o a gas
mix u e (usually me hane and hyd ogen). In his me hod, adicals such as
CH•
3
and
H•
will be o med, which a e in ansi i e o diamond g ow h. NCD ilm can be o med on a
silicon wa e coa ed wi h diamond powde and ac ing as a si e o NCD nuclea ion. Finally,
a con inuous ilm can be o med as an NCD ilm [
296
]. Feudis e al. [
298
] p oduced NDs
wi h massi e b igh ness ia he CVD me hod wi hou equi ing any seeded subs a e.
Op ical esul s a low empe a u es con i med his CVD me hod can gene a e NDs wi h
p ope dispe sibili y, which can be applied in quan um echnologies [298].
High P essu e—High-Tempe a u e me hod: HPHT is ano he main me hod o he
syn hesis o NDs ha was in oduced by Wen o o he i s ime in 1965 [
299
]. No me al
impu i ies we e obse ed in NDs p oduced om o ganic compounds. These NDs a e e y
biocompa ible. High oughness, he mal s abili y, and, wea - esis ance a e h ee conside -
able p ope ies o NDs syn hesized h ough he HPHT me hod [
292
]. In he HPHT p ocess,
p essu e and empe a u e should be almos 6 Gpa and 1500
◦
C, espec i ely, o change
g aphi e powde in o diamonds in he p esence o a ca alys . Applying ma e ials such as
ulle enes and CNTs ins ead o g aphi e o p oducing diamonds needs much lowe empe -
a u e and p essu e [
300
]. CNTs can be con e ed o diamond a 1300
◦
C and
4.5 Gpa
in he
p esence o NiMnCo as a ca alys . NDs’ size can be con olled accu a ely when syn hesized
om chlo oadaman ane molecules ia HPHT echnology [
301
]. Silicon and ni ogen-doped
NDs we e success ully manu ac u ed by he HPHT me hod.
Da ydo e al.
[
302
] sugges ed
a no el echnology o syn hesizing NDs based on a blend o o gano-silicon compounds,
hyd oca bons, and, luo oca bons a high p essu e. Small c ys al diamonds we e o med in
he shape o i anium capsules wi h olumes less han 2 mm
3
a a p essu e o 12–13 Gpa
and a empe a u e ange o 1300–2300
◦
C [
303
]. Onode a e al. epo ed ano he syn hesis
me hod wi h so e condi ions (p essu e o 6–9 Gpa and empe a u e o up o 1300
◦
C) o
p oducing nano-c ys alline diamonds in 1992 [
304
]. In his p ocess, he an alum capsule is
used as a ca alys o ans o ming g aphi e in o diamond. Ekimo e al. [
305
] ound an
op imum condi ion o la ge-scale syn hesis o nano- and mic o-c ys al diamonds om
adaman ane (a ype o a ac i e hyd oca bon o he syn hesis o mic o- and nano-c ys al
diamonds) by his me hod. They syn hesized samples in i anium capsules a p essu es o
7.7 and 9.4 Gpa and a empe a u e ange o 300–1600
◦
C. They concluded ha a p essu e o
9.4 Gpa and empe a u e o 1250–1330 ◦C a e he bes ope a ing condi ions o la ge-scale
syn hesis. Also, hey epo ed ha he syn hesiza ion o ND is a di ec esul o adaman ane
ca boniza ion [
305
]. Liu and cowo ke s [
306
] syn hesized NDs om naph halene h ough
a wo-s ep HPHT me hod wi hou he need o a me al ca alys . They obse ed he g ain
sizes o NDs wi h 35 min ca boniza ion ime we e so he e ogeneous, and he g ain sizes o
NDs wi h 90 and 135 min ca boniza ion ime we e smalle and homogeneous [
306
]. They
obse ed ha he a e age g ain size educed as ca boniza ion ime inc eased [306].
De ona ion Technique: The de ona ion me hod is clea ly mo e di e en when com-
pa ed wi h o he echniques. The explosi e impac me hod is he i s me hod o p oducing
explosi e ma e ials. In his p ocess, a phase ansi ion happens ou doo s on he g aphi e
p ecu so s and con e s o diamond unde shock wa e p essu e and high- empe a u e
condi ions. Shock comp ession o g aphi e and de ona ion o explosi e ma e ials unde
lack o oxygen a e wo echnologies o gene a ing NDs. NDs we e i s gene a ed ia
de ona ion echnology in he USSR in he 1960s [
292
]. G eine and cowo ke s p oduced
Pha maceu ics 2024,16, 288 32 o 46
ca bon nanos uc u es wi h biological sys ems, shedding ligh on he in ica e cellula and
molecula p ocesses ha unde lie hei he apeu ic e ec s. As we na iga e he in ica e
landscape o ca bon nanos uc u e-based gene he apy, his comp ehensi e e iew aims o
p o ide a o wa d-looking pe spec i e, discussing an icipa ed challenges, u u e di ec ions,
and he ans o ma i e impac ha hese inno a i e app oaches may ha e on he landscape
o molecula medicine. By un a eling he in icacies o ca bon nanos uc u e-media ed
gene he apy, his e iew con ibu es o he ongoing discou se in he scien i ic communi y
and lays he g oundwo k o he de elopmen o nex -gene a ion he apeu ic s a egies
wi h he po en ial o e olu ionize clinical p ac ice.
Resea che s all o e he wo ld belie e ha de elopmen s and he p o iling o
di e en non- i al nanos uc u es o gene deli e y would ha e a g ea impac on u u e
gene he apies. In he u u e, we will obse e some o he equi ed high-cos ea men s
o a ge ed diseases eplaced wi h inexpensi e he apies. New gene ic ea men s will
be c ea ed o bo h o dina y as well as uncommon diseases. Resea che s ha e epo ed
ha simila o o he biologics, gene he apies a e also expec ed o see no able signs o
p og ess in he coming yea s.
Nanos uc u e-based gene deli e y sys ems such as CNTs, QDs, o NDs, a e eme g-
ing as an exci ing new me hod wi h he possibili y o o e come known obs acles and
mul iple biological and medical equi emen s. Despi e he ac ha hey sha e a common
Ca bon-based nanos uc u e, he e a e ele an di e ences be ween hem in e ms o physic-
ochemical p ope ies, syn hesis me hod, unc ionaliza ion s a egies, and applica ions in
gene he apy ha me i he a en ion o he esea ch communi y.
The main cha ac e is ic o all deli e y sys ems is he need o he ans e o gene ic
ma e ials in o he cells, whe e hei a o able ope a ions will be exposed. The e o e, a
equi emen o a deli e y sys em is no o le he gene ic ma e ials en e he cells passi ely.
The eme ging ield o nano-gene deli e y in oduces he u iliza ion o no el nanos uc u es
and hei ea u es o gene a e deli e y ec o s ha can e ec i ely deli e di e en gene ic
ma e ial in o a a ie y o a ious ypes o cells. The physicochemical p ope ies o he
ca bon-based deli e y ec o s can be applied o add ess he ongoing challenges exis ing
in deli e ing gene ic ma e ials a
in i o
and
in i o
scales. While he e is an inc easing
in e es in nanos uc u e-based gene deli e y sys ems, he s ing is s ill in he ini ial s eps,
and he e is a powe ul need o igu e ou nanos uc u es and hei physicochemical ea u es
on biological g ounds.
Au ho Con ibu ions: Concep ualiza ion, S.Y., M.M., G.P. (Gholam eza Pazukiand), J.Z., G.P. (Gus-
a o Pu as) and J.L.P.; me hodology, S.Y. and I.V.-B.; o mal analysis, S.Y.; in es iga ion S.Y.; esou ces,
S.Y.; da a cu a ion, S.Y. and N.H.; w i ing—o iginal d a p epa a ion, S.Y.; w i ing— e iew and
edi ing, S.Y., M.M., G.P. (Gholam eza Pazukiand), J.Z., G.P. (Gus a o Pu as) and J.L.P.; isualiza-
ion, S.Y., M.M., G.P. (Gholam eza Pazukiand), J.Z., G.P. (Gus a o Pu as) and J.L.P.; supe ision,
M.M., G.P.(Gholam eza Pazukiand), G.P. (Gus a o Pu as), and J.L.P.; p ojec adminis a ion, M.M.
and J.L.P.; unding acquisi ion, J.L.P. All au ho s ha e ead and ag eed o he published e sion o
he manusc ip .
Funding: This esea ch was unded by he Basque Coun y Go e nmen (Consolida ed G oups,
IT1448-22), and by CIBER -Conso cio Cen o de In es igación Biomédica en Red- CB06/01/1028,
Ins i u o de Salud Ca los III, Minis e io de Ciencia e Inno ación. The au ho s hank he in ellec ual
and echnical assis ance om he ICTS ‘NANBIOSIS’, mo e speci ically by he D ug Fo mula ion
Uni (U10) o he CIBER in Bioenginee ing, Bioma e ials, and Nanomedicine (CIBER-BBN) a he
Uni e si y o he Basque Coun y (UPV/EHU).
Ins i u ional Re iew Boa d S a emen : No applicable.
In o med Consen S a emen : No applicable.
Da a A ailabili y S a emen : No new da a we e c ea ed.
Con lic s o In e es : The au ho s decla e no con lic s o in e es .

Pha maceu ics 2024,16, 288 33 o 46
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