Hybrid Hydroxyapatite–Metal Complex Materials Derived from Amino Acids and Nucleobases

7.44.2
Hyb id Hyd oxyapa i e–Me al
Complex Ma e ials De i ed om
Amino Acids and Nucleobases
Alond a Jiménez-Pé ez, Ma a Ma ínez-Alonso and Ja ie Ga cía-Tojal
Special Issue
Ad ances in Coo dina ion Chemis y 2.0
Edi ed by
P o . D . Juan Niclós-Gu ié ez and D . Miquel Ba celó-Oli e
Re iew
h ps://doi.o g/10.3390/molecules29184479
Ci a ion: Jiménez-Pé ez, A.;
Ma ínez-Alonso, M.; Ga cía-Tojal, J.
Hyb id Hyd oxyapa i e–Me al
Complex Ma e ials De i ed om
Amino Acids and Nucleobases.
Molecules 2024,29, 4479. h ps://
doi.o g/10.3390/molecules29184479
Academic Edi o s: Juan
Niclós-Gu ié ez and Miquel
Ba celó-Oli e
Recei ed: 30 July 2024
Re ised: 12 Sep embe 2024
Accep ed: 15 Sep embe 2024
Published: 20 Sep embe 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/).
molecules
Re iew
Hyb id Hyd oxyapa i e–Me al Complex Ma e ials De i ed om
Amino Acids and Nucleobases
Alond a Jiménez-Pé ez , Ma a Ma ínez-Alonso and Ja ie Ga cía-Tojal *
Depa amen o de Química, Facul ad de Ciencias, Uni e sidad de Bu gos, Plaza Misael Bañuelos s/n,
09001 Bu gos, Spain; [email p o ec ed] (A.J.-P.); [email p o ec ed] (M.M.-A.)
*Co espondence: [email p o ec ed]
Abs ac : Calcium phospha es (CaPs) and hei subs i u ed de i a i es encompass a la ge numbe o
compounds wi h a as p esence in na u e ha ha e a oused a g ea in e es o decades. In pa icula ,
hyd oxyapa i e (HAp, Ca
10
(OH)
2
(PO
4
)
6
) is he mos abundan CaP mine al and is signi ican in he
biological wo ld, a leas in pa due o being a majo compound in bones and ee h. HAp exhibi s
excellen p ope ies, such as sa e y, s abili y, ha dness, biocompa ibili y, and os eoconduc i i y, among
o he s. E en some o i s d awbacks, such as i s agili y, can be edi ec ed hanks o ano he essen ial
ea u e: i s g ea e sa ili y. This is based on he compound’s endency o unde go subs i u ions
o i s cons i uen ions and o inco po a e o ancho new molecules on i s su ace and po es. Thus,
i s a ini y o biomolecules makes i an op imal compound o mul iple applica ions, mainly, bu
no only, in biological and biomedical ields. The p esen e iew p o ides a chemical and s uc u al
con ex o explain he a ini y o HAp o biomolecules such as p o eins and nucleic acids o gene a e
hyb id ma e ials. A size-dependen c i e ium o inc easing complexi y is applied, anging om
amino acids/nucleobases o he co esponding mac omolecules. The inco po a ion o me al ions o
me al complexes in o hese unc ionalized compounds is also discussed.
Keywo ds: amino acid; calcium phospha e; hyb id ma e ial; hyd oxyapa i e; nucleobase; nucleic
acid; pep ide; p o ein
1. In oduc ion
The geological ele ance o phospha es is conside able. They a e ound in se e al
o ma ions, such as ossils and abou 200 g oups o mine als p esen in igneous and sedi-
men a y phospha e ocks (PRs) [
1
–
4
]. In pa icula , calcium phospha es (CaPs) ha e gained
a en ion due o bo h hei geological ele ance as p ima y phospho us o es and hei bio-
logical oles. The abundance o apa i e- ype mine als (chlo o-, luo -, and hyd oxy-apa i e),
wi h he o mulae Ca
10
(Cl,F,OH)
2
(PO
4
)
6
, make hem s and ou as o es om a mining poin
o iew. O he p ominen examples o CaP mine als a e b ushi e CaHPO
4·
2H
2
O, dahli e
3Ca3(PO4)2·CaCO3, mone i e CaHPO4, and whi locki e Ca9Mg(HPO4)(PO4)6.
Ne e heless, many o he CaPs, apa om he abo e-men ioned mine al phases, ha e
been s udied in dep h [
5
]. Thei o mulae usually exhibi a omic Ca/P a ios be ween
0.5 and 2 (in gene al, he lowe he Ca/P a io, he mo e acidic and soluble he calcium
phospha e phase). Table 1shows some o he CaPs we will discuss in his wo k due o
hei in ol emen in he p ocesses desc ibed he e [
6
]. None heless, he mos common
membe s o his amily, acco ding o hei solubili y p oduc s [
7
], a e hyd oxyapa i e
and he polymo phic o ms o icalcium phospha e (TCP). F om now on, i mus be
emphasized ha he o mulae gi en in he p esen e iew ollow he In e na ional Union
o Pu e and Applied Chemis y (IUPAC) ecommenda ions o chemical nomencla u e, bu
we ha e e ained he adi ional names gi en in he li e a u e o a be e unde s anding
and connec ion wi h he sou ces [8].
Molecules 2024,29, 4479. h ps://doi.o g/10.3390/molecules29184479 h ps://www.mdpi.com/jou nal/molecules
Molecules 2024,29, 4479 2 o 39
Table 1. Selec ed calcium phospha e phases and s uc u al de ails.
Name (Abb e ia ion)
Fo mula
Ca/P
Ra io
Sys em (Space G oup)
Cell Pa ame e s (Å, 0)Re s.
Monocalcium phospha e anhyd ous (MCPA)
Ca(H2PO4)20.50
T iclinic (P1)
a = 7.5577(5), b = 8.2531(6), c = 5.5504(3)
α= 109.87(1), β= 93.68(1), γ= 109.15(1)
[9]
Monocalcium phospha e monohyd a e (MCPM)
Ca(H2PO4)2·H2O0.50
T iclinic (P1)
a = 5.6261(5), b = 11.889(2), c = 6.4731(8)
α= 98.633(6), β= 118.262(6), γ= 83.344(6)
[10]
Dicalcium phospha e anhyd ous (DCPA, mone i e)
CaHPO41.00
T iclinic P1)
a = 6.90(1), b = 6.65(1), c = 7.00(1)
α= 96.35(2), β= 103.90(2), γ= 88.73(2)
[11]
Dicalcium phospha e dihyd a e (DCPD, b ushi e)
CaHPO4·2H2O1.00
Monoclinic (Ia)
a = 5.812(2), b = 15.180(3), c = 6.239(2)
β= 116.42(2)
[12]
Amo phous calcium phospha es (ACPs) 1
CaxHy(PO4)z·nH2O (n = 3.0–4.5) 21.20–2.20 3
Oc acalcium phospha e (OCP)
Ca8H2(PO4)6·5H2O1.33
T iclinic P1)
a = 19.692(4), b = 9.523(2), c = 6.835(2)
α= 90.15(2), β= 92.54(2), γ= 108.65(2)
[13,14]
α- icalcium phospha e (α-TCP)
α-Ca3(PO4)21.50
Monoclinic (P21/a)
a = 12.887(2), b = 27.280(4), c = 15.219(2)
β= 126.20(1)
[15]
β- icalcium phospha e (β-TCP, syn he ic whi locki e)
β-Ca3(PO4)21.50
Rhombohed al (R3c)
(hexagonal se ing)
a = b = 10.439(1), c = 37.375(6)
[16]
Hyd oxyapa i e (HAp)
Ca10(OH)2(PO4)61.67 Hexagonal (P63/m)
a = b = 9.424(4), c = 6.879(4) [17]
Hyd oxyapa i e (HApM)
M-Ca10(OH)2(PO4)61.67
Monoclinic (P21/b)
a = 9.419(3), b = 18.848(6), c = 6.884(2)
β= 119.98(2)
[18]
Oxyapa i e (OAp, oelcke i e) 4
Ca10O(PO4)61.67 Hexagonal P6)
a = b = 9.432, c = 6.881 [19]
Te acalcium phospha e (TTCP, hilgens ocki e)
Ca4O(PO4)22.00
Monoclinic (P21)
a = 7.023(1), b = 11.986(4), c = 9.473(2)
β= 90.90(1)
[20]
Dicalcium diphospha e dihyd a e (DCDD)
Ca2(P2O7)·2H2O1.00
T iclinic P1)
a = 7.365(4), b = 8.287(4), c = 6.691(4)
α= 102.96(1), β= 72.73(1), γ= 95.01(1)
[21]
1
ACPs a e p obably me as able amo phous s a es o di e en c ys alline calcium phospha es. Roughly speaking,
a dozen phospha e phases could exis in an amo phous s a e (e.g., amo phous HAp, amo phous TCP, e c.). An
excellen e iew abou hem was published by Do ozhkin [
22
].
2
The amoun o wa e a ies be ween 15 and
20%.
3
The ange is wide , bu he majo i y exhibi a Ca/P alue close o 1.5. This would be consis en wi h he
p esence o Posne ’s clus e s, common uni s in ACPs, wi h o mula Ca
9
(PO
4
)
6
[
23
], which would e ol e in o
di e en c ys alline phases h ough dis inc expe imen al condi ions.
4
The na u e and c ys al s uc u e o his
compound emains con o e sial. The c ys allog aphic in o ma ion gi en in he able comes om he wo k by
Henning e al. An in e es ing his o ical backg ound abou he di e en p oposals published up o da e is co e ed
by Bulina e al. [24].
Rega ding he CaP-con aining apa i e Ca
10
X
2
(PO
4
)
6
amily, di e en mine als wi h a
Ca/P=1.67mola a iocanbe ounddependingon heXanion,suchas luo apa i e(Ca
10
F
2
(PO
4
)
6
),
ca bona e– luo apa i e (Ca
10
F
2
(PO
4
,CO
3
)
6
) and chlo apa i e (Ca
10
Cl
2
(PO
4
)
6
) [
25
]. They exhibi
a ying le els o c ys allini y and solubili y [
26
]. Amongs hem, hyd oxyapa i e (HAp,
Ca
10
(OH)
2
(PO
4
)
6
) is he mos signi ican compound in he con ex o bo h biology and
geology. In he li ing wo ld, HAp is in ol ed in calci ica ion, which is he biological
Molecules 2024,29, 4479 3 o 39
p ocess o he deposi ion o calcium in issues and body s uc u es. In e ms o weigh ,
HAp is he main componen o bones and ee h in e eb a es. In his sense, abou 60–70%
o bone [
27
,
28
] and e en 96% o oo h enamel [
29
,
30
] is HAp, wi h a sligh amoun o
eplacemen o he PO
43−
/OH
−
g oups by anions, mainly CO
32−
(2–8%, gene a ing he
so-called bioapa i e [31,32]).
HAp can ypically be ound in wo c ys allog aphic o ms [
33
,
34
]: he hexagonal and
monoclinic phases (see Table 1). S oichiome ic HAp gi es ise o he he modynamically
mo e s able monoclinic polymo ph [
35
–
37
]. Howe e , ac o s such as he inclusion o ions
and he o ma ion o acancies cause i o ake he hexagonal o m, he mos common
phase in he mine al and biological wo lds. In hexagonal HAp, hyd oxide OH
−
ions
s ack in channels along he [001] di ec ion. The a angemen o e ahed al phospha e ions
dis ibu es he calcium ions (Ca
2+
) in wo di e en c ys allog aphic si es. Ca1 is pa allel o
he c-axis and links o nine oxygen a oms om six di e en phospha e e ahed a: h ee
phospha e oxyanions ac as monoden a e ligands h ough he O1 oxygen a oms, and he
o he h ee phospha es beha e as biden a e h ough he O2 and O3 se s o a oms. The Ca2
a oms a e placed on he hexagonal sc ew axes, in polyhed a wi h an i egula se en old
coo dina ion whose en i onmen con ains one O1, one O2, and ou O3 phospha e a oms
and a hyd oxide ion [
38
,
39
]. Di e ences wi h he monoclinic s uc u e a e sub le and mainly
in ol e he o ien a ion o hyd oxide anions. In he hexagonal cell, wo adjacen hyd oxides
poin in he opposi e di ec ion, bu in he monoclinic s uc u e, all he hyd oxides in a gi en
column poin in he same di ec ion, which is e e sed in he nex column [40] (Figu e 1).
ff
ff
− − −
−
⁺ ff
ff
ff
−
−ff
Figu e 1. View o he hexagonal c ys al s uc u e o HAp (a). PO
43−
e ahed a a e ep esen ed in
pu ple, he posi ions o he OH
−
anions in ed, and he wo di e en si es o he Ca
2+
ions in blue.
The me al ions a e depic ed as balls (Ca2) and blue polyhed a (Ca1), espec i ely. (b) Schema ic
d awings o he hyd oxide a angemen s o hexagonal (le ) and monoclinic ( igh ) s uc u es along
he z-axis.
HAp is a highly e sa ile ma e ial and, he e o e, he ield o applicabili y o his
ce amic co e s se e al a eas. I has ound use in biomedical esea ch (implan s and bone
egene a ion; sca olds o issue enginee ing and d ug deli e y), wa e pu i ica ion (ad-
so ben o seques e ing con aminan s like hea y me als, dyes, and o ganic and ino ganic
pollu an s, such as hyd oca bons and phospha es, and o educing wa e ha dness), ba e -
ies (ene gy s o age), ca alysis (ca alys s, such as pho oca alys s, o as ac i e phase suppo ),
nanoca ie o biocides o elici o s in ag icul u e, ion exchange (memb anes and il e s o
he sepa a ion and pu i ica ion o liquids), and senso s (gas, empe a u e, biomolecule, ion,
and pH senso s) [41–45].
The e sa ili y o HAp and i s mul iple applica ions can be ailo ed by a ho ough
con ol o ce ain design ac o s. These ac o s, which can be modi ied by di e en syn he ic
me hods, a e he eac ion ime, p essu e, a e, na u e and o de o he p ecu so ’s addi ion,
Molecules 2024,29, 4479 4 o 39
concen a ion o he eac an s, pH, and empe a u e [
46
–
49
]. The a ained p oduc s show
dis inc composi ion (e.g., Ca/P a io), pa icle size (powde , g anula , mac o- o mic o-
po ous), deg ee o c ys allini y, and mo phology. Nume ous syn he ic ou es o ob ain
polyc ys alline HAp powde ha e been de eloped o e he las decades. Pos -syn hesis
pa ame e s, such as e-imme sion in solu ions o he isola ed solids o u he he mal
ea men s, ha e also been analyzed [
50
]. All hese p ocedu es can be summa ized in ou
di e en g oups o me hods (Figu e 2) [51–56].
ff
ff
ff
ff−
−
−
Figu e 2. Summa y o me hods o he syn hesis o HAp.
The mo phology and c ys al size o HAp depend on he c ys al o ma ion a e. The
la e , in u n, is in luenced by supe sa u a ion, which co ela es wi h he ini ial concen-
a ions o calcium (i[Ca]) and phospha e (i[PO
4
]) ions, he so-called iCa/P a io, and ipH
o he solu ion [
57
]. In a s udy conduc ed by Sz e ne and Bie na [
58
], i was ound ha
lowe [Ca] le els (0.025 and 0.050 mol/dm
3
) p oduced HAp whiske s, whe eas highe
concen a ions (0.1 and 0.2 mol/dm
3
) led o he o ma ion o hexagonal ods. Fu he mo e,
he c ys alli e size o HAp nanopa icles diminishes wi h dec easing [Ca]. These esul s
sugges a signi ican in luence o calcium ion concen a ion on he shape and size o HAp
c ys als du ing syn hesis [59].
The ela ionship be ween he pH and shape o HAp c ys als is c ucial. The modi i-
ca ion o he ipH alue causes a change in he s uc u e and mo phology o he c ys als,
including sphe es, ods, needles, wi es, whiske s, sphe uli es, bel s, e c. [
60
–
66
]. pH is
a pi o al pa ame e o be conside ed o he solubili y and dissolu ion o se e al ions in
solu ion. Va ia ions in his alue gene a e di e en concen a ions o OH
−
and H
3
O
+
ions,
he eby inducing changes in Ca
2+
and PO
43−
le els [
67
,
68
]. In he p ocess o syn hesizing
HAp, inco po a ing a base like NH
4
OH leads o an ele a ed concen a ion o OH
−
ions,
consequen ly boos ing he eac ion’s alkalini y. This occu ence a ises om he elease
o addi ional hyd oxide ions, which can acili a e p ecipi a ion du ing syn hesis. HAp
is p e e en ially o med unde neu al o alkaline condi ions. Acidic condi ions gi e ise
o he o ma ion o di e en phases [
69
,
70
]. Depending on he pH alue, a ious c ys-
alline phases a e ob ained, p ima ily due o he p e alence o he phospha e anion. In
ac , H
2
PO
4−
ions emain s able a pH le els be ween 3 and 6. I he pH inc eases be-
ween 8 and 11, HPO
42−
ions become p edominan , bu beyond pH 12, phospha e ions
PO
43−
p e ail [
71
]. Thus, he in e play be ween empe a u e, pH, and he o de o he
addi ion o p ecu so s yields CaP p ecipi a es, usually as mix u es o he OCP, DCPA, and
HAp phases, whe e HAp ends o be he mos abundan phase a pH > 5.3, whe eas he
o me p e ails a pH < 3.8 [72,73].
Tempe a u e and p essu e du ing syn hesis also ha e a signi ican impac on he
c ys al g ow h o HAp [
74
], i.e., c ys al size and shape. An op imal me hod o achie ing

Molecules 2024,29, 4479 5 o 39
pu e and uni o m HAp in ol es using high empe a u es and p essu es, as lowe alues
esul in he o ma ion o di e se c ys alline phases [58,66].
The chemical composi ion and acancies p esen in he HAp c ys al s uc u e allow
o a wide a ie y o anionic subs i u ions (in ol ing hyd oxide o phospha e g oups) o
ca ionic subs i u ions (like mono-, di-, and i alen me als). The eplacemen s cause dis u -
bances in he c ys alline ne wo k, which dec eases c ys allini y and he e o e inc eases i s
capaci y o eabso p ion in physiological media. Ionic subs i u ion in his ce amic ma e ial
has gained impo ance in ecen yea s, as summa ized in Figu e 3, which shows some o
he eplacemen s ca ied ou [75–84].
Figu e 3. Alphabe ically o de ed ions in doped HAp, bo h ca ionic and anionic posi ions.
The in e ac ion o biologically ac i e me al ion complexes wi h ha d issues, like bones
o ee h, has p opelled he s udy o he in e play be ween HAp and coo dina ion com-
pounds [
85
,
86
]. In some cases, an inhibi ion o HAp g ow h in he p esence o a me al
complex has been shown [
87
]. In addi ion, he sea ch o HAp-con aining mul i unc ional
ma e ials wi h new o imp o ed p ope ies has led o he ab ica ion o hyb id HAp–me al
complexes as new s eps in he p ocess o achie ing sys ems wi h inc easing complexi y.
Thus, coo dina ion compounds o med by ansi ion me al ions linked o ca boxyla es,
phosphona es, Schi bases, o polypy idyl- ype ligands, amongs o he s, ha e been inco -
po a ed in o he ino ganic HAp ke nel [
88
–
96
]. A ew yea s ago, Ba bosa e al. w o e a e y
in e es ing e iew in his ield [
97
]. E en hough a deep bibliog aphic sea ch on his ma e
alls ou side he scope o he p esen e iew, he ligand beha io o mos biomolecules is
a nexus o hese sys ems, including o he e na y HAp–biomolecule–me al sys ems ha
will be discussed la e . This has p omp ed us o include he sho insigh gi en in his
pa ag aph. Some HAp–biomolecule–me al compounds ha e been published ecen ly. One
o hem inco po a es glucose-6-phospha e and Cu(II)/Zn(II) ions in o he HAp ma ix,
gene a ing HAp- unc ionalized nanopa icles wi h good su i abili y and adhesion o
os eoblas cells [
98
]. Ano he example links polydopamine o an algina e/S (II)/HAp
composi e, p omo ing os eogenic di e en ia ion and ascula iza ion [
99
]. In ano he case,
β
-cyclodex in eac s wi h an ino ganic zinc phospha e@HAp ma ix, gi ing ise o a
composi e ha se es as a nanoca ie o he an i umo al d ug cispla in [100].
Cu en ly, a ious e o s a e unde way o achie e he syn hesis o new ma e ials om
biomime ic and bio-inspi ed pe spec i es [
30
,
101
,
102
]. This sea ch mus ake in o accoun
he ea u es in ol ed in he biomine aliza ion p ocesses, which a e induced by physical and
chemical ac o s, bu also condi ioned by he biological en i onmen o p esence o di e en
li ing o ganisms [
103
–
108
]. In pa icula , esea ch on inno a i e bioma e ials aimed a
bone issue egene a ion h ough he co alen unc ionaliza ion o ce amic ma e ials wi h
biomolecules, o closely ela ed models, has been ui ul [
109
–
111
]. O cou se, CaPs a e
among he ino ganic ma e ials ha a e mos likely o be used in bone healing [
112
–
115
].
Bu he ele ance o hese s udies is also ela ed o he da k side o he biomine aliza ion
p ocess o HAp and o he CaPs, which a e in ol ed in he o ma ion o u ina y s ones
and in ascula calci ica ion, which can p omo e ca dio ascula diseases [
116
,
117
]. The
knowledge o he unde lying mechanisms in bo h biologically essen ial and undesi able
p ocesses can be applied o di e en he apeu ic s a egies.
In he case o bone [
118
–
122
], mine aliza ion occu s on he bone su ace, whe e cells
called os eoblas s sec e e ma ix s uc u al p o eins (mainly collagen, bu also glycop o eins
Molecules 2024,29, 4479 6 o 39
and p o eoglycans) and he pep ide ho mone os eocalcin. The laye s o med by ype I col-
lagen, mic o ib ils con aining iple-helix collagen, ac as empla es in a complex p ocess
ha has no ye been ully cla i ied. A e a possible ansien o ma ion o ACP pa icles,
he p ocess leads o he deposi ion o HAp nanoc ys als wi h pla ele shapes and hei
c-axis aligned wi h he collagen ib ils. Hence, he mine alized collagen ibe s cons i u e he
s uc u al uni s o bones [
123
,
124
]. In pa icula , he beha io o he ino ganic ma ix was
explo ed by a combined Raman/
31
P-NMR s udy whose syn he ic me hodology p o ided
a slow inco po a ion o base (NH
3
) om pH 2 o pH 10 [
125
]. The s udy ound ha he
concen a ion o he es ed biological componen s (a syn he ic polyaspa a e mimicking
non-collagenous p o eins, ci a e, and collagen) could con ol he usual sequence o solid
p ecipi a es, ep esen ed in Equa ion (1), o each he inal c ys alline HAp. Thus, polyas-
pa a e s abilized OCP and ci a e inhibi ed i s o ma ion and p ecluded HAp p ecipi a ion,
whe eas he g ea in luence o collagen in he s uc u e o HAp showed no dependence on
he concen a ion.
Solu ion 0–96 min
−−−−−→ ACP 96–480 min
−−−−−−→ OCP 480 min–6days
−−−−−−−−→ HAp (1)
As a esul , bone issue is p oduced. By weigh , i s a e age composi ion is app oxi-
ma ely 65% ino ganic componen s, 25% o ganic componen s, and 10% wa e . The main
ino ganic componen is calcium-de icien ca bona e hyd oxyapa i e (90%). In he case o
he o ganic ac ion, i is la gely ype I collagen (a ound 90%), non-collagenous p o eins
(like os eocalcin, os eopon in, bone sialop o ein, os eonec in, and SPARC, among o he s,
2.50–3.75%), oge he wi h small amoun s o ci a e (1.5–2.0%) and lipids (1–10%) [
126
–
129
].
In he case o ee h, h ee ha d s uc u es can be dis inguished: den in, cemen , and
enamel. The amoun o ino ganic apa i e ma ix in den in and cemen is simila o ha
in bones, 70 and 65% in weigh , espec i ely, and he pe cen ages o o ganic and wa e
con en a e 20 and 10% in bo h cases. None heless, he HAp con en eaches nea ly
95–97% in enamel [
130
–
132
], whe e amelogenin is he mos abundan p o ein in he o ganic
ma ix [133].
The way o ackle he inco po a ion o biomolecules in he HAp bone/ ee h ma ix
in ol es ensu ing he e ec i e immobiliza ion o biomolecules on he su ace o HAp. Thus,
i equi es high a ini y and speci ici y wi h he ce amic moie y, achie ing a p ecise immo-
biliza ion a he desi ed si e and ensu ing he main enance o biological ac i i y [
134
]. In
esea ch on he unc ionaliza ion o HAp wi h biomolecules, a ious syn he ic app oaches
ha e been desc ibed [
135
]. Gi en ha we will ocus ou e iew on he ancho age o pep-
ides and nucleic acid de i a i es on HAp, we will p o ide, in he ollowing pa ag aphs, a
e y b ie su ey on he unc ionaliza ion o HAp wi h ca bohyd a es, lipids, and i amins.
-
The biodeco a ion o HAp wi h ca bohyd a es has been achie ed by di ec ly and
co alen ly bonding nanos uc u ed apa i e g anules o a ious polysaccha ides, like
cellulose [
136
,
137
], chi osan [
138
], pec ine [
139
], ca ageenan [
140
], algina e [
141
],
hyalu onic acid [
142
,
143
], and, e y ecen ly, acemannan mucopolysaccha ide [
144
].
Addi ionally, monosaccha ides such as D-glucose, D-galac ose, and L- uc ose a e also
u ilized in his con ex [145,146].
-
The in e ac ion o HAp wi h di e en ca boxylic acids has been ex ensi ely an-
alyzed based on he a ini y o Ca
2+
ions o ca boxyla e g oups, such as hose
p esen in alipha ic (p opionic, malonic, glu a ic, adipic, maleic, uma ic
. . .
), a o-
ma ic, polyca boxylic, and lac ic/glycolic acid de i a i es o e en mo e complex
ca boxyla e-con aining o ganic compounds [
147
–
151
]. S udies ha e also included
a y acids and lipids, including s ea ic acid, icinoleic acid, linoleic acid, and oleic acid,
among o he s [
152
–
155
]. In ac , he p esence o lipids p omo es he p ecipi a ion o
HAp [
156
], gi en, a leas in pa , ha phospholipids igge he
in i o
ans o ma ion
o OCP in o HAp [
157
]. These phase ansi ions seem o be c ucial in he ea ly s ages
o bone biosyn hesis, p obably boos ed by he o ma ion o calcium–phospholipid
complexes [158].
Molecules 2024,29, 4479 7 o 39
-
The c ea ion o hyb id ma e ials o HAp ma ices unc ionalized wi h i amins,
such as olic acid [159] and bio in [160], has been desc ibed in he li e a u e.
The a o emen ioned indings highligh he essen ial ole ha HAp plays in he con-
s uc ion o he ha d issues o e eb a es. Thei o ganic componen s a e mainly p o eins.
Because o his, he p esen e iew is ocused on he s udy o syn he ic HAp–biomolecule
ma e ials con aining p o eins, o hei simples cons i uen s, such as amino acids and
pep ides. We ha e also included HAp–nucleic acid bioma e ials and hei nucleobase bio-
logical b icks, emphasizing he ele ance o phospha e anions in many biological p ocesses,
including hose in ol ing ene gy o in o ma ion ans e ence. As a as we a e awa e, no
nea e iews simul aneously co e ing bo h aspec s—p o eins and nucleic acids o hei con-
s i u ing b icks—ha e been published up o da e. No wi hs anding his, pe haps he mos
in e es ing no el y o he p esen e iew a e he sec ions dealing wi h he inco po a ion o
me al complexes, which we ha e included a he end o each chap e .
A bibliog aphic insigh in o he scien i ic li e a u e on hese sys ems gi es an im-
p ession o he cumula i e e o s dedica ed o hem o yea s. Wi h his pu pose, we
ca ied ou a sea ch in he Web o Science da abase using “hyd oxyapa i e” AND “(amino
acid OR pep ide OR p o ein)” as key e ms p esen in abs ac s. The sea ch yielded
23,958 esul s [
161
]; he oldes pape was he ea ly Ca ie publica ion om 1948 [
162
]. In
he same way, 2554 esul s we e ob ained o “hyd oxyapa i e” AND “(nucleic acid OR
nucleo ide OR nucleobase)”. Figu e 4depic s he esul s published om 1961 o 2023,
showing a o al o 23,569 and 2537 esul s o he pep ide and nucleo ide amilies, espec-
i ely. As can be seen, pape s on HAp–p o ein ela ed sys ems a e much mo e nume ous
han hose dealing wi h nucleic acid de i a i es. Thus, his e iew is no an exhaus i e
desc ip ion o he ex ensi e bibliog aphy abou HAp–pep ide–nucleo ide sys ems bu an
essay aiming o in oduce hem. The pe spec i e o his wo k is chemical, and i is mainly
aimed a beginne s o esea che s who wish o ha e an ini ial and b ie in oduc ion o
hese hyb id sys ems.
≈
ffi
Figu e 4. Ch onological e olu ion o he numbe o en ies in he bibliog aphic sea ch on
HAp–(AA–pep ide–p o ein) (in blue) and HAp–(nucleobase/nucleo ide/nucleic acid) (in o ange)
sys ems. The ange o yea s co e ed in he igu e is om 1961 o 2023. Da a we e collec ed om Web
o Science (see main ex ).
2. Func ionaliza ion o HAp wi h Amino Acids, Pep ides, P o eins, and Me al
Complex Hyb ids
2.1. HAp and Amino Acids
Amino acids (AAs) ha e a wide ange o biological unc ions. They a e he building
blocks o p o eins and play essen ial oles in me abolism, enzyma ic ac i i y, cellula
signaling, ni ogen balance, and de oxi ica ion [
163
]. The s uc u al AAs inside p o eins
ha e a ca boxyl (-COOH) agmen , an amino (-NH
2
) moie y, and o ganic R-subs i uen s
Molecules 2024,29, 4479 8 o 39
co alen ly bonded o he same ca bon a om (Figu e 5). Amino acids a e classi ied as
acidic, basic, o neu al, depending on he na u e o hei side chains. Ou o he 20 known
AAs wi h which cells o m p o eins, 9 canno be syn hesized by mammals (i.e., hey a e
die a y essen ial).
≈
ffi
Figu e 5. Gene al s uc u e o p o ein- o ming AAs, wi h one- and h ee-cha ac e codes in pa en heses.
P ebio ically ele an AAs, such as his idine, cys eine and a ginine, ha e been epo ed
o enhance phospha e adso p ion on o i on oxy(hyd oxide) mine als by
≈
30% [
164
]. In
he con ex o he in e play be ween AAs and phospha e ions, i can be expec ed ha
he a angemen o phospha e and calcium ions in he c ys al s uc u e o HAp [
165
]
could a o hei binding o AAs. In ac , he a ini y be ween HAp and AAs es s on he
p esence o bo h ca boxyl and amino unc ional g oups in AAs, as well as in he side chain
subs i uen s (R) such as he -COOH (e.g., aspa ic acid (Asp), glu amic acid (Glu)), -NH
2
(e.g., lysine (Lys), a ginine (A g)), and -OH g oups (e.g., se ine (Se ), h eonine (Th )). These
subs i uen s a e able o o m co alen , ionic, and hyd ogen bonds wi h he calcium and/o
phospha e ions on he su ace o HAp, a ec ing i s s uc u e and i s physical, chemical, and
biological p ope ies.
Se e al p epa a i e me hods ha e been applied o ob ain HAp-AA hyb id ma e ials.
Some o hem in ol e di ec syn hesis in wa e unde con olled condi ions using solu ions
o soluble calcium and phospha e sal s, such as Ca(NO
3
)
2·
4H
2
O and (NH
4
)
2
HPO
4
. The
desi ed amino acid is added o he phospha e solu ion be o e adjus ing he pH abo e
9 wi h NH
4
OH. Reac ions a e o en ca ied ou in a ni ogen a mosphe e o a oid ca -
bona ion p ocesses in such a basic medium. No e ha ca bona e ions a e inco po a ed
in o he HAp s uc u e by pa ial eplacemen o he OH
−
(subs i u ion in he A-si es) o
PO
43−
ions (subs i u ion in he B-si es) [
166
–
169
]. Finally, he hyb ids a e ob ained as
solids and, some imes, u he ea men s (like mode a e hea ing o hyd o he mal) a e
pe o med [
170
]. No wi hs anding his, many o he me hods such as ul asonic and mi-
c owa e i adia ion ha e been applied [
171
]. Bu ega dless o he kinds o me hods used,
he expe imen al esul s un eil he complexi y o he HAp/AA in e ac ion. S udies show
ha complexes o med be ween cha ged AAs and Ca
2+
and PO
43−
ions a e ime-dependen
and eac di e en ly ollowing pa hways ha depend on hei le el o o ganiza ion and
s uc u e. Consequen ly, he ime be ween he p epa a ion o he solu ion o he p ecu so
and hei mix should be aken in o accoun as an impo an a iable in any biomine aliza-
ion expe imen [172].
The su ace o HAp is neu al o sligh ly nega i ely cha ged in aqueous suspensions
a neu al pH alues. In he case o a basic pH, amino acids exis in hei ca boxyla e ion
(-COO
−
) o m wi h a neu al amino g oup. Due o hese nega i e cha ges, he elec os a ic
HAp-AA in e ac ion could be conside ed weak because o he cha ge epulsion. No wi h-
s anding his, an in es iga ion pe o med wi h he simples AA (Gly) showed ha he
HAp–glycine (HAp-Gly) in e ac ion modula ed he mo phology and size o he pa icles:
he g ea e he amoun o Gly, he smalle he size o he HAp-Gly c ys als [
173
]. In o he
wo ds, he c ys allini y o HAp dec eased wi h an inc easing amoun o Gly. And, mo e
impo an ly, his esul sugges ed ha , o he in e ac ion mechanism, he coo dina ion o
Molecules 2024,29, 4479 15 o 39
molecules and ions p esen on he HAp su ace, o ming he hyd a ion and he non-apa i e
laye s, espec i ely, a ec he immobiliza ion o p o eins on he pa icle [232].
This e iew will co e non-collagenous p o eins (NCPs) in a b oad manne bu will
p ima ily ocus on he ole o Clg in hei linkage o he ino ganic CaP ma ix, as colla-
gen ep esen s he mos abundan p o ein in mammals, a a ound 20–30% o he p o ein
weigh [233].
As men ioned in he In oduc ion, bones a e composed o 65–70% mine als and 30–35%
o ganic molecules, p edominan ly ype I collagen [
234
]. Type I collagen is cha ac e ized by
i s high con en o p oline, glycine, and hyd oxyp oline, which oge he ep esen o e 50%
o he amino acid composi ion, o en a anged as Gly-X-Y epea s (whe e X and Y a e P o
o Hyp). These amino acids assemble in o Clg ib ils o ming he undamen al iple-helix
seconda y s uc u e. A ep esen a ion o he p ima y s uc u e o Clg is gi en in Figu e 7.
α α
ffi
γ
ff α
ff
−
ff
Figu e 7. P ima y s uc u e o collagen.
The s uc u al o ganiza ion o his p o ein is ele an o he deposi ion o HAp wi hin
bone issue. Type I collagen ib ils consis o opocollagen as hei basic uni , composed o
h ee chains: wo
α
-1 collagen chains (COL1A1) and one
α
-2 collagen chain (COL1A2) [
235
].
T opocollagen has a diame e o 1.5 nm and a leng h o 300 nm. These opocollagen uni s
a e aligned in an o ganized manne , and he egions be ween he ib ils, known as “hole
zones”, a e app oxima ely 40 nm in leng h and 5 nm in wid h [
236
], exhibi ing a high
cha ge densi y, which is c i ical o mine al nuclea ion. These hole zones c ea e a o able
condi ions o he accumula ion o mine al ions, ini ia ing he o ma ion o incipien nuclei,
which subsequen ly g ow in o la ge , o ganized mine al s uc u es. Fu he mo e, he size o
hese holes appea s o limi ino ganic g ow h. Bone sialop o eins, os eonec in, os eopon in,
os eocalcin, and/o den in ma ix p o eins—all NCPs—bind o opocollagen and egula e
he mine aliza ion p ocess o hyd oxyapa i e. These NCPs a e ich in acidic amino acid
esidues o expe ience pos - ansla ional modi ica ions ha add acidic g oups in o hei
sequences, enhancing hei a ini y o Ca
2+
ions. Wi hin bone p o eins, os eocalcin s ands
ou o ha ing a dis inc amino acid esidue ha binds o calcium,
γ
-ca boxyglu amic acid
(Gla), so os eocalcin is also called bone Gla p o ein (BGP) [237].
App oxima ely 28 ypes o collagens ha e been iden i ied, each sha ing a iple-helix
(TH) s uc u e while di e ing in he composi ion o hei
α
chains, he eby con ibu ing o
hei dis inc unc ional p ope ies.
The i e main ypes o collagens and hei oles include he ollowing [238–242]:
-
Type I o ms 90% o o ganic bone mass and is a majo p o ein cons i uen in a ious
issues, such as endons, ligamen s, he co nea, o he skin.
- Type II is ound in elas ic ca ilage, p o iding esilience and suppo o join s.
-
Type III is p esen in muscles, a e ies, and o gans, o e ing s uc u al suppo and elas ici y.
-
Type IV is loca ed in skin laye s, con ibu ing o basemen memb anes and
issue o ganiza ion.

Molecules 2024,29, 4479 16 o 39
-
Type V is ound in he co nea o he eye, some skin laye s, hai , and placen al issue,
con ibu ing owa ds issue s abili y and unc ion.
S udies on he mine aliza ion o apa i e in he p esence o p o ein sugges ha collagen
ib ils acili a e he o ma ion o apa i e om low [Ca
2+
] and [PO
43−
] alues [
243
]. B ad
e al. [
244
] desc ibed a we me hod o he a ainmen o mine alized Clg gel by mixing
an acid calcium-con aining Clg solu ion wi h a bu e ed neu alized phospha e solu ion.
This p ocess allowed o he simul aneous assembly o collagen ib ils and p ecipi a ion o
amo phous calcium phospha e (ACP), which subsequen ly ans o med in o c ys alline
HAp. The c ys alliza ion o HAp on he ib ils imp o ed wi h he addi ion o polyaspa a e,
a syn he ic polyme ha mimics NCP unc ion. Ano he app oach s udied by Qu e al. [
245
]
employed ype I collagen subs a es imme sed in a solu ion called simula ed body luid
(SBF), which con ained ino ganic ions ( om sal s such as NaCl, NaHCO
3
, KH
2
PO
4
, MgCl
2
,
and CaCl
2
) in simila concen a ions o hose in human blood plasma. The p e o med
subs a es ac ed as empla es o HAp deposi ion, gels on which mine als could nuclea e
and g ow, mimicking he na u al mine aliza ion p ocess in biological issues like bones and
ee h. The binding o Ca
2+
o nega i ely cha ged ca boxyla e g oups in collagen was ound
o be c ucial in acili a ing his nuclea ion [
246
]. Molecula dynamic simula ions o he
in e ac ion mechanism o aspa ic acid esidues in collagen on he c ys al HAp su ace ha e
e ealed he impac o calcium acancies on ca boxyla e adso p ion and he s abilizing ole
o hyd ogen phospha e in he p ocess [
247
]. In addi ion, i has been p oposed ha HAp
nuclea ion mainly occu s a ound cha ged amino acid esidues in human ype I collagen.
In pa icula , a ginine seems o play a pi o al ole in he p ocess. The he modynamic
ba ie heigh o he o ma ion o complexes wi h Glu and Asp wi h PO
43−
is highe han
hose wi h Lys and A g [
248
]. Mo eo e , he phospho yla ion (inco po a ion o nega i ely
cha ged phospha e g oups) o Clg nano ibe s p omo ed he deposi ion o HAp [249].
Mesopo ous hyd oxyapa i e nanopa icles coa ed wi h collagen ha e been success ully
syn hesized o he selec i e deli e y o d ugs o cance cells [
250
]. These NPs exhibi ed
biocompa ibili y, non oxici y, and an i-in lamma o y p ope ies, highligh ing hei po en ial
o u u e biomedical applica ions.
Rega ding esea ch on non-collagenous p o eins, i has been demons a ed ha ce -
ain highly acidic NCPs, cha ac e ized by mul iple phospho yla ion si es [
219
] o an
in eg in-binding RGD (A g-Gly-Asp) domain, can bind HAp h ough hei acidic p o-
ein egions [
251
] and di ec ly in luence con olled mine aliza ion [
252
]. Some NCPs used
as linke molecules o unc ionalize he su ace o HAp include bo ine se um albumin
(BSA) and a small in eg in-binding ligand, N-linked glycop o ein (SIBLING). P o eins om
he SIBLING amily loca ed on human ch omosome 4q21 include den in ma ix p o ein 1
(DMP1), den in sialophosphop o ein (DSPP), ma ix ex acellula phosphoglycop o ein
(MEPE), os eopon in (OPN), and bone sialop o ein (BSP). BSP and OPN a e ound in highe
concen a ions in bone issues, whe eas DMP1, DSP, and DPP a e p edominan ly ound in
den in. These p o eins a e cha ac e ized by domains ha media e cell adhesion and can
unc ionalize mine aliza ion by inhibi ing calci ica ion. Despi e hei s ong a ini y o
HAp c ys al su aces, hei s uc u al lexibili y enables o he pa s o he molecule o in e -
ac wi h o he p o eins o acili a e cell binding h ough he exposed RGD in eg in-binding
domains. SIBLING p o eins a e cha ac e ized by a high con en o acidic amino acids such
as Asp and Glu, bu also con ain basic esidues like A g and Lys. Upon ioniza ion, hese
esidues, along wi h Gln, Gly, P o, and Se , a e known dis up o s o he p o ein s uc-
u e, which may in luence he long- e m o de ing o hei main con o ma ional s abili y.
Addi ionally, he SIBLING p o ein amily has been obse ed o s ably bind o Clg ib ils.
The concen a ion o o ganic addi i es, like collagen, ci a e, and a syn he ic polyas-
pa a e mimicking an NCP, in luences HAp c ys alliza ion. This concen a ion was ound
o modi y he sequence o HAp o ma ion (usually, i s ACP, a e wa ds OCP, and, inally,
HAp) [
253
]. The mos ou s anding esul in his wo k was ha con inemen he mo-
dynamically d i es HAp o ma ion by slowing down he kine ics in he o ma ion o
CaP p ecu so s.
Molecules 2024,29, 4479 17 o 39
Apa om bones, HAp is also p esen in ee h. As p e iously men ioned, amelogenin
is he mos abundan p o ein in enamel (abou 90% o he p o ein con en ). The e, his
hyd ophobic pep ide sel -assembles o o m an ex acellula ma ix which ac s as a empla e
o he con inuously g owing HAp c ys als, p esumably h ough nanosphe e o ma ion
ia oligome s [
254
]. Habeli z e al. e ealed ha he enamel p o ein amelogenin adop s
ibbon-like sup amolecula s uc u es ha empla e he g ow h o highly o ien ed HAp
nano ibe s. The mechanism is egula ed by enzyma ic p ocessing and in e ac ion wi h
acidic nonamelogenin p o eins [
255
]. I is ema kable ha e y small a ia ions in he
amino acid p ima y sequence can d as ically in luence he biomine aliza ion o HAp. Thus,
he change in one amino acid, p oline o h eonine, wi hin he sequence in amelogenin,
gi es ise o de ec i e enamel; his is p esen in a g oup o congeni al diso de s known as
amelogenesis impe ec a [256].
Rega ding o he p o eins, Kolla h e al. [
201
] explo ed me hods o imp o e he adso p-
ion capaci y o HAp powde o p o eins such as BSA. Unde neu al pH condi ions in an
aqueous solu ion, HAp has a neu al o sligh ly nega i e cha ge, while BSA is nega i ely
cha ged. Speci ic linke molecules (L-A g, L-Lys, and O-phospho-L-Se ) we e used as
unc ionalizing agen s o modi y he cha ge o BSA. Thus, he elec os a ic in e ac ions on
he su ace o he c ys alline ma e ial we e al e ed, imp o ing he a ac ion be ween he
powde and he p o ein. The ca boxyl g oup o hese linke molecules can in e ac wi h
Ca
2+
ions p esen on he HAp su ace h ough elec os a ic eac ions, lea ing he amino
g oup a ailable o eac wi h BSA. Addi ionally, he amino g oup can o m a hyd ogen
bond wi h he HA su ace ia a wa e molecule, al hough his in e ac ion is weake . Lys
and A g inc eased p o ein adso p ion, whe eas phosphose ine educed i . This inc ease
seemed o be due o a change in he su ace cha ge o apa i e, making he posi i ely
cha ged esidues mo e p ominen a e unc ionaliza ion, he eby enhancing he adso p-
ion o nega i ely cha ged BSA. A sligh inc ease in he ze a po en ial also signi ican ly
boos ed p o ein adso p ion. The indings indica ed ha adso p ion capaci y can be con-
olled h ough di e en unc ionaliza ion, depending on he speci ic p o ein–ca ie pai
unde conside a ion.
Medicinal esea ch on bioma e ials, which includes he sea ch o nanoca ie s o be
used as d ug deli e y sys ems, has success ully ound good candida es in hyb id com-
pounds o med by HAp unc ionalized wi h p o eins such as ke a in [257], collagen [258],
BSA [
259
], and bu e milk p o eins [
260
], among o he s. Howe e , no only HAp, bu o he
CaPs, oo, ha e been used as bioce amics de i ed om collagen sca olds, including
β
–TCP
o a silicon-based bioac i e glass composed o 60% SiO
2
, 36% CaO, and 4% P
2
O
5
(mol%)
o yield a SiO
2
–CaO–P
2
O
5
ne wo k [
261
]. The use o CaPs as ino ganic ma ices o bone
mo phogene ic p o eins (BNPs) has also been in es iga ed and ecen ly e iewed [
262
–
264
],
oge he wi h he ield o p o ein-based ac i e coa ings in biomedical ma e ials [
265
]. In
ac , he c ea ion o a syn he ic bi- unc ional usion p o ein has allowed o he a ge ing
and moni o ing o HAp biomine aliza ion p ocesses [266].
2.4. HAp–Pep ide–Me al Complex Hyb ids
The in e ac ion o unc ionalized HAp–pep ide hyb ids wi h me al ions and coo dina-
ion compounds has been explo ed. Fo ins ance, he use o HAp o emo ing Cu(II) ions
in solu ion was in es iga ed in he p esence o Gly and ligands (e hylenediamine, en, and
e hylenediamine e aace ic acid, EDTA). The s udy a i ied ha he ligand seques a ion
e ec minimizes he inco po a ion o ansi ion me al ions in o he HAp ma ix [
267
]. Bu
Cu(II) ions ha e also been included in o calcium-de icien hyd oxyapa i e/mul i-(amino
acid) copolyme s, showing good capaci y o angiogenesis and os eogenesis [268].
The in e ac ion o Zn-subs i u ed OCP and he co esponding Ca-de icien Zn-HAp
de i a i e wi h AAs (Asp, Cys, Glu, His, and Lys) was analyzed by Suzuki e al. [
269
], who
epo ed ha he elease o Zn
2+
ions in he p esence o AAs was la ge in he case o Cys
and His.
Molecules 2024,29, 4479 18 o 39
Hyb id Sm-doped luo oapa i es (Sm-FAp) unc ionalized wi h Asp, Glu, Gly, and
His we e es ed as ca alys s in he syn hesis o 1,2,4- iazole om 2-ni obenzaldehyde and
hiosemica bazide, highligh ing he excellen yield o he Gly hyb id [
270
]. Fe-de i a i es
in he same luo oapa i e–AA sys em showed good ca aly ic ac i i y in he syn hesis o
hio- iazole compounds, in pa icula in he a ainmen o 1,2,4- iazolidine-3- hione p od-
uc s [
271
]. Fluo escence in Cd-FAp-Glu/His hyb ids e ealed ha luo escence in ensi y
enhanced wi h he amoun o AA adso bed [272]
In u n, Ch issan opoulos e al. [
273
] c ea ed a e na y o ganome allic–AA–HAp by
eac ion o i anocene wi h Gly/Ala and HAp, whose g ow h was ound o be inhibi ed in
he p esence o he complex.
Li e al. cap u ed phospho yla ed pep ides by means o a hyb id compound o med
by a magne ic Fe-con aining me al–o ganic amewo k (Fe-MOF buil wi h benzene-1,3,5-
ica boxylic acid) and ino ganic HAp nanowi es [274].
In he case o p o eins, he adso p ion o myoglobin on he su ace o HAp mod-
i ied wi h Ni
2+
, Cu
2+
, and Zn
2+
has been analyzed [
275
]. Fo hei pa , Kalidas and
Suma hi [
276
] ha e ecen ly epo ed he p epa a ion o a sca old o bone issue engi-
nee ing based on a gela in/poly inyl alcohol/silk ibe ein o ced wi h Cu-subs i u ed
HAp, which showed an imic obial ac i i y, biocompa ibili y, s ong mechanical s eng h,
and p omising os eos imula ion clues. On he con a y, he p esence o Pb
2+
was ound o
inhibi he binding o os eocalcin o hyd oxyapa i e [277].
No only complexes, bu also me al nanopa icles ha e been linked o HAp-AA sca -
olds, like he hyd oxyapa i e/gold nanopa icles/A g nanocomposi e designed by Vuko-
mano i´c e al. [
278
], o ice e sa, as in he case o he cons uc ion o a silica/HAp/gold
nanopa icle assembly o be used in phage display echniques [
279
]. The opposi e s a egy
allowed o he cons uc ion o Asp-capped gold nanopa icles o induce HAp c ys alliza-
ion [
280
]. F om he same pe spec i e, PEGyla ed, pep ide-coa ed supe pa amagne ic i on
oxide nanopa icles (SPIONs) we e in es iga ed o bind he HAp p esen , in small amoun s,
in diseased ca dio ascula issues, in o de o de ec a he oscle osis o ao ic s enosis [
281
].
Finally, he use o sil e nanopa icles in den is y, which in ol es in e ac ions wi h CaP–
p o ein composi es, has ecen ly been e iewed [282].
3. Func ionaliza ion o HAp wi h Nucleobases, Nucleo ides, Nucleic Acids, and Nucleic
Acid–Me al Complex Hyb ids
3.1. HAp and Nucleobases
Nucleobases, o ni ogenous bases, a e o ganic compounds ha make up nucleo ides,
which a e he essen ial building blocks o deoxy ibonucleic acid (DNA) and ibonucleic acid
(RNA). The e a e di e en nucleobases, bu hose likely ound in DNA and RNA and hus
in ol ed in he gene ic code a e i e: adenine (Ade, A), guanine (Gua, G), cy osine (Cy ,
C), hymine (Thy, T), and u acil (U a, U). Se e al au ome ic o ms o hem a e possible.
In he case o Ade, he h ee monoca ionic au ome s wi h he lowes ene gy a e shown
in Figu e 8; one o hem is p o ona ed a N1 o he 9H au ome o Ade, ano he a N3 o
he 7H au ome , and he las one a N3 o he 9H au ome [
283
]. A physiological pH,
app oxima ely 7.4, he i e main nucleobases exis almos comple ely in hei ke o and
amino au ome ic o ms. The co esponding pKa alues a e shown in Table 4[284–287].
The lack o unc ional g oups o es ablish s ong enough linkages wi h HAp p e-
cludes he di ec binding o nucleobases o CaPs, so no pape s dealing wi h his i em ha e
been ound. The ein, he in o ma ion gi en he e mus be placed in he con ex o he
whole sec ion.
Molecules 2024,29, 4479 19 o 39
ff
ć
ff
Figu e 8. Nucleobases in hei unp o ona ed o m and he h ee lowes -ene gy au ome s o
p o ona ed Ade.
Table 4. pKa alues o nucleic acid ni ogenous bases. Ni ogen acidic a oms a e indica ed.
Base A om pKa
U acil N3 9.63
Thymine N3 10.30
Guanine N1 9.56
Guanine N7 3.11
Cy osine N3 4.60
Adenine N1 4.10
3.2. HAp and Nucleo ides
Nucleo ides a e essen ial o ganic compounds ha , a anged in an an i con o ma-
ion, ac as he monome ic cons i uen s o nucleic acids. Nucleo ides ha e a wide ange
o unc ions, se ing as he p ima y ene gy cu ency in cells, as coenzymes o co ac-
o s in enzyma ic eac ions, as second messenge s in signal ansduc ion, and playing
a c ucial ole in he me abolism o ca bohyd a es, lipids, and p o eins, e c. Figu e 9
ep esen s he basic nucleo ide s uc u e and he a om numbe ing. As can be seen, a
nucleo ide comp ises h ee undamen al componen s: a ni ogenous base, pen ose suga
(a i e-ca bon monosaccha ide), and om one o h ee phospha e g oups. Nucleo ides can
adop nume ous con o ma ions in solu ion, engaging in apid dynamic equilib ium [
288
].
′
′
− − −
′
ff
′− − − ′ ′
− − − ′
− − − ′ ′ −
Figu e 9. Basic s uc u e o nucleo ides wi h hei h ee essen ial componen s. The ni ogenous base
can be ei he a pu ine o a py imidine; he pen ose suga is ei he ibose o deoxy ibose, and he
phospha e g oup is a ached o he 5′ca bon o he suga .
Molecules 2024,29, 4479 20 o 39
The p o ona ion si es in 2
′
- deoxynucleo ides (dNXP
n
whe e N = pu ine o py imidine;
X = M, D and T; n =
−
2,
−
3 and
−
4, espec i ely) exhibi g ea e basici y compa ed o
hei ibose analogs (NXP
n
). The pK
a
alues o 2
′
-deoxy ibose a e mo e basic han hose o
ibose nucleo ides. Table 5shows he acid s eng hs o he di e en nucleo ides: adenosine
5
′
-mono-, di-, and iphospha e (AMP
2−
, ADP
3−
, ATP
4−
); 2
′
-deoxyadenosine 5
′
-mono-, di-,
and iphospha e (dAMP
2−
, dADP
3−
, dATP
4−
); guanosine 5
′
-mono-, di-, and iphospha e
(GMP
2−
, GDP
3−
, GTP
4−
); 2
′
-deoxyguanosine 5
′
-mono-, di-, and iphospha e (dGMP
2−
,
dGDP
3−
, dGTP
4−
); cy osine 5
′
-mono-, di-, and iphospha e (CMP
2−
, CDP
3−
, CTP
4−
);
2
′
-deoxycy osine 5
′
- mono-, di-, and iphospha e (dCMP
2−
, dCDP
3−
, dCTP
4−
); u idine
5
′
-mono-, di-, and iphospha e (UMP
2−
, UDP
3−
, UTP
4−
); and hymidine 5
′
-mono-, di-,
and iphospha e (dTMP2−, dTDP3−, dTTP4−).
Table 5. Compa ison o pK
a
alues o se e al deoxy- and ibonucleo ides as de e mined by po en io-
me ic pH i a ions in wa e a 25
◦
C and I = 0.1 M (NaNO
3
). Adap ed wi h pe mission om [
289
].
Copy igh © 2008 WILEY VCH Ve lag GmbH & Co. KGaA, Weinheim.
Re s. Acid
NXP/dNXP
pKa o N1H+o N7H+
NXP/dNXP (4a)
pKa o PO2(OH)−
NXP/dNXP (5a)
pKa o N1H o N3H
NXP/dNXP (6a)
[290,291] H2(GMP)±/H2(dGMP)±2.48 ±0.04/2.69 ±0.03 6.25 ±0.02/6.29 ±0.01 9.49 ±0.02/9.56 ±0.02
[289,290]
H
2
(AMP)
±
/H
2
(dAMP)
±3.84 ±0.02/3.97 ±0.02 6.21 ±0.01/6.27 ±0.04
[292,293] H2(CMP)±/H2(dCMP)±4.33 ±0.04/4.46 ±0.01 6.19 ±0.02/6.24 ±0.01
[293] H(UMP)−/H(dTMP) 6.15 ±0.01/6.36 ±0.01 9.45 ±0.02/9.90 ±0.03
[289,294] H2(GDP)−/H2(dGDP)−2.67 ±0.02/2.91 ±0.07 6.38 ±0.01/6.46 ±0.03 9.56 ±0.03/9.64 ±0.04
[289,295] H2(ADP)−/H2(dADP)−3.92 ±0.02/4.00 ±0.03 6.40 ±0.01/6.45 ±0.01
[296] H3(CDP)±6.39 ±0.02/
[296] H2(UDP)−/H2(dTDP) 6.38 ±0.02/6.44 ±0.01 9.47 ±0.02/9.93 ±0.02
[289,297]
H
2
(GTP)
2−
/H
2
(dGTP)
2−2.94 ±0.02/3.16 ±0.05 6.50 ±0.02/6.64 ±0.02 9.57 ±0.02/9.66 ±0.04
[289,297]H2(ATP)2−/H2(dATP)2−4.00 ±0.01/4.14 ±0.02 6.47 ±0.01/6.62 ±0.03
[297,298]H2(CTP)2−4.55 ±0.02 6.55 ±0.02
[297,298]H2(UTP)2−/H2(dTTP)2−6.45 ±0.01/6.52 ±0.02 9.57 ±0.02/10.08 ±0.05
Taking H
2
(GMP) as an example, h ee dep o ona ion eac ions can occu : om (a)
N7H
+
si e; (b) PO
3
(OH)
−
g oup; and c) N1H uni . Thus, in a gene al o mula ion, he
dep o ona ion eac ions o nucleoside 5
′
-mono-, di-, and iphospha es (NP
2−
/
3−
/
4−
) a e
desc ibed in Equa ions (4)–(6) [289], which yield he pKa alues gi en in Table 5.
H2(NP)±/−/2−⇌H(NP)−/2−/3−+H+(4a)
KH
H2(NP)=[H(NP)−/2−/3−][H+
[H2(NP)±/−/2−](4b)
H(NP)−/2−/3−⇌NP2−/3−/4−+H+(5a)
KH
H(NP)=[NP2−/3−/4−]H+
[HNP)−/2−/3−(5b)
NP2−/3−/4−⇌(NP −H)3−/4−/5−+H+(6a)
whe e NP minus H means a N1H si e o a guanine esidue o he N3H si e o a u acil/ hymine
esidue loses i s H.
KH
NP =[(NP −H)3−/4−/5−][H+]
[NP2−/3−/4−](6b)
Depending on he speci ic nucleobase, only ce ain equilib ia a e applied. The nu-
cleo ides GXP and dGXP ollow equilib ia (4a), (5a), and (6a). Fo he nucleo ides A/CXP
and dA/CXP, only equilib ia (4a) and (5a) a e impo an , as hey conside he dep o o-
na ion o he N1H
+
si e (4b) and he monop o ona ed phospha e g oup (5b). Fo he

Molecules 2024,29, 4479 21 o 39
nucleo ides U/TXP and dU/TXP, i is only necessa y o conside equilib ia (5a) and (6a),
which quan i y he elease o he p o on om he monop o ona ed phospha e esidue and
he dep o ona ion o he N3H si e (6b).
An inc ease in basici y a ises om he eplacemen o he 2
′
OH g oup wi h a
2
′
H a om, which diminishes he hyd ophilici y o he nucleo ide. As a esul , he nu-
cleo ide sol a ion by wa e molecules is a ec ed, leading o changes in i s dep o ona ion
beha io . Among all he nucleo ides, he one wi h guanine is he mos impac ed, wi h
he N7 si e showing a no able inc ease in basici y, leading o a highe acidi y cons an .
Consequen ly, he e ec on he phospha e g oups and N1H o N1H
+
is smalle , bu s ill
p esen . These e ec s become mo e p onounced again only when he phospha e chain is
long enough o o m a mac ochela e wi h N7, as in he case o iphospha es.
The bases o ansphospho yla ion, he exchange o phospha e g oups, be ween nu-
cleo ides and HAp ha e been explo ed. In 1962, specula ion began abou he possibili y
o a s uc u al ela ionship be ween nucleo ides and he su ace o apa i e ha could ex-
plain he accele a ed ansphospho yla ion eac ion ound [
299
]. Se e al nucleosides di-
and iphospha e we e es ed, oge he wi h ino ganic py ophospha e, in hei eac ion
wi h di e en phospha es, including subs i u ed apa i es wi h S o Pb. The binding o
nucleo ides o apa i es was ound o be mo e e icien han ha o o he phospha es. In
addi ion, he p oduc ion o ino ganic py ophospha e in he eac ion wi h nucleo ides was
de ec ed. The e minal PO
43−
o he nucleo ide was eleased o combine wi h a phospha e
om he apa i e c ys al, o ming P2O74−. Fu he s udies e idenced he ole o P2O74−as
an inhibi o o he biomine aliza ion o HAp [300,301].
Mo e ecen s udies ha e demons a ed ha adso p ion on he HAp ma ix is a ec ed
by he cha ge o he nucleo ide [
302
]. The p esence o a ca ionic o neu al cha ge in a
nucleo ide esul s in absen o signi ican ly educed adso p ion. Con e sely, a ne nega i e
cha ge p omo es signi ican chemical adso p ion, which can be neu alized by acidi ica ion.
Addi ionally, a neu al pH, i is known ha he me e p esence o phospha es in he
nucleo ide does no ensu e adso p ion on HAp. The numbe o phospha es can only
in luence he adso p ion e iciency o a molecule i i ca ies an o e all nega i e cha ge.
3.3. HAp and Nucleic Acids
Nucleic acids a e essen ial biological mac omolecules ha s o e and ansmi gene ic
in o ma ion, play a c ucial ole in p o ein syn hesis, and a e also in ol ed in egula ing
gene exp ession and ac i a ing speci ic genes. These unc ions a e undamen al o he
de elopmen , machine y, and ep oduc ion o all li ing o ganisms. The e a e wo main
ypes o nucleic acids: RNA and DNA (Figu e 10). In 1953, Wa son and C ick (WC) [
303
]
p oposed he h ee-dimensional model o DNA s uc u e, which consis s o wo s ands o
nucleo ides ha wind oge he o o m a double helix, whe eas RNA is single-s anded.
The base pai ing in DNA in ol es he ni ogenous base A always combined wi h T, and
C wi h G. This speci ic pai ing is go e ned by he o ma ion o hyd ogen bonds be ween
complemen a y bases: A-T o ms wo hyd ogen bonds and C-G o ms h ee hyd ogen
bonds. These hyd ogen bonds play a c i ical ole in he s abili y and speci ici y o double-
s anded DNA.
DNA and RNA de i a i es a e known o be able o adso b on o HAp [
303
]. In ac ,
like in he case o p o eins, some o he ea lies s udies on he in e ac ion be ween HAp and
(poly)nucleo ides a ose om he u iliza ion o ino ganic ma ices in ch oma og aphy [
304
].
Soon, he e iciency o HAp was disco e ed o be ema kable as a esul o he high a ini y
o phospha e g oups in he nucleo ides [
305
–
307
], allowing e en ine sepa a ions o double-
s anded DNA, single-s anded DNA, and RNA [308].
Molecules 2024,29, 4479 22 o 39
(a) (b)
ffi
ffi
ffi
Figu e 10. S uc u e o (a) double-helix DNA and (b) single-s anded RNA.
One o he i s applica ions o he nucleic acid condensa ion induced by CaP was i s
use by G aham and Van De Eb o ca ying and deli e ing adeno i us 5 DNA in o KB
cells [
309
]. S udies on HAp pa icles as ec o s o DNA deli e y in gene he apy ha e
ecen ly been e iewed by Zhu e al. [310].
Baglioni e al. [
311
] s udied he in e ac ions be ween DNA and CaPs in he sea ch o
composi es o be used in nanomedicine. Ino ganic ca ie s play a c ucial ole in enhancing
cell adhesion and acili a ing he en y o he apeu ic ma e ials in o cells. In addi ion, and
ollowing he same idea, D oue ’s esea ch g oup e alua ed he adso p ion o DNA on
HAp, e i ying he s ong binding a ini y be ween DNA and HAp. They also s udied he
deso p ion p ocess igge ed when he e is an excess o phospha e ions in he medium by
he compe i ion o ee phospha es wi h he DNA–phospha e backbone [312].
Yazaki e al. used lipids o p o oke he p ecipi a ion o DNA on o he HAp
su ace [
313
,
314
], which has been demons a ed o enhance he gene exp ession o mes-
enchymal s em genes [
315
]. Fu he mo e, s udies conduc ed by Gibbs e al. [
316
] suppo ed
a model o p ebio ic polynucleo ide syn hesis in which a mine al, such as HAp, wi h anion
exchange p ope ies immobilizes high-molecula -weigh p oduc s o a empla e-di ec ed
eac ion. This a oids he spon aneous hyd olyza ion p ocesses ha b eak he oligonu-
cleo ides in solu ion and a e incompa ible wi h he su i al o long p e o med oligome s.
These au ho s obse ed ha HAp adso bs polyu idylic acid (poly(U)) om aqueous so-
lu ion almos comple ely, wi hou educing i s abili y o unc ion as a empla e o he
syn hesis o oligoadenyla es. The adenine ni ogenous base (monome ic A) was ound
no o bind HAp di ec ly; howe e , he unc ionalized HAp/poly(U) hyb id was ound
o inco po a e 74% ee adenine om he solu ion. The p esence o HAp in he p ebio ic
en i onmen could ha e led o he s abiliza ion o nucleo ides on i s su ace and made
possible he u he acc e ion o monome s o o m polynucleo ides. In his sense, i mus be
conside ed ha wo ac o s, an inc ease in he molecula weigh and he seconda y s uc u e
o he oligonucleo ide, go e n he HAp/polynucleo ide binding. Rega ding he seconda y
s uc u e, i has been known o a long ime ha he linkage o double-s anded nucleo ides
and HAp is s onge han he one wi h single-s anded polynucleo ides. T iple-s anded
is e en s onge han double-s anded, and quad uplexes e en mo e so [
317
,
318
]. In he
case o DNA, he nega i ely cha ged polyanion can be s abilized by posi i e cha ges, like
Ca
2+
ions in HAp, sugges ing ha DNA sequences will ha e an a ini y o he c ys alline
mine al. The adso p ion a ini y cons an , K
a
, may change as he seconda y s uc u e is
modi ied by inc easing ionic s eng h. I has been shown ha ap ame sequences wi h
G-quad uplex s uc u es ha e a highe a ini y o apa i e, ela i e o o he sequences, when
highe ionic s eng h is used o s abilize he G-quad uplex [319].
Molecules 2024,29, 4479 23 o 39
The use o DNA ap ame s ob ained by he p ocess known as SELEX (Sys ema ic
E olu ion o Ligands by EXponen ial en ichmen ) bonded o calcium phospha e ma e ials
has ecen ly been s udied. Ap ame s a e single-s anded oligonucleo ides, ypically ang-
ing om 15 o 100 nucleo ides in leng h [
320
]. Expe imen al and compu a ional s udies
ha e shown ha DNA ap ame s a e in ol ed in he mine aliza ion p ocess and ac as
c ucial a ini y eagen s o ma ke s, enabling he di e en ia ion be ween amo phous and
c ys alline ma e ials. Du y e al. [
321
] selec ed h ee ap ame s (wi h a highe pe cen age o
G nucleo ides) and checked hei a ini y o HAp, ACP, and
β
-TCP. La ge and simila K
a
alues and binding a low ap ame concen a ions (~50 nM) indica ed he s ong a ini y
o h ee ap ame s o HAp (Table 6). The ap ame s showed high selec i i y o c ys alline
HAp o e ACP and TCP. Kine ic analysis o he ap ame s e ealed a highe o wa d a e
cons an (k ) o ap ame 1, wi h he mos compac G-quad uplex seconda y s uc u e.
Table 6. Sequence, Gibbs ee ene gy, a ini y, and kine ics o ap ame s o binding o HAp (*).
Adap ed wi h pe mission om [321]. Copy igh © 2020 Else ie B.V.
Ap ame Sequence k (min−1) Ka (M−1)∆G
(Kcal·mol−1)
1
CAGGGCGCTACGGTATGTGTTGGGTCTGGCG
TAGGGCTGGC 12 ±2×1053±1×106−7.37
2
GAGCGCGCTACGGTATGTGTTGCGTGTGGCG
TAGCGGTGCG 6±1×1057±4×106−8.54
3CAGCGCCCTACGCTATGTCTT
GCGTCTCGCCTAGCGCTCGC 2±2×1057±4×106−7.99
* K : kine ic a e cons an ; Ka : adso p ion a ini y cons an ; ∆G: Gibbs ee ene gy o olding o ap ame s.
3.4. HAp–Nucleic Acid–Me al Complex Hyb ids
Me al ions play a ious oles in nucleic acid chemis y [
287
] and can be ca ego ized
as ollows:
1.
Na u al coun e ions: Common cellula ions like K
+
, Mg
2+
, and Na
+
ac o neu alize
he cha ges o polyanionic nucleic acids.
2.
Folding and s abiliza ion: These a e essen ial o he p ope olding o nucleic acids
and o he s abiliza ion o many RNA s uc u es, as well as o he ca aly ic unc-
ion o ibozymes, main aining DNA s uc u es such as Gua-qua e s in elome es
and in Holliday junc ions, and o he c oss-shape s uc u es o med du ing gene ic
ecombina ion.
3.
Exogenous ions and mimic y: Bo h physiological and non-physiological (exoge-
nous) me al ions can mimic na u al ions, a ec ing nucleic acid s abili y and cha ge
neu aliza ion and po en ially causing DNA condensa ion o mu a ions.
4.
Damage by Reac i e Oxygen Species (ROS): Redox-ac i e me al ions can cause
damage o nucleic acids by b eaking DNA s ands. These ions can be essen ial (e.g.,
Cu
+
, Fe
2+
), bo h in ce ain disease s a es and in he apeu ic and DNA sequencing
applica ions.
5.
Phosphodies e eac ions: Me al ions a e in ol ed in he o ma ion and deg ada-
ion o nucleic acid phosphodies e bonds. They can p o ide he OH
−
nucleophile,
pola ize P-O bonds, o s abilize ansi ion s a es o lea ing g oups.
Nucleobases in he s uc u e o nucleic acids a e ypically uncha ged wi hin he phys-
iological pH ange (4 < pH < 9). Me al coo dina ion, like o he chemical modi ica ions
o nucleobases, al e s hei acid–base p ope ies and causes changes in pK
a
alues. The
binding o me als o nucleic bases has been s udied by se e al au ho s [
322
–
326
]. S udies
by Sigel demons a e ha he p o ons o endocyclic NH g oups become mo e acidic when
a me al ion binds o an a ailable ni ogen a om in he nucleobase ing. This phenomenon
leads o changes in pK
a
alues, which can shi in ei he di ec ion as he me al ion displaces
a p o on om he nucleobase and eloca es i wi hin he he e ocycle, he eby gene a ing
a me al-s abilized a e au ome . Me al–nucleobase bond o ma ion occu s h ough he
Molecules 2024,29, 4479 24 o 39
ollowing con ibu ions: (a) elec os a ic in e ac ion: be ween a me al ion and he nucle-
obase dipole, dominan in he gas phase bu in luenced by sol en pola i y in solu ion o
solid s a es; (b) hyd ogen bond o ma ion: be ween a me al’s coligands and nucleobase,
con ibu ing o he s abili y o he complex; and (c) pola iza ion and cha ge ans e e ec s:
in ol ing elec on edis ibu ion wi hin he me al–nucleobase complex, less in luenced by
sol en s and coun e ions. As expec ed, he subs i u ion o nucleobase p o ons wi h me al
ions inc eases his con ibu ion compa ed o he binding o he me al o an a ailable lone
pai o a ing ni ogen a om o an exocyclic oxygen.
The discussion will ocus on guanine, which has a huge dipole momen and a o able
o ien a ion in he isola ed base, esul ing in high a ini y o me al ions o he N7 posi ion.
In double-helical DNA, he a ini y o me al ions o G-N7 is in luenced by he na u e o
he base a he 5
′
side, hus depending on he molecula elec os a ic po en ial and N7 ac-
cessibili y. Addi ionally, wi hin nucleic acids, he a ini y o me al ions is highe o DNA
G-N7 han o RNA G-N7 [
289
]. Pla ina ed DNA agmen s con i m ha guanine esidues
become mo e acidic a e P coo dina ion a N7 [
327
–
329
]. Con e sely, he dipole momen
and o ien a ion o adenine make i less a o able o me al binding a N7, compounded by
he s e ic hind ance o he exocyclic amino g oup.
As has been indica ed be o e, HAp has been ex ensi ely used in column ch oma og a-
phy, and he li e a u e co e s mul iple examples o his echnical app oach. Howe e , as
a as we a e awa e, he way unc ionalized HAp–nucleic acid hyb ids engage wi h me al
ions and coo dina ion compounds has been in es iga ed li le. In one o he ew ins ances,
Benede i e al. [
302
] ocused hei s udy on he adso p ion o pla ina ed nucleo ide analogs
on o HAp. The adso p ion o hese nucleo ide complexes occu s h ough elec os a ic
in e ac ions be ween he nega i e phospha e g oups and posi i e ions on he su ace o
hyd oxyapa i e c ys als (Figu e 11). Bu he me e p esence o phospha es does no ensu e
he adso p ion o he nucleo ide o HAp. The adso p ion e iciency o hese nucleo ide
de i a i es was ound o be in luenced by he o e all elec ical cha ge o he me al complex.
Pla ina ed compounds wi h a ne nega i e cha ge exhibi ed signi ican chemical adso p ion
on o he HAp su ace, which could be e e sed by acidi ica ion. In con as , complexes
wi h ca ionic o neu al cha ges showed e y low adso p ions.
ffi
ffi
′
ffi
ffi
Figu e 11. S uc u e and in e ac ion o he pla inum complex wi h he apa i e su ace.
On he o he hand, guanosine 5
′
- iphospha e (GTP) was ancho ed o he su ace
o Zn-subs i u ed HAp nanopa icles, and i s ac i i y agains os eosa coma cells (Saos-2)
was e alua ed [
330
]. The unc ionalized nanopa icles induced di e en ia ion in o no mal
os eoblas cells in Saos-2 and p o oked an enhancemen o in acellula GTP con en .
In o he wo k, luminescen HAp nanopa icles con aining Eu
3+
ions we e p epa ed by
amida ion o p e iously inse ed AMP and inal unc ionaliza ion o he nano ods wi h
poly(e hylene glycol) me hac yla e (PEGMA) [331].
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