A drug-loaded nanoscale metal-organic framework with a tumor targeting agent for highly effective hepatoma therapy

Article abstract of DOI:10.1039/c6cc07321b

Drug delivery systems with targeting agents for precise drug release in cancer therapy are very significant and important. Herein, we report the rational design and synthesis of a DOX (doxorubicin) loaded UiO-68-type of nanoscale metal-organic framework (NMOF) with a tumor targeting agent (folic acid, FA), DOX@UiO-68-FA (3), as a multifunctional drug delivery system for hepatoma (Hep G2) therapy via tail-vein injection. Compared to free DOX, FA-unloaded DOX@Mi-UiO-68 (2), 3 exhibits a much higher antitumor efficacy, which was confirmed by cell imaging, standard 3-(4,5-dimethylthiahiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation and in vivo experiments.

Full text of DOI:10.1039/c6cc07321b

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Dong, Y. Li, X.
Zhao, H. Yin, G. Chen and S. Yang, Chem. Commun., 2016, DOI: 10.1039/C6CC07321B.
Volume 52 Number
1
4
January 2016 Pages 1–216
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Chemical Communications
www.rsc.org/chemcomm
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
3
N@C2n (2n
=
68 and 80). Synthesis of the
3
N@D5h-C80
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 5
View Article Online
DOI: 10.1039/C6CC07321B
Journal Name
COMMUNICATION
Drug-loaded nanoscale metal-organic framework with tumor
targeting agent for highly effective hepatoma therapy
Received 00th January 20xx,
Accepted 00th January 20xx
a
a, b
b
a
a
a∗
Yan-An Li, Xiao-Dong Zhao, Hai-Peng Yin, Gong-Jun Chen, Song Yang, Yu-Bin Dong
DOI: 10.1039/x0xx00000x
www.rsc.org/
Drug delivery systems with targeting agents for precise drug
release in cancer therapy is very significant and important. Herein,
we report rational design and synthesis of a DOX (doxorubicin)
loaded UiO-68-type of nanoscale metal-organic framework
(
NMOF) with tumor targeting agent (folic acid, FA), DOX@UiO-68-
FA (3), as a multifunctional drug delivery system for hepatoma
Hep G2) therapy via tail-vein injection. Compared to free DOX,
(
FA-unloaded DOX@Mi-UiO-68 (2), 3 exhibits a much higher
antitumor efficacy, which was confirmed by cell imaging, standard
3
-(4,5)-dimethylthiahiazol-2-yl)-2,5-diphenytetrazolium bromide
(
MTT) proliferation and in vivo experiments.
Nanoscale metal-organic frameworks (NMOFs), as a typical
class of nano-sized porous hybrid material, provided a variety
of attractive potential applications, including adsorption
[1]
/separation, heterogeneous catalysis and sensing.
Due to
their nanoscale particle size, high surface area, large porosity,
and low toxicity, NMOFs have been recently demonstrated to
be the ideal platforms for drug upload and controlled delivery
[2]
in medical application, especially cancer therapy.
It is known that the surface functionality of NMOFs can be Scheme 1. Design and fabrication of FA targeting agent decorated drug delivery
system , and its application in cell imaging and in vivo antitumor therapy.
[3]
3
covalently modified by virtue of post-synthetic approach. In
principle, as drug carriers, NMOFs could be endowed targeting
property towards specific tumor biosignals via purposefully
functional decoration on the organic groups attached to
organic linkers. In this way, targeting functionality, together
with drug loading, delivery and medical treatment properties,
could be logically integrated into a single NMOF platform,
consequently,
a higher efficient chemotherapy would be realized. So far, only
a few examples of NMOF materials for in vivo cancer therapy,
including photodynamic therapy (PDT) and drug delivery
NMOF systems, have been reported. The targeting agent
decorated NMOF drug delivery system, derived from the post-
synthetic covalent modification, for cancer therapy via tail-vein
[4]
injection, to our knowledge, is unprecedented. On the other
hand, the targeting antitumor treatment base on drug delivery
system via vein injection would be more significant potential
for clinical translation.
In this contribution, we report a multifunctional integrated
drug delivery system DOX@UiO-68-FA (3, DOX = doxorubicin,
FA = folic acid) based on a UiO-68-type of NMOF via post-
synthetic covalent modification (Scheme 1). It exhibits high
efficient antitumor efficacy which is confirmed by cell imaging,
MTT proliferation and in vivo experiments on Hep G2
subcutaneous xenograft murine model via tail-vein injection.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
View Article Online
DOI: 10.1039/C6CC07321B
COMMUNICATION
Journal Name
Fig. 2 Left: HR-TEM and SEM images of
measurement of
3. Right: dynamic light scattering (DLS)
3.
narrow size distribution and the size of the NPs are centered at
40 21 nm. Such sized nanoparticles ( 200 nm) definitely
1
±
<
Fig.
Compared to 1, there are no characteristic differences in the intensities in XRPD
peaks of and after Dox loading and FA decoration because of the low
included Dox and FA amount (ESI). Right: normalized solid-state emission spectra
of 1-3. Photographs of 1-3 samples are inserted.
1 Left: XRPD patterns of 1-3 and simulated XRPD pattern of UiO-68.
meet the requirement for tumor chemotherapy. Elemental
analysis demonstrated that the post-synthetic FA decorating
yield is ca. 4.2 mol % (ESI). For further confirmation this post-
2
3
We hypothesized that the UiO-68-based NMOF could be the synthetic thiolated FA decoration, the reaction of the
ideal candidate for this multifunctional NMOF drug delivery esterified maleimide-substituted organic linker
system. First, UiO-68-type MOF is known to be very stable in thiolated FA was examined before the synthesis of
H
2
L
with
3
under the
aqueous media, and it possesses large internal pores (the same reaction conditions (DMF, r.t., 10 min.). The reaction
distance between the opposite oxygen atoms in the larger readily proceeded and the expected thiolated FA decorated
5
) which will facilitate relative
octahedral SBUs pores is 25.6
Å
product was unambiguously confirmed by the MS spectrum
ESI). Compared to (ESI), although no detectable changes
larger sized drug molecule (for example DOX, dimension of
2
(
2
f
15.3 × 211.9
Å
)
loading; second, UiO-type MOFs are low
were observed after FA decoration based on SEM and DLS
measurement, the corresponding Zeta potential changed from
g
toxicity, and their size can be readily scaled down to
6
nanoregime (< 200 nm), which is allowed it to be suitable for
-
15.7(
±
0.9) mV (
2
) to -13.5(
±
0.4) mV (
3
).
were determined by
chemotherapy; third, the surface of UiO-type NMOFs can be
covalently modified via post-synthesis with small molecular
target agent FA, which is a widely recognized targeting agent
The DOX loading amounts in
2
and
3
fluorescence spectroscopy to be 4.84 and 4.79 wt %,
1
respectively (ESI). When accounting for the involved FA (ca.
1
7
for tumor cells.
4.2 mol %) in 3, the DOX content in 2 and 3 are basically the
The preparation of nano-sized DOX@UiO-68-FA (
in Scheme 1. Its precursor of Mi-UiO-68 ( ) was prepared by
heating a DMF solution of the maleimide-attached ligand
and ZrCl at 120 C (ESI). The obtained Mi-UiO-68 MOF ( ) was
3) was shown
same, indicating that no DOX leaching occurred during the FA-
decorated post-synthetic process.
1
2
H L
4
°
1
simply immersed in a DOX hydrochloride aqueous solution (1
mg/mL, 5 mL) at room temperature for 24 h (monitored by
UV-vis spectra, ESI) to generate DOX@Mi-UiO-68 (
image and DLS measurement of indicated that the NPs are
centered at 140 21 nm (ESI). After that, DOX@Mi-UiO-68 (2)
2). SEM
2
±
was decorated by thiolated FA species (DMF, r. t.) via thiol-
8
maleimide Michael-type addition to yield drug delivery
Fig. 3 DOX release profiles from DOX@Mi-UiO-68 (
PBS (pH = 7.4) and deionized aqueous solution (pH = 7.0) at 37
NMOF particles (1 mg) of or were uniformly dispersed in PBS (25 mL) and
ex
deionized water (25 mL) with shaking at 100 rpm. The fluorescent intensity (λ =
2
) and DOX@UiO-68-FA (
3) in
°
C, respectively.
system of DOX@UiO-68-FA (3) with the targeting agent (ESI).
2
3
The XRPD patterns of 1-3 are identical to that of pristine
9
UiO-68, and thus indicated that the structural feature and
4
85 nm, λem = 590 nm) of the DOX solution (1 mL each time) from above systems
was measured at different time.
crystallinity of UiO-68 framework were maintained during the
DOX encapsulation and post-synthetic processes (Fig. 1).
Next, we evaluated the DOX release at 37°C using either a
cell culture fluid (phosphate buffered saline (PBS), 0.1 M at pH
Furthermore,
3 is stable in cell culture fluid, making it suitable
1
2
=
7.4) or deionized water. As indicated in Fig. 3, the total
amount of DOX in and was released in 40-50 and 50-55 h in
both PBS and water media, respectively. So the complete drug
release of and is faster in PBS than in water, which would
for application in cancer therapy (Fig. 1 and ESI). In addition,
1
0
2
3
the encapsulated DOX emission was clearly detected in the
solid state luminescent spectra of and ex = 485,
nm), which further confirmed this DOX encapsulation.
Correspondingly, the colour of changed from off-white to
brown ( ) and red-brown ( ) (Fig. 1).
2
3
(λ
λem = 590
2
3
be helpful for the in vivo anticancer application. In all case,
1
2
3
release rate was fast over a first period of 12 h, and the release
High resolution transmission electron microscopy (HR-TEM) rate went down during the rest time. Compared to
and scanning electron microscope (SEM) showed that the (complete release at ca. 40 h) in PBS, DOX release from
obtained DOX@UiO-68-FA (
distributed (Fig. 2), which is further confirmed by the dynamic resulted from the blocking effect of the surface decorated FA
light scattering (DLS) measurement. As shown in Fig. 2, the
hydrodynamic diameters of the DOX@UiO-68-FA ( ) possess a
2
3
is
3) nanoparticles are uniformly slightly slower (complete release at ca. 50 h), which is logically
species.
For examination of the cellular biocompatibility and
membrane permeability of DOX@Mi-UiO-68 and
3
(2)
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
Please dCo h ne omt Ca do j um s mt margins
View Article Online
DOI: 10.1039/C6CC07321B
Journal Name
COMMUNICATION
-
4
mg/mL) and DOX@Mi-UiO-68 (2, 10 mg/mL). c-d) HL-7702 incubated with
DOX@UiO-68-FA (
3
), cell imaging experiments were carried
-4
-4
DOX@UiO-68-FA (
G2 and HL-7702 respectively incubated with DOX. Incubation was carried out at
C under a humidified atmosphere containing 5 % CO . Scale bars are 25 m in
3, 10 mg/mL) and DOX@Mi-UiO-68 (2, 10 mg/mL). e-f) Hep
out. Human hepatoma cells (Hep G2) and human hepatocyte 37
°
µ
2
all images.
(
HL-7702) were selected and visualized by using a green
channel for NMOFs ( ex = 405 nm) and a red channel for DOX
ex = 485 nm). DOX@UiO-68-FA ( ) and DOX@Mi-UiO-68 (
nanocrystals were respectively incubated with Hep G2 cells for
h, and we notice that the both red ( em = 560 - 610 nm) and
green ( em = 470 - 520 nm) luminescence are located in the
λ
(λ
3
2)
2
λ
λ
cytoplasm, indicating that UiO-68 NMOFs with DOX is able to
pass across the tumor cell membrane. Compared to
Fig. 5 The mean fluorescence intensity (MFI) of HL-7702 and Hep G2 cells treated
by 2, 3 and Dox, respectively (P<0.001). The observation indicates that the
binding of to the Hep G2 cells is much stronger than that of , which is clearly
attributed to the high specific interaction between FA and Hep G2 cells. For
comparison, HL-7702 cells only display very weak fluorescence in both green and
3
2
DOX@UiO-68-FA
luminescence was observed in the case of Hep G2 incubated
with DOX@Mi-UiO-68 ( ) nanocrystals without FA targeting
agent (Fig. 4b), which implies targeting ability of FA species in
is the key factor to affect the cellular uptake and cause this
(
3,
Fig. 4a), however, much fainter
red channels, suggesting a very low nonspecific binding of
2 to the cells. Dox
incubated with both Hep G2 and HL-7702, also no visual detectable red
fluorescence for Dox was observed, indicating Dox has bad penetration ability
through cell membrane.
2
3
distinct difference in emission intensity, which is further well
demonstrated by the flow cytometry analysis. As shown in Fig.
5
, the mean fluorescence intensity (MFI) value in Hep G2 cells
treated with increased ca. 2.6-fold compared to that treated
with . In addition, when and were respectively incubated
3
2
2
3
Fig. 6 MTT experiments for cell viability (P<0.005). Left: control experiment and
incubation of Hep G2 cells with DOX-unloaded 3 for 24 and 48 h. Right: control
with normal liver cells of HL-7702 under the same conditions,
no obvious fluorescence in either green or red channel was
observed (Fig. 4c and 5), demonstrating the targeting agent
experiment and incubation of Hep G2 cells with free DOX,
respectively.
2 and 3 for 48 h,
FA-decorated NMOFs could be selectively enriched in
Hepatocellular carcinoma cells (FR-positive) instead of normal DOX,
In addition, cell viabilities of DOX unloaded framework, free
and was evaluated and the values were determined by
standard 3-(4,5)-dimethylthiahiazol-2-yl)-2,5-
2
3
the
liver cells (FR-negative). This is consistent with the fact that FA
diphenytetrazolium bromide (MTT) proliferation test at 37°C
and 48 h incubation. As shown in Fig. 6, DOX unloaded NMOF
receptors such as FRα, FRβ and FRγ are expressed at higher
levels in many kinds of cancers, including liver cancer, to meet
the FA demand of rapidly dividing cells under low FA
-3
(
10 mg/mL) showed basically no cytotoxicity to Hep G2 cells,
indicating that the inhibition effect of the DOX-unloaded UiO-
8 framework is negligible (viability: 93.8% (24 h), 92.8% (48
h)). In addition, MTT experiments were also performed to test
the cytotoxicity of free DOX, DOX@Mi-UiO-68 ( ) and
DOX@UiO-68-FA ( ) toward Hep G2 cells. Fig. 6 shows that
DOX@UiO-68-FA ( ) exhibits the highest cytotoxicity to tumor
cells among free DOX, DOX@Mi-UiO-68 ( ) and DOX@UiO-68-
7
conditions. On the other hand, when free Dox incubated with
6
both Hep G2 and HL-7702, also no visual detectable red
fluorescence for Dox was observed (Fig. 4), indicating MOF
carrier is significantly important for Dox delivery.
2
3
3
2
-5
FA (
viability treated by free DOX is 85.4 % after 48 h. After
treatment with DOX@Mi-UiO-68 ( ) and DOX@UiO-68-FA (
concentration of 10 mg/mL (equivalent to a
3). At the concentration of 4.84 × 10 mg/mL, the cellular
2
3)
-3
at
a
-5
concentration of DOX of 4.84 × 10 mg/mL) for 48 h, the
viability is 63.5 and 48.9 %, respectively (Fig. 6).
Encouraged by above observation, we performed in vivo
anticancer test. Xenografts were established from cultured
cells to evaluate the in vivo antitumor effect of 3. Human
HepG2 cells were suspended via trypsinization and collected
6
by centrifugation (1500 rpm, 4 min) and approximately 5 × 10
HepG2 cells in Dulbecco's Modified Eagle Medium (DMEM,
1
00 μL) were subcutaneously injected into right of the nude
2
mice. The tumor volume (V) was calculated as V = L × W /2 by
measuring the length (L is the longest diameter) and width (W
is the shortest diameter). The relative tumor volumes were
calculated for each sample as V /V (V was the original tumor
t
0
0
Fig. 4 Overlaid DIC confocal fluorescence image of living Hep G2 and HL-7702
cells. a-b) Hep G2 cells respectively incubated with DOX@UiO-68-FA (3, 10
-
4
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
View Article Online
DOI: 10.1039/C6CC07321B
COMMUNICATION
Journal Name
volume). The treatments were administrated when the tumor release, targeting and medical treatment can be logically
3
volume reach to about 150 mm .
When the tumor volume reached to ca. 150 mm , the approach to access multifunctional cancer treatment system.
tumor-bearing mice were weighed and randomly divided into
We are grateful for financial support from NSFC (Grant Nos.
groups (6 mice each group). The mice were subjected with 21671122, 21475078 and 21271120), 973 Program (Grant Nos.
integrated into NMOF platform, which might be an alternative
3
4
2
013CB933800) and the Taishan scholar’s construction project.
different treatments: PBS (50 μL) only, free DOX, DOX@Mi-
UiO-68 (2)
Notes and references
1
2
(a) M. O’Keeffe, O. M. Yaghi, Chem. Rev., 2012, 112, 675-702.
b) J.-R. Li, J. Sculley, H.-C. Zhou, Chem. Rev., 2012, 112, 869-
(
9
1
2
32. (c) Y. Cui, Y. Yue, G. Qian, B. Chen, Chem. Rev., 2012,
12, 1126-1162. (d) C. Wang, T. Zhang, W. Lin, Chem. Rev.,
012, 112, 1084-1104. (e) M. Yoon, R. Srirambalaji, K. Kim,
Chem. Rev., 2012, 112, 1196-1231.
(a) C. He, D. Liu, W. Lin, Chem. Rev., 2015, 115, 11079–
1
1108. (b) P. Horcajada, R. Gref, T. Baati, P. K. Allan, G.
Maurin, P. Couvreur, G. Férey, R. E. Morris, C. Serre, Chem.
Rev., 2012, 112, 1232–1268. (c) E.-K. Lim, T. Kim, S. Paik, S.
Haam, Y.-M. Huh, K. Lee, Chem. Rev., 2015, 115, 327–394. (d)
Y. Tu, F. Peng, A. Adawy, Y. Men, L. K. E. A. Abdelmohsen, D.
A. Wilson, Chem. Rev., 2016, 116, 2023–2078. (e) J. D. Rocca,
D. Liu, W. Lin, Acc. Chem. Res., 2011, 44, 957-968. (f) P.
Horcajada, T. Chalati, C. Serre, B. Gillet, C. Sebrie, T. Baati, J.
F. Eubank, D. Heurtaux, P. Clayette, C. Kreuz, J.-S. Chang, Y.
K. Hwang, V. Marsaud, P.-N. Bories, L. Cynober, S. Gil, G.
Fig. 7 In vivo anticancer test via tail-vein injection on Hep G2 tumor bearing mice
P<0.05). a) Tumor volume after treatment. b) Corresponding mice weight after
treatment. c) Photographs of mice on day 14. d) Photographs of corresponding
excised tumors of each group after 14 days treatment. The Zr species was
detected by ICP-MS after 48 h of injection, and biodistribution of and in mice
organs after intravenous injection are given in ESI.
(
Férey, P. Couvreur, R. Gref, Nat. Mater., 2010, 9, 172 – 178.
(g) À. Ruyra, A. Yazdi, J. Espin, A. Carné-Sánchez, N. Roher, J.
2
3
Lorenzo, I. Imaz, D. Maspoch, Chem. Eur. J., 2015, 21, 2508-
2518.
and DOX@UiO-68-FA (3) via tail-vein injection every two days
3
4
(a) S. M. Cohen, Chem. Rev., 2012, 112, 970. (b) M. F. Lin, R.
Matsuda, S. Kitagawa, Chem. Mater., 2014, 26, 310. (b) J. D.
intervals with the same dosage of 5 mg DOX/kg body weight.
The tumor size and the body weight of each mouse were
measured every two days intervals during two weeks.
Evans, C. Sumby, C. J. Doonan, Chem. Soc. Rev., 2014, 43
,
5933-5951. (c) V. Valtchev, G. Majano, S. Mintova, J. Pérez-
Ramírez, Chem. Soc. Rev., 2013, 42, 263-290.
(a) K. Lu, C. He, W. Lin, J. Am. Chem. Soc., 2014, 136, 16712–
As shown in Fig. 7, the relative tumor size follows a
sequence of PBS
DOX-loaded with targeting agent of FA exhibited the highest
antitumor efficacy among free DOX, and . Fig. 7a shows that
> free DOX > 2 > 3 group, indicating that
1
7
6715. (b) K. Lu, C. He, W. Lin, J. Am. Chem. Soc., 2015, 137
600–7603. (c) M. Zheng, S. Liu, X. Guan, Z. Xie, ACS Appl.
, 22181-22187. (d) X.-G. Wang, Z.-
Y. Dong, H. Cheng, S.-S. Wan, W.-H. Chen, M.-Z. Zou, J.-W.
Huo, H.-X. Deng, X.-Z. Zhang, Nanoscale, 2015, , 16061-
6070.
,
3
2
3
Mater. Interfaces, 2015, 7
the mice tumor growth treated with PBS and free DOX could
not be suppressed after 14 days, while the HepG2 proliferation
7
1
treated with
the fact that almost no size expansion was detected in 14 days.
In contrast, the tumor growth was significantly depressed by
2 was effectively inhibited which is reflected by
5
6
7
A. Schaate, P. Roy, A. Godt, J. Lippke, F. Waltz, M. Wiebacke,
P. Behrens, Chem. Eur. J. 2011, 17, 6643-6651.
A. Schaate, P. Roy, A. Godt, J. Lippke, F. Waltz, M. Wiebcke,
and P. Behrens, Chem. Eur. J., 2011, 17, 6643-6651.
(a) C. Chen, J. Ke, X. E. Zhou, W. Yi, J. S. Brunzelle, J. Li, E.-L.
Yong, H. E. Xu, K. Melcher, Nature, 2013, 500, 486–489. (b)
D. Peer, J. M. Karp, S. Hong, O. M. Farokhzad, R. Margalit, R.
Langer, Nat. Nanotechnol., 2007, 2, 751-760. (c) M. J. Sailor,
J.-H. Park, Adv. Mater., 2012, 24, 3779-3802. (d)
3
and their size distinctly decreased. The corresponding size
ratio compared to original tumor size is 2.90 (PBS), 2.06 (DOX),
1.14 (2) and 0.38 (3), respectively. As shown in Fig. 7b, the fast
weight growth in PBS and DOX groups could be attributed to
the aggressive tumor growth. The steady and slight body
weight increase in
2
and
3
groups was observed after 14 days
8
9
Y.-A. Li, C.-H. Zhao, N.-X. Zhu, Q.-K. Liu, G.-J. Chen, J.-B. Liu,
X.-D. Zhao, J.-P. Ma, S. Zhang, Y.-B. Dong, Chem. Commun.
treatment, indicating their lower systemic toxicity and higher
antitumor efficacy. Such observation was further supported by
the excised tumors from the sacrificed mice (Fig. 7c and 7d).
In conclusion, we have designed and prepared a target
2
015, 51, 17672-17675.
J. H. Cavka, S. Jakobsen, U. Olsbye, N. Guillou, C. Lamberti, S.
Bordiga, K. P. Lillerud, J. Am. Chem. Soc., 2008, 130, 13850-
13851.
agent bearing NMOF drug delivery system. The DOX loaded 10 D. K. Rana, S. Dhar, A. Sarkar, S. C. Bhattacharya, J. Phys.
Chem. A 2011, 115, 9169–9179.
Mi-UiO-68 NMOF was covalently decorated by the targeting
1
1 Y. Shen, E. Jin, B. Zhang, C. J. Murphy, M. Sui, J. Zhao, J.
Wang, J. Tang, M. Fan, E. V. Kirk, W. J. Murdoch, J. Am.
Chem. Soc. 2010, 132, 4259-4265.
agent FA via thiol-maleimide Michael-type addition into this
multifunctional drug delivery system. The cell imaging, MTT
proliferation and in vivo studies demonstrated that the 12 H. Zheng, Y. Zhang, L. Liu, W. Wan, P. Guo, A. M. Nyström, X.
targeting FA-decorated DOX@UiO-68-FA exhibits the best
therapeutic effect compared to free DOX and FA-undecorated
DOX@Mi-UiO-68. This work demonstrates that drug loading,
Zou, J. Am. Chem. Soc., 2016, 138, 962-968.
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Please dCo h ne omt Ca do j um s mt margins
View Article Online
DOI: 10.1039/C6CC07321B
Journal Name
COMMUNICATION
Drug loading, release, targeting and medical treatment are successfully integrated into a UiO-68-type NMOF platform via post-synthetic covalent modification,
and the obtained DOX@UiO-68-FA can be a highly effective drug system for hepatoma therapy.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins