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ICN2OI4 CtrRTIFICATION
This certification is awarded to Mrs/Mr
Shokoofeh Geranmayeh (with affiliation of the department
of chemistry, AIzaIva University, Tehran, Iran)
[]
for acceptance and fully registration
of the paper with the title of
Investigation the cytotoxicity and release of 5-FU
loaded nanoporous metal-organic framework
and co-authors
of
Ahreza Abbasi, Amir-Hassan Zarnani, Zotueh Mohammadi
tnZnd International Conference on
Nanotechnolo gy (ICN 20 1 4)
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Investigation the cytotoxiciQ and release of 5-FU
loaded nanoporous metal-organic framework
Shokoofeh Gerarulayeh
Department of chemistry
Alzahra University
Tehran, Iran
A\reza Abbasi
Amir-Has san Zarnam, Zohr eh Mohammadi
School of chemistry, college of science
University of Tehran
Tehran, Iran
Abstract-Metal-Organic Frameworks (MOFs)
are
emerging as a powerful platform for delivery and release of
several drug molecules. Herein we report the ultrasonic
preparation of new nano-sized metal-organic framework
(NMOF, l) as drug carrier and the potential cytotoxicity of
I was evaluated on human amniotic epithelial cells (hAECs)
by XTT assay, The results clearly shorved that this
compound exerted little in vitro cytotoxic effcct in a wide
range of concentration and tinre intervals, implying
excellent biocompatibility. Therefore, this matrix can be
regarded as a sal'e carrier for drug delivery systen.rs. We also
report the incorporation of the anti-cancer drug
5-
Fluorouracil (5-FU) into the newly prepared carrier with
high load and progressive release. Adsorption
that 5-FU is incorporated into MOF
22.8204. 5-FU is released in a
progressive fashion rvith 40"/" of the drug release after 12
measurements shorv
with a load content of
hours
Due to this lack of toxicity results of MOFs, herein we
report a nerv crystal structure derived from the zinc- 4,4'biphenyldicarboxylic acid-dimethylformamid system, and
investigate its toxicity and possibility for biomedical
applications. The cytotoxicity of the studied con.rpound
has been evaluated and its possibility of being as a caffler
in drug delivery systems discussed. Furthermore, the drug
loading and delivery
I.
INTRODUCTION
Metal-organic frameworks (MOF0 represent an
incredibly growing class of nanoporous materials and are
the latest class of ordered porous compounds. The drive
behind this rapid development lies on the irnportant
specific structures, properties and
potential
applications.[ 1]
Frnnr tlre svrrtlretin noirrl nf view di .nd tl icarboxylates are one of the most successflil classes of
polytopic ligands in designing MOFs due to the relatively
labile M-O bonds. E,ven though the reactions of nany
transition metals with dicalboxylates have been srudied,
those of Zn-based MOFs have been mainly significant.
Yaghi and co-wolkers have reported a number of
interesting sttuchues based on zinc that show remarkable
methane and hydrogen adsorption properties.[2] Although
industrial applications of this type of MOFs have so far
been well srudied, toxiciff results dealing with MOFs or
coordination polyrners al'e very scarce.[3] In general, the
use ofporous solids for biomedical applications lequiles a
biologicrlly fliendly conrpositiorr.
of the
compound have been
investigated.
II.
MATERIALS AND METHoDS
Most of the reagents were acquired from Merck and
used as received. Dimethyl sulfoxide (DMSO) were
obtained from Sigrna. fronr GIBCO.The solvents were
purified prior to use.
A multi-wave ultrasonic
3200;Bandeline,
Keywords-cotnponett; tlrug tlelivery; nanoparticle; ntetalorgattic frametuork; 5-FU
Nanobiotechnology Research Center,
Avicenna Research Institute (ACECR)
Tehran, Iran
genel'ator (Sonicator
KE 76, Germany),
equipped
with
a
converter/transducer and titanium oscillator (horn), 6 mm
in diameter, operating at 50/60 Hz with a maximum power
output of 200 W, was used for the ultlasonic irradiation.
Scaming electron microscopy (SEM) observations were
performed by Oxfold LEO 1445 V.
Synthesis
of
[Zn3@pdc)a],
1. A mixture of
Zn(NO3)2.6H2O (0.29Ig, lmmol), C12H16Oa Q.2429,
2mmol) in 10 mL of DMF were sealed in Teflonelined
autoclave and heated under autogenous pressure to 120"C
for four days. After the rnixture was cooled to room
temperahre at a rate
of 6'Clh, colorless crystal of
the
compound were collected, washed with ethanol, and dried
at room temperature to give 82.3 % yield based on
Zn(NO3)2.6H2O.
In order to get the nanoparticle of l, the solution
containing crystals of compound, exposed by ultrasonrc
irradiation at diffetent power at roonl temperature for
various time. The white precipitates were cenh'ifuged,
washed with ethanol and dried at 50'C.
Dissolving 5-Fu (25mg) and desoh'ated 1 (25mg) in
methanol (5ml). Then the rnixture rvas centrifuged and the
solid washed with methanol. The 5-FU content
calculated tluough llV/Vis results.
was
15 mg of drug loaded I was dissolved into 5 rnl- of
PBS buffer solr-rtion @H:7.4). During each time interval,
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ca. 200 rnicloliter was pulled out to test. The content of 5-
FU in the sarnples taken out was monitored by
fluorometery in rvhich the detection wavelength was
453run..
III.
RESULTS AND DISCUSSION
X-ray single crystal determination of structure I shows
a neutral 3D metal-organic network which crystallizes rn
the orthorombic system, space group Pna21 [4]. The
structure comprise of two crystallographically
independent Zn(II) atoms forming Trinuclear zinc
carboxylate as SBUs. The distorted Zn(1) center is
coordinated by four oxygen atoms which associate with
four bpdc ligands. the distorted octahedral Zn (2) centers
are coordinated by six oxygen atoms , which associate
with six bpdc (fig 1).
This arrangement forming the 3-dimensional skeleton
with two-dimensional porous system with channels
characterized by dimensions of 5 x 8 A, based on the
Zn...Zn separation (excluding van der Waals radii) (fig.
2). Based on a PLATON [5] analysis (filling of
the
cavities with probe spheres of radius 1.2 A), the fi'ee
volume in the absence of guest molecules was found to be
49.1%.
Fig. 2. 3-dirnensional skeleton with two-dimensional porous system
A better insight into the nature of I can be achieved by
the application of topological approach. The topology is
an 8-connected uninodal hex with the ooint svmbol of
(36.418.53.6). The overall structure of 1 comprises of two
independent interpenetrated networks niaybe due to the
lenghth bpdc linker (fig. 3).
In order to prepale nanoparticles of
1, the top-down
approach was used, and the effect of, concentration, tinre
of exposure and power of ultrasound were investigated. In
order to make it brief the optimurn result which is gain at
72o/o of power and 15 min exposu'e with ultrasound
irradiation is presented and it's SEM inrage depicted in
fig. 4. The PXRD pattern of the obtained nanoparticles is
similar to the as-synthesized and also flom the simulated
single-clystal structures showing no structural
defbrrration in nanoparticle preparation.
Fig. L ORTEP plot ofthe Zn(ll) and bpdc linker
Fig. 3. The two-fold interpenetrated nefwork s'ith hex topology
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As a matter of fact, drug carrier systems should be
biocornpatible with minimal cytotoxicity. In ordel to test
tlre potential in vitro cytotoxic effect ofbpdc, t and ZnO
compounds and with this in mind that most cancer cells
are from epithelial origin, normal epithelial cells were
employed for assessment of their cytotoxicify over normal
cellular compartment. To evaluate the toxicity of bpdc, I
and ZnO courpounds, human amniotic epithelial cells
were treated with different concentrations of these
conrpounds for differ-ent time intervals of 24-72 h. As
depicted in fig. 5, biphenyl dicarboxylic acid and zrnc
oxide exhibited negligible cytotoxicity of under 5o/o over
the all time periods examined.
Impoltantly, MOFs as drug-delivery nanocaniers are
highlydesirable due to their large loading of drugs,
biodegladability and versatile flinctionaliry [6]. Owing to
the accessible porosity and the window size (5 x 8 A) of 1,
it is potentially useful in the encapsulation of small drug
molecules. 5-Fluorouracil (5-FU, 3 * 6 A) is specifically
chosen in the study for its small size, which is widely used
as an anti-cancer chemothelapy drug for the treatment of
colorectal, breast and head and neck cancers [7]. 1 showed
remarkable 5-FU adsorption and the loading content was
Fig. 4. Thc SEM imagc ofthc prcparcd nanoparticlcs.
+
24n
-l-
48h
72n
;e
measured to be 22.82o/o by UV,n/is measurement. The
kinetic process of5-FU delivery in simulated body fluid at
37"C is shown in Fig. 6. Arourrd 40% of the loaded 5-FU
was released during the initial fast release (12 h), and
43.5% within 24 houls (Fig. 6). Compared with other
MOFs calriels, I shows a fast release rate of 5-FU.
bpdc (pM)
+
+
+
24n
48h
45
,
l
40i
72h
c
9,.
s
E:o
0.01 0.1
1
compound
10 100
t (pM)
1001
10
+
+
+
-J
o
1000
*01
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73h
T t0
0510152023
nme (h)
Fig. 6. The release process of5-FU frorr the drug-loaded
t0
0+-
Fig.5. Cytotoxiciry asscssment ol'bpdc.
0 I -------
I
and ZrrO conrpounds
1
ii
,ihtfu
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ACKNowLEDGMENT
Financial suppoft of the project by the Alzahra
University is grateflilly acknowledged.
REFERENCES
tl]
S. Henke, A. Schneemann, A. Wiitscher, R.A. Fischer, "Directing
thc
brcathing bchavior
of
pillarcd-laycred mctal-organic
frameworks via a systematic library of functionalized linkers
bcaring flcxiblc substitucnts", J. Am. Chcrn. Soc. Vol. 134 pp.
9464-9474,20t2.
Lzl
[3]
H. Li, M. Eddaoudi, M. O'Kccffe, O. M. Yaghi, "Dcsign
and
synthesis of an exceptionally stable and highly porous metalorganic framework", Nature. Vol. 402 pp. 276-279,1999.
P. Horcajada, R. Cre{ T. Baati, P. K. Allan, G. Maurin, P.
Couvreur, G. Ferey, R. E. Monis, C. Sere, "Metal-organic
framcworks in biomcdicinc" Chcm. Rcv. vol. 112, pp. 1232-1268,
2012.
t4l
S. A. Sapchcnko, D. N. Dybtsev, D. G. Samsonenko,
V.
P. Fedin,
"Synthesis, crystal structures, luminescent and themal propeI1ies
of two new metal-organic coordination polyners based on zinc
(ll) carboxylates:" New. J. Chem. Vol. 34, pp. 2445-2450,2010
tsl A. L.Spck, "Singlc-crystal
structurc validation"J. Appl.
Crystallogr. Vol. 36, pp. 7-13,2003.
[6) Z.Y. Gu, Y. J. Chcn, J. Q. Jiang and X. P. Yan,
"Metal-organic
frameworks for efficient enrichment ofpeptides with simultaneous
exciusion of proteins from conrplex biological sanrples" Chem.
Comnrun., vol. 47 , pp.4'1 87 -4789,2011.
D, Wyatt and D. M. Wilson, "Participation of DNA repair in
thc rcsponsc to 5-fluorouracil" Ccll. Mol. Lifb Sci., vol. 66, pp.
11) M.
7
88-799,2009.