Subscriber access provided by UNIVERSITY OF CALGARY

Article
Controlled Zn2+-Triggered Drug Release by Preferred Coordination of Open
Active Sites within Functionalization Indium Metal Organic Frameworks
Xi Du, Ruiqing Fan, Liangsheng Qiang, Kai Xing, Haoxin
Ye, Xinya Ran, Yang Song, Ping Wang, and Yulin Yang
ACS Appl. Mater. Interfaces, Just Accepted Manuscript DOI: 10.1021/acsami.7b09227 Publication Date (Web): 04 Aug 2017
Downloaded from http://pubs.acs.org on August 7, 2017

Just Accepted

Just Accepted manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides Just Accepted as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. Just Accepted manuscripts
appear in full in PDF format accompanied by an HTML abstract. Just Accepted manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI). Just Accepted is an optional service offered
to authors. Therefore, the Just Accepted Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the Just
Accepted Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these Just Accepted manuscripts.

ACS Applied Materials & Interfaces is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.
Page 1 of 26 ACS Applied Materials & Interfaces

1
2
3
4
5
Controlled Zn2+-Triggered Drug Release by Preferred
6
7 Coordination of Open Active Sites within Functionalization
8
9
10 Indium Metal Organic Frameworks
11
12
13
14
Xi Du, Ruiqing Fan,*, Liangsheng Qiang, Kai Xing, Haoxin Ye, Xinya Ran, Yang
15 Song, Ping Wang, and Yulin Yang*,
16
17
18
19
20
21 MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion
22 and Storage, School of Chemistry and Chemical Engineering, Harbin Institute of
23
24 Technology, Harbin 150001, P. R. China
25
26
27
28
29
30
31 * Corresponding Author: Ruiqing Fan and Yulin Yang
32
33 E-mail: fanruiqing@hit.edu.cn and ylyang@hit.edu.cn
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 2 of 26

1
2
3
4 ABSTRACT: Drug delivery in target regions could make extraordinary progress in
5
6 chemo-selective therapies. A novel preferred coordination (PC) strategy referring to
7
8 proactive interacting with open active sites to replace previous occupation by
9
10 ion-exchange for controlling release of drug molecules is well constructed. Two
11
12 topological types of MOF-In1 (Schlfli symbol: (4,8)-connected of (41061583)(456)2)
13
14 and MOF-In2 (Schlfli symbol: (4,4)-connected of (66)) show the specific way.
15
16 Increasing node connectivity as well as the trapping of guest OH anions,
17
18 5-fluorouracil (5-FU) is preferentially captured into the MOF-In1, which exhibits an
19
19
20 outstanding loading capacity around 34.32 wt%. F NMR spectroscopy was further
21
22 employed to investigate host-guest interaction and reveal the binding constant (Ka =
23
24 3.84 102 M1). Meanwhile, the controlled release of 5-FU in a simulated human
25
26 body with liquid phosphate-buffered saline solution by bio-friendly Zn2+-triggered is
27
28 realized. With an elevated Zn2+ concentration, the drug release will be enhanced. This
29
30 efficient strategy for MOFs as multifunctional drug carrier opens a new avenue for
31
32 biological and medical applications.
33
34 KEYWORDS: preferred coordination strategy, open active sites, host-guest
35
36 interaction, nano-MOFs, Zn2+-triggered drug release
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

ACS Paragon Plus Environment

Page 3 of 26 ACS Applied Materials & Interfaces

1
2
3
4 INTRODUCTION
5
6 In order to achieve ideal therapeutic effect, traditional small molecule drugs are
7
8 usually at a high concentration in the circulation of the blood stream and subsequently
9
10 reach a desired final concentration for the target tissue. This practice inevitably brings
11
12 about some defects, including poor solubility and nonselective drug distribution,
13
14 which may damage the healthy tissues and limit the therapeutic effect. Recently in the
15
16 drug delivery field, some chemists are devoted to overcome these negative effects.1-5
17
18 Generally, to ensure the efficient therapy, the drug carriers are required not only to
19
20 capture drugs with high payloads, but also are hoped to be in nanoscale, which
21
22 facilitate the release of drugs to the whole body and absorbed by the specific tissues
23
24 by intravenous administration. Different from most of the existing pure organic and
25
26 inorganic carrier materials, metal organic frameworks (MOFs) as novel porous
27
28 functionality materials6-9 possess the well-defined pore structure and the open active
29
30 sites, which are conducive to bind or transport specific guests within the
31
32 frameworks.10-14 Thus, it is possible to improve drug solubility issues by choosing
33
34 appropriate nano-MOFs as drug carrier to ensure a targeted delivery.
35
36 In addition to ensuring above therapeutically level requirements, achieving
37
38 sustained release is an important prerequisite for efficient nanoparticulate drug
39
40 carriers employed to improve drug efficacy and safety.15-16 Inspired by host-guest
41
42 interaction,17-21 anionic nano-MOFs can selectively trap cations through ion exchange
43
44 to achieve a controlled drug delivery. Zinc as one of essential trace elements in human
45
46 body, plays ubiquitous biological role. Compared with other organs, the zinc
47
48 content is the highest in brain. In brain extracellular fluid, zinc concentration is about
49
50 500 nM. In some named zinc-containing neurons, zinc concentration might exceed
51
52 1 mM through weak coordination interaction with endogenous ligand.22 Thus, zinc
53
54 displays a strong influence on central nervous system23 and zinc imbalance may lead
55
56 to autism spectrum disorders, Parkinsons disease, epilepsy, schizophrenia and
57
58 amyotrophic lateral sclerosis.24-28 The increased Zn2+ concentration in these diseases
59
60 offers a new avenue for drug delivery to target regions and reduces the limitation for

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 4 of 26

1
2
3
4 treatment central nervous system disease.
5
6 Herein, a novel preferred coordination (PC) strategy referring to proactive
7
8 interacting with open active sites to replace previous occupation by ion-exchange for
9
10 controlling release of drug molecules is constructed. Two topological types of
11
12 MOF-In1 ({H[In3(TPO)2(OH)4]2H2O}n) and MOF-In2 ([In(TPO)]n) are selected
13
14 to specify the implementation effect of the PC strategy (Scheme 1). MOF-In1 is built
15
16 on 8-connected [In3(CO2)6(OH)4] SBUs to form two kinds of 1D square channels with
17
18 windows size of about 12.5038.546 and 8.6016.121 2, respectively, which
19
20 displays a (4,8)-connected topology network with the Schlfli symbol of
21
22 (41061583)(456)2. While MOF-In2 possesses 4-connected [InO(CO2)3] SBUs and
23
24 integrates in a SBUs-by-SBUs way through bridging
25
26 tris-(para-carboxylphenyl)phosphine oxide (H3TPO) ligands, generating a 2-fold
27
28 interpenetrating (4,4)-connected diamond-like topology structure with the Schlfli
29
30 symbol of (66). The first type (MOF-In1) consists of 8-connected SBUs and open
31
32 active site is occupied by OH anion, making entire host framework is negatively
33
34 charged. In the second type (MOF-In2), carboxylate TPO3 ligand provides all
35
36 4-coordination sites in a regular mode to interact with metal source and the resulting
37
38 structure exhibits the dia net as a neutral framework.
39
40 As a result of the node connectivity increasing from (4,4)-connected to
41
42 (4,8)-connected, as well as the trapping of guest OH anions, the framework contains
43
44 different pore sizes with the overall charge negative or neutral, which could
45
46
encapsulate or remove guest molecules based on the shape and charge.29-31 Driven by
47
48
49
the above mentioned host-guest interaction, 5-fluorouracil (5-FU) as one of the
50
51 broad-spectrum drug molecule is preferentially captured into the MOF-In1 (loading
52
53 capacity around 34.32 wt%) as a novel drug delivery system in comparison to the
54
55 MOF-In2. 19F NMR spectroscopy was employed to investigate host-guest interaction
56
57 and reveal the binding constant (Ka = 3.84 102 M1). Meanwhile, MOF-In1
58
59 exhibited outstanding behavior for the controlled release of 5-FU in a simulated
60
human body with liquid phosphate-buffered saline solution by appropriate

ACS Paragon Plus Environment

Page 5 of 26 ACS Applied Materials & Interfaces

1
2
3
Zn2+-triggered. This method provides a platform to deliver the sufficient quantities of
4
5
6
drugs to a target region accurately (Scheme 2).
7
8
9
10
11
12
13
14
15
16
17 [In3O2(CO2)6(OH)4] H3TPO [InO(CO2)3]
18
19
20
21
22
23
24
25
26
27
28 8-c node 4-c node 4-c node 4-c node
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46 (4,8)-connected topology (4,4)-connected topology
47 MOF-In1 MOF-In2
48
49 Scheme 1. Syntheses route of MOF-In1 and MOF-In2
50
51
52
53
54
55
56 5-Fu Zn2+
57
58
59 MOF-In1 5-Fu@MOF-In1 Zn2+@MOF-In1
60
Scheme 2. Preferred coordination strategy for creating 5-FU@MOF-In1 and Zn2+@MOF-In1

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 6 of 26

1
2
3
4 RESULTS AND DISCUSSION
5
6
7
Structural Description of MOF-In1. The structure of MOF-In1 is determined by
8
9
single crystal crystallography and displays a 3D porous framework. It is crystallized
10
11 in the Monoclinic C 2/c space group and its asymmetric unit contains one and a half
12
13 In(III) ions, one TPO3 anion, two OH anions, a half H3O+ guest cation and a half
14
15 neutral H2O guest molecule (Table 1). After symmetry operation, each 6-coordinated
16
17 In(III) cation is coordinated with four independent TPO3 ligands and two OH anions
18
19 in a octahedron coordination geometry to form a 8-connected [In3(CO2)6(OH)4]
20
21 secondary building unit (SBU) (Figure S1). For the C3-symmetric TPO3 ligands, two
22
23 carboxylate groups are coordinated in the chelating mode to link two [In3(CO2)6(OH)4]
24
25 SBUs, one remaining carboxylate group and the oxygen atom (O1) from P=O bond
26
27 are connected to the other two [In3(CO2)6(OH)4] SBUs in monodentate coordination
28
29 mode, in which all the observed bond lengths of InO range from 2.076(4) to 2.183(4)
30
31 shown in Table S1.32-34 In this way, the ligands could be deemed to 4-connected
32
33 nodes with quadrilateral geometry. As a result, the structure of MOF-In1 displays a
34
35 (4,8)-connected topology network with the Schlfli symbol of (41061583)(456)2
36
37 (Figure 1b).
38
39 In this 3D structure, MOF-In1 exhibits two types of 1D square channels divided by
40
41 these [In3(CO2)6(OH)4] SBUs via alternating the organic linker molecules rotational
42
43 orientation along the b axis. As depicted in Figure 1a, two types of 1D channels adopt
44
45 the ABAB connection mode, with the compositions of four [In3(CO2)6(OH)4] SBUs
46
47 (A) and two [In3(CO2)6(OH)4] SBUs (B). Under careful observation, there exist open
48
49 Lewis basic oxygen active sites in the Type A channel, H3O+ and H2O guest molecules
50
51 in the Type B channel, respectively. Calculated using the PLATON program35-37
52
53 shows the overall solvent-accessible volume equal to 2240.6 3 per unit cell, which
54
55 accounts for about 37.4% of the cell volume of 5991.0 3 (Figure 1c).
56
57
58
59
60

ACS Paragon Plus Environment

Page 7 of 26 ACS Applied Materials & Interfaces

1
2
3
4 Type A Type B
5 (a)
6
7
8
9
10
11
12
13
14
15
16
17
18
19 (b) (c)
20
21
22
23
24
25
26
27
28
29
30
31
32
33 Figure 1. MOF-In1 showing (a) 3D framework containing two types of channels (left: Type A
34 and right: Type B); (b) 3D topology structure; (c) natural tiling structure.
35
36 Structural Description of MOF-In2. The study reveals MOF-In2 is crystallized
37
38 in the Hexagonal R3 space group and features [InO(CO2)3] SBUs based 3D
39
40 diamond-like framework. In its asymmetric unit, there is one In(III) ion and one
41
42 TPO3 anion. Metal In(III) ion adopts typical 7-coordinated geometry by six oxygen
43
44 atoms (chelating coordination mode) from three carboxylate groups of three
45
46 individual TPO3 ligands (Figure S2), as well as one oxygen atom (monodentate
47
48 coordination mode) from the P=O of the fourth TPO3 ligand to give 4-conneceted
49
50 mononuclear [InO(CO2)3] SBUs, in which the observed InO bond lengths are
51
52 comparable with those reported.38-40 After symmetry operation, the ligands joint four
53
54 [InO(CO2)3] SBUs in four directions and are equal 4-connected nodes. The overall
55
56 structure of MOF-In2, integrated in a SBUs-by-SBUs way through these bridging
57
58 TPO3 ligands, generates a well-constructed 3D 2-fold interpenetrating diamond-like
59
60 topology structure with the Schlfli symbol of (66) (Figure 2). Usually
interpenetrating structure minimizes pore sizes and restricts porosity. The PLATON
7

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 8 of 26

1
2
3
4 calculation shows the overall solvent-accessible volume equal to 296.0 3 per unit
5
6 cell, which accounts for about 17.9% of the cell volume of 1654.2 3.
7
8 (b)
9
(a)
10
11
12
13
14
15
16
17
18
19
20 (c) (d)
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36 Figure 2. MOF-In2 showing (a) [InO(CO2)3] hexagonal cage; (b) 2D layer; (c) 3D framework; (d)
37 3D 2-fold interpenetrating diamond-like topology structure.
38
39 Table 1 Crystal data and structure refinement for the two MOFs.
40 Identification code MOF-In1 MOF-In2
41
42 Empirical formula C42H33O20P2In3 C21H12O7PIn
43 Formula weight 1264.08 522.10
44
45 Crystal system Monoclinic Hexagonal
46
Space group C 2/c R3
47
48 a()
49 28.825(6) 14.1755(8)
50 b()
51 11.472(2) 14.1755(8)
52 c()
53 18.905(4) 9.5058(11)
54 ()
55 90.00 90.00
56 ()
57 106.62(3) 90.00
58 ()
59 90.00 120.00
3
60 Volume( ) 5991(2) 1654.2(2)

ACS Paragon Plus Environment

Page 9 of 26 ACS Applied Materials & Interfaces

1
2
3
Z 4 3
4
5 Dc/(g cm-3) 1.402 1.572
6 -1
7
(Mo K)/mm 1.260 1.182
8 F(000) 2488 774
9
10 Crystal size/mm 0.28 0.26 0.24 0.30 0.24 0.23
11 range () 1.47 to 27.52 2.71 to 27.52
12
13 Limiting indices -36<=h<=37 -18<=h<=12
14
-14<=k<=14 -18<=k<=18
15
16 -23<=l<=23 -11<=l<=10
17
Data/restraints/parameters 6603 / 6 / 305 1579 / 1 / 91
18
19 Goodness-of-fit on F2 1.072 1.004
20
21 Final R indices [I > 2(I)]
22
23 R1a
0.0526 0.0199
24 b
25 wR2
0.1798 0.0428
26
27 R indices (all data)
28
29 R1
0.0647 0.0199
30
31 wR2
0.1944 0.0428
32 3
33 Largest diff. peak and hole(e )
2.835 and -1.248 0.417 and -0.252
34
35 CCDC 1554083 1554084
36
37
[a]
R1 = ||Fo| |Fc||/|Fo|; [b]wR2 = [[w (Fo2 Fc2)2]/[ w (Fo2)2]]1/2.
38
39 Drug Delivery. Given the channel size and the accessible porosity, MOF-In1 and
40
41 MOF-In2 are potential candidates in encapsulation of small drug molecules.
42
43 5-Fluorouracil (5-FU, 5.3 5.0 2) is a widely-used drug molecule and selected as a
44
45 drug model in this drug delivery study.41-43 The drug-delivery capacity of the two
46
47 MOFs was evaluated by impregnating desolvated MOF-In1 and MOF-In2 (20mg)
48
49 respectively, in 5 mL methanol solution containing 5-FU (30 mg) with stirring, and
50
51 investigated the encapsulation of 5-FU into them by UV-vis spectroscopy. As shown
52
53 in Figure 3a, the entry of 5-FU into the framework of MOF-In1 leads to the decrease
54
55 of adsorption intensity obviously.44 However, MOF-In2 did not show obviously 5-FU
56
57 adsorption properties. The encapsulation of 5-FU drug molecule into the framework
58
59 of MOF-In1 is verified by IR spectra (Figure 3b) via the v(CH) at 3133 cm-1 and the
60
OCO group vibrational band between 1684 and 1377 cm-1. In addition, the

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 10 of 26

1
2
3
4 fluorine atom on the ring absorption band is about at 1247 cm-1.45 The shift of
5
6 carboxylic group v(C=O) vibrational band of drug molecule from 1667 cm-1 to 1684
7
8 cm-1 related to the v(OH) vibrational band of MOF-In1 from 3195 to 3130 cm-1,
9
10 resulted from the influence of host-guest interaction between 5-FU and MOF-In1.
11
12 (a) 1.0 (b)
13 5-Fu@MOF-In1
14 5-Fu MOF-In1

15 0.8

Transittance/%
Absorbance

16
17 0.6
18
19 0.4
20
21 0.2
22
23 0.0
24 250 300 350 400 450 4000 3500 3000 2500 2000 1500 1000 500
25 Wavelength/nm Wavenumbers/cm-1
26 Figure 3. (a) UV-vis spectroscopy of MOF-In1 (black) and 5-FU@MOF-In1 (red). (b) Infrared
27
28 spectroscopy of 5-FU, MOF-In1 and 5-FU@MOF-In1.
29 A common strategy to achieve effective drug delivery is to scale down
30
31 drug-carrying material to the nanometer size.46-47 As shown in Figure 4a, the
32
33 nanocrystalline MOF-In1 was prepared by a reflux method at low temperature and
34
35 characterized by the scanning electron microscope (SEM). The PXRD reflection of
36
37 the obtained nanocrystalline MOF-In1 corresponds well with the simulated pattern,
38
39 readily indexing high crystallinity of the obtained MOF-In1 nanomaterial (Figure S3).
40
41 Due to the open OH sites in the channel of MOF-In1 nanocrystalline and its small
42
43 particle size about 190 nm, the MOF-In1 is preferred as drug carrier by conjugation
44
45 with the targeted agent 5-FU to form nanocomposite 5-FU@MOF-In1 (Figure 4b).
46
47 Further evidence for the uniformly distribution of In and F components in the
48
49 5-FU@MOF-In1 is identified by the elemental mapping. As shown in Figure 4c and
50
51 d, the elemental mapping images of In and F clearly demonstrate the
52
53 5-FU@MOF-In1 nanoparticles are homogeneous distribution in the 3D framework.
54
55 The diameters are calculated to be 256 nm for MOF-In1 and 295 nm for
56
57 5-FU@MOF-In1 (in methanol solution) by dynamic light scattering (DLS) (Figure
58
59 S4), which shows the particle size became larger after encapsulation 5-FU drug
60
molecules. The particle diameters of MOF-In1 and 5-FU@MOF-In1 are also larger
10

ACS Paragon Plus Environment

Page 11 of 26 ACS Applied Materials & Interfaces

1
2
3
4 than that measured by SEM. This phenomenon can ascribe to the exact real diameter
5
6 are replaced by the hydration diameter. Meanwhile, the zeta potentials of MOF-In1
7
8 and 5-FU@MOF-In1 are measured to be ca. -30.6 and -21.2 mV, respectively (Table
9
10 S2), which indicate that MOF-In1 is capable of encapsulation 5-FU and
11
12 5-FU@MOF-In1 can maintain certain stability. The loading procedure followed the
13
14 literature to immerse the nanoparticles in a methanol solution of 5-FU for one day.
15
16 The structure of MOF-In1 possesses two pores and the pore diameters are
17
18 approximately 0.776 and 1.147 nm, respectively (Figure S5). After encapsulation
19
20 5-FU molecules, 5-FU@MOF-In1 shows the two pore diameters are 0.498 and 0.848
21
22 nm, which are smaller than that of MOF-In1. The smaller pore volume can be
23
24 attributed to the aggregation of 5-FU molecules in the framework of MOF-In1. The
25
26 loading amount was determined by thermogravimetric analysis (TGA) and the result
27
28 showed 34.32 wt% 5-FU uptake, which corresponds to 5 molecules of 5-FU per
29
30 formula unit of MOF-In1 (Figure S6).
31
32 (a) (b)
33
34
35
36
37
38
39
40
41
42
100 nm 100 nm
43
44
45 (c) (d)
46
47
48
49
50
51
52
53
54
55
56 In
57
F
58 Figure 4. SEM images for (a) MOF-In1 and (b) 5-FU@MOF-In1; Corresponding to the
59
60 elemental mapping image of 5-FU@MOF-In1 for (c) the indium element and (d) the fluorine
element.

11

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 12 of 26

1
2
3
4 Binding Behavior. The binding stoichiometry between 5-FU and MOF-In1 was
5 19
6 further determined through Jobs method, by using F NMR at 243 K because the
7 19
8 variation of the guest chemical shift in F NMR spectra is more distinct than in 1H
9
10 NMR spectra. As listed in Table S3, the resonance of the F atom shifted upfield as the
11
12 molar fraction of MOF-In1 increased (Figure 5a). A maximum of 0.832 was obtained
13
14 in the Jobs curve, indicating a complexation stoichiometry of 1:5 (Figure 5b), in
15
16 agreement with the above-mentioned 5-FU@MOF-In1 stoichiometry obtained from
17
19
18 the TGA result. Based on the F NMR results, the coefficient value (n) and binding
19
20 constant (Ka) were estimated by using the Hill equation:48
21
22 [ HGn ]
23
24
[ HGn ] [ H ]
25
26 [G ]n
27 n
1
28 [G ]
n

29 Ka
30
31

32 l o g n l o gG[ ] n l o gK a
33 1
34
35 In the hill equation, the value of 1- can be obtained with divide observed by the
36
37 maximum change of chemical shift in 19F NMR spectra. The coefficient value (n)
38
39 of MOF-In1 indicates that the guest molecules are independent binding. Derived
40
41 from the Hill function plot of the 5-FU@MOF-In1 system (Figure 5c), a Hill
42
43 coefficient (n) of 2.74 indicates a strongly positive cooperative binding mode between
44
45 5-FU and MOF-In1. The measured apparent association constant Ka is 3.84102 M-1.
46
47 In striking contrast, similar titrations of 5-FU into the solution of MOF-In2 showed
48
49 no chemical shift of F signals in the 19
F NMR spectra. The finding suggests that the
50
51 structure of MOF-In2 is not suitable to capture 5-FU molecules. The window of
52
53 MOF-In2 is approximately 16.59816.598 2 in diagonal line, which is larger than
54
55 those two windows of MOF-In1 (12.5038.546 and 8.6016.121 2) and results in
56
57 less steric hindrance of the guest molecule 5-FU. Moreover, the structure of
58
59 MOF-In2 is 2-fold interpenetrating, which minimizes pore sizes and restricts porosity.
60
Therefore, the observed binding between 5-FU and MOF-In1 underlines that the size
12

ACS Paragon Plus Environment

Page 13 of 26 ACS Applied Materials & Interfaces

1
2
3
4 selectivity may be dependent on the channel window.
5
6 (a) (b)
7 0.30
8
=0.168 0.25
9

5-Fu/ppm
5-Fu

10 =0.292 0.20
5-Fu
11 =0.416 0.15
5-Fu
12 =0.542 0.10
5-Fu
13 0.05
=0.668
14 5-Fu
0.00
=0.792
15 5-Fu
0.0 0.2 0.4 0.6 0.8 1.0
16 =0.832 5-Fu
17
5-Fu
(c)
=0.876
18 5-Fu -0.4 y=2.74x-7.08
=0.916
19 5-Fu -0.6 R2=0.99
20

log [/(1)]
=0.960
5-Fu -0.8
21 =1.000 -1.0
5-Fu
22
-1.2
23 -172.1 -172.2 -172.3 -172.4 -172.5 -172.6 -172.7 -172.8
24
/ppm
-1.4

25 -1.6
-3.1 -3.0 -2.9 -2.8 -2.7
26 log[5-Fu]
27
28 Figure 5. (a) The chemical shift change of 5-FU in 19F NMR spectra (CD3OD, 243K) of
29
30 5-FU@MOF-In1 with different molar fraction of 5-FU (5-FU). (b) Job plot between MOF-In1
31 and 5-FU in CD3OD at 243 K showing a maximum at 0.832. (c) The hill function plot of
32 log[(1-)/] vs log[5-FU].
33
34 Drug Release. The drug sustained-release experiment was performed at 37 C by
35
36 dialyzing the drug-loaded 5-FU@MOF-In1 against simulated human body liquids
37
38 (phosphate buffered saline pH = 7.4) and monitored via luminescence spectra.49 As
39
40 shown in Figure 6, the luminescence intensity (412 nm) of the 5-FU@MOF-In1
41
42 increases obviously with the number of 5-FU release increasing, which shows fast
43
44 release (within initial 8 h) and has been released 56.8% after 72 h. Study on the
45
46 release process, it has a great relationship with the position of the 5-FU molecules in
47
48 the channels of MOF-In1. The two 1D channels of MOF-In1 comprising open OH
49
50 site, are larger than 5-FU molecule size, which offers favorable advantage to
51
52 encapsulate a large number of 5-FU molecules. Thus, there exist two kinds of
53
54 interactions for 5-FU molecules in the structure of MOF-In1.50-53 One force is
55
56 primarily dominated by 5-FU5-FU intermolecular interactions according to 5-FU
57
58 molecules away from the pore walls, which leads to the fast release of the 5-FU in
59
60 initial 8 h. However, the other force is the hydrogen bonds and stacking due to
the host-guest interactions between 5-FU molecules and the framework of MOF-In1,
13

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 14 of 26

1
2
3
4 which results in the slow release in the second process. Note that the release rate of
5
6 5-FU in this system is relative low. After the release of 5-FU molecules, the pore
7
8 diameters are 0.753 and 0.992 nm, which are larger than that of 5-FU@MOF-In1 but
9
10 smaller than that of MOF-In1. The measurement results demonstrate the release of
11
12 5-FU molecules is incomplete. In addition, the structure of MOF-In1 could still
13
14 remain the integrity of framework after the release of 5-FU molecules.
15
16 (a) (b)
17 60000
1
4
2
5
3
6
60
18 7
10
8
11
9
12
19 50000 13 14 15 50
16 17 18
20
Intensity/a.u.

24 36 48

Released/%
40000 60 66 72 40
21
22 30000 30
23
24 20000 20

25 10000 10
26
27 0 0
360 390 420 450 480 510 540 0 10 20 30 40 50 60 70 80
28
29 Wavelength/nm Time/hour
30 Figure 6. (a) Luminescence spectra of 5-FU releasing from 5-FU@MOF-In1 in PBS (pH 7.4)
31
32 with time; (b) Release process of 5-FU from the 5-FU@MOF-In1.
33 Zn2+ Cations Exchanging with MOF-In1. Based on anionic MOFs usually
34
35 comprising of neutral ligand and metal ion, extra-framework cations are often located
36
37 at the framework pore or infirmly coordinated with host framework through open
38
39 active sites.54 Exchanging cations inside the framework with other cations might
40
41 result in the structure and property change. As expected, Zn2+ ions have been
42
43 introduced into the 1D channels of anionic MOF-In1 by soaking the samples in
44
45 methanol solution of nitrate salts of Zn2+ to obtain anion-exchanged material
46
47 Zn2+@MOF-In1. It was found that the luminescence spectrum changed little after the
48
49 zinc salt treatment (Figure 7a), demonstrating that Zn(NO3)3 has no effect on the
50
51 luminescent emission of MOF-In1.55 Consideration MOF-In1 containing open
52
53 oxygen active site, the X-ray photoelectron spectroscopy (XPS) studies of O 1s were
54
55 performed on MOF-In1 and Zn2+@MOF-In1 to further illustrate the exchange
56
57 behavior. The O 1s peak from free oxygen atoms at 531.35 eV in MOF-In1 is moved
58
59 to 532.16 after anion-exchange with Zn2+ ions (Figure 7b), indicating the formation of
60
the weak bond between oxygen atoms and Zn2+ ions in Zn2+@MOF-In1, which
14

ACS Paragon Plus Environment

Page 15 of 26 ACS Applied Materials & Interfaces

1
2
3
4 results in the change of the electron energy level of ligand and the energy transfer
5
6 occurs between MOF-In1 and Zn2+ ions. The intensities of the IR curves (Figure 7c)
7
8 for Zn2+@MOF-In1 at some peaks are relatively weaker than those of MOF-In1,
9
10 which are also primarily due to Zn2+ combination. The inductively coupled plasma
11
12 (ICP) data of MOF-In1 and Zn2+@MOF-In1 are listed in Table S4 and show that Zn
13
14 contents in Zn2+@MOF-In1 are 16.02%. In addition, In3+ contents in MOF-In1 and
15
16 Zn2+@MOF-In1 are 27.25% and 23.61%, respectively. These results indicate that the
17
18 Zn2+ ions are successfully combined to the framework of MOF-In1. Meanwhile, the
19
20 PXRD pattern of the Zn2+@MOF-In1 is similar to MOF-In1 (Figure 7d), which
21
22 indicate the main frameworks of MOF-In1 are maintained.
23
24 (a) 80000 (b)
25 70000 Zn2+@MOF-In1 Zn2+@MOF-In1
MOF-In1 MOF-In1
26 60000
27
Intensity/a.u.
Intensity/a.u.

50000
28
29 40000
30 30000
31
20000
32
33 10000
34 0
35 350 400 450 500 550 528 530 532 534 536
36 Wavelength/nm Binding Energy/eV
37 (c) (d)
Zn2+@MOF-In1 Zn2+@MOF-In1
38 MOF-In1 MOF-In1
39
Transittance/%

40
41
42
43
44
45
46
47
48 4000 3500 3000 2500 2000 1500 1000 500 10 20 30 40 50
49 Wavenumbers/cm-1 2-thete/degrees
50 Figure 7. MOF-In1 and Zn2+@MOF-In1 of (a) Luminescence emission spectra; (b) X-ray
51
52 photoelectron spectroscopy of O 1s; (c) Infrared spectra; (d) PXRD patterns.
53 Zn2+ Stimuli-Triggered Drug Release. Inspired by Zn2+ cations exchanging with
54
55 MOF-In1, we imagine over-expressed Zn2+ ions might serve as competitive binding
56
57 sites to modulate release rate of 5-FU from 5-FU@MOF-In1. Thus, we have
58
59 immersed 5-FU@MOF-In1 in phosphate buffered saline of Zn(NO3)3 containing
60
varied Zn2+ concentrations, ranging from 500 nM, 1 mM, 5 mM to 10 mM. The
15

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 16 of 26

1
2
3
4 Zn2+-triggered drug release was monitored and the release curves of
5
6 5-FU@MOF-In1 are presented in Figure 8. When the concentration of Zn2+ is 500
7
8 nM in phosphate buffered saline, 65% of 5-FU molecules are released, demonstrating
9
10 that Zn2+ can trigger the system of 5-FU molecules release. Meanwhile, the more
11
12 amounts of 5-FU molecules are released from 5-FU@MOF-In1 when Zn2+
13
14 concentration are increased.
15
16 (a) (b)
17 100
18 100
90
19 90
80
20 80
70 70
21
60 60
22
Release/%

23 50 50
10 mM Zn2+ 40
24 40
5 mM Zn2+
25 30 30
1 mM Zn2+
26 20 500 nM Zn2+ 20
27 0 mM Zn2+ 10
10
28 0
0 0 mM 500 nM 1 mM 5 mM 10 mM
29 0 10 20 30 40 50 60 70 80 90
30 Time/hour Zn2+ concentrations
31
32 Figure 8. (a) Release processes of 5-FU@MOF-In1 operated by competitive binding with varied
33 Zn2+ concentrations with time at 37; (b) Comparison of release rate in different Zn2+
34 concentrations.
35
36 As we known, zinc possesses a strong influence on central nervous system. Thus
37
38 this novel strategy could offer significant perspectives for treating central nervous
39
40 system diseases: Firstly, due to existing higher Zn2+ concentrations in the brain, the
41
42 drug molecules from drug carriers could be delivered to the target regions. Secondly,
43
44 the bio-friendly drug carriers could not only delivery the effectual medicines but also
45
46 diminish side effect. Thirdly, based on the different Zn2+ concentrations in patients,
47
48 the drug release could be fine-tuned.
49
50 In addition, external heating as another stimuli-responsive is selected to investigate
51
52 the release process of 5-FU from 5-FU@MOF-In1. Upon increasing temperature, the
53
54 host-guest interactions between 5-FU and MOF-In1 are weakened,56 the released
55
56 amount of 5-FU molecules are gradually enhanced, shown in Figure S7. This system
57
58 displays fast and high release at 37 C in the initial 3 h. Furthermore, the release rates
59
60 of 5-FU@MOF-In1 by competitive binding with varied Zn2+ concentrations at 40
are obviously higher than that at 37 (Figure S8). Thus, the result reveals the
16

ACS Paragon Plus Environment

Page 17 of 26 ACS Applied Materials & Interfaces

1
2
3
4 synergistic effect of external heating and Zn2+-triggered is more conducive to drug
5
6 release.
7
8 It is also necessary to investigate the cytotoxicity of 5-FU@MOF-In1 for its
9
10 potential application in bioimaging. Figure S9 shows the effects of 5-FU@MOF-In1
11
12 and 5-FU on the viabilities of HASMC cells using the MTT method. After HASMC
13
14 cells were incubated with 5-FU@MOF-In1 at various concentrations, the cell
15
16 viabilities reach about 92% at the 50 g mL1 concentration, which display negligible
17
18 toxicity for normal human cell. These data indicate that our novel drug carrier
19
20 possesses excellent biocompatibility and could give highly efficient and selective
21
22 treatment for drug delivery.
23
24
25 CONCLUSION
26
27 In summary, we have demonstrated the effectiveness of the PC strategy to controlling
28
29 capture and release of drug molecules. Owing to the size- and charge-selective anion
30
31 19
exchange, 5-FU is preferentially captured by MOF-In1. The F NMR spectroscopy
32
33 was employed to estimate the binding constant (Ka = 3.84 102 M1) between the
34
35 5-FU and MOF-In1, which provides important evidence for the understanding of
36
37 drug loading (around 34.32 wt%) in agreement with the TGA result. In addition,
38
39 Zn2+-triggered drug release in phosphate buffered saline also exhibits an excellent
40
41 method for central nervous system diseases treatment. These results revealed the great
42
43 potential of MOFs as an ideal nanomaterial for drug delivery and we envision that this
44
45 new targeted drug delivery system will have increased biological and medical
46
47 applications.
48
49
50
51
EXPERIMENTAL SECTION
52
53 Synthesis of {H[In3(TPO)2(OH)4]2H2O}n (MOF-In1). A mixture of In(NO3)3
54
55 (0.1206 g) and tris-(para-carboxylphenyl)phosphine oxide (H3TPO) (0.0413 g) having
56
57 the molar ratio about 4 : 1 is dissolved in CH3CN solvent (2 mL) with pH 2.2 by
58
59 addition of HNO3. While stirring for 30 min in air, it was heated at 85 C in a
60
teflon-lined stainless steel autoclave (20 mL) for 72 h. Slowly cooling, block crystals

17

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 18 of 26

1
2
3
4 are obtained at room temperature (yield 67.6% based on H3TPO). Elemental analysis
5
6 calcd for [C42H33O20P2In3 (Mr: 1264.08)]: H, 2.63; C, 39.91%; found: H, 2.65; C,
7
8 39.90%. IR (KBr pellet, cm1): 3123 (br), 1947 (w), 1773 (w), 1712 (w), 1610 (vs),
9
10 1549 (s), 1381 (vs), 1163 (w), 1109 (m), 1019 (m), 832 (w), 771 (w), 741 (m), 705
11
12 (w), 579 (w), 494 (m), 428 (w). 1H NMR (400 MHz, CD3OD): = 7.52 (s, 12 H,
13
14 TPO-H3,5,10,12,17,19), 7.17 (s, 12 H, TPO-H2,6,9,13,16,20), 2.00 (s, 4 H, OH-H2,4) ppm
15
16 (Figure S10).
17
18 Synthesis of [In(TPO)]n (MOF-In2). A mixture of In(NO3)3 (0.6003 g) and
19
20 H3TPO (0.0210 g) having the molar ratio about 2 : 1 is dissolved in CH3CN solvent (6
21
22 mL) with pH 3.4 by addition of HNO3. While stirring for 30 min in air, it was heated
23
24 at 120 C in a teflon-lined stainless steel autoclave (20 mL) for 120 h. Slowly cooling,
25
26 block crystals are obtained at room temperature (yield 78.6% based on H3TPO).
27
28 Elemental analysis calcd for [C21H12O7PIn (Mr: 522.10)]: H, 2.321; C, 48.3%; found:
29
30 H, 2.33; C, 48.30%. IR (KBr pellet, cm1): 3423 (br), 1951 (w), 1827 (w), 1727 (w),
31
32 1586 (m), 1529 (m), 1422 (s), 1206 (s), 1115 (s), 1024 (s), 884 (vs), 751 (vs), 693 (s),
33
34 635 (w), 594 (m), 503 (m), 445 (w) (Figure S11). 1H NMR (400 MHz, CD3OD): =
35
36 7.43 (s, 6 H, TPO-H3,5), 7.06 (s, 6 H, TPO-H2,6) ppm.
37
38 Preparation of nanoparticle of MOF-In1 for drug carrier. To load
39
40 5-fluorouracil (5-FU) into the channels of MOF-In1, dehydrated MOF-In1 (20 mg)
41
42 is dispersed in a 5-FU (25 mg) containing methanol solution (5 mL) by a reflux
43
44 method and stirred for one days yielding homogenous light white solution. Then the
45
46 mixtures are centrifuged (12000 r/min for 20 min) and subsequently the solid
47
48 materials are washed with chloroform to obtain drug-loaded materials.
49
50 Drug Loading and Release. Drug release experiments are carried out by a
51
52 pretreated semipermeable dialysis bag (Mw = 1000) at 37 C with gentle shaking.
53
54 10.0 mg of prepared 5-FU@MOF-In1 sample is dispersed in 8.0 ml PBS (PH = 7.4).
55
56 In the release process of certain time interval, 1.0 mL solution is extracted out for
57
58 measurement and 1.0 mL fresh PBS buffer is then refilled.
59
60
ASSOCIATED CONTENT
18

ACS Paragon Plus Environment

Page 19 of 26 ACS Applied Materials & Interfaces

1
2
3
4 Supporting Information
5
6 The Supporting Information is available free of charge on the ACS Publications
7
8 website at Internet http://pubs.acs.org.
9
10 Additional experimental details, characterization and data (PDF)
11
12
13 AUTHOR INFORMATION
14
15 Corresponding Authors
16
17 *E-mail: fanruiqing@hit.edu.cn
18
19 *E-mail: ylyang@hit.edu.cn
20
21 Notes
22
23 The authors declare no competing financial interest.
24
25 ACKNOWLEDGEMENTS
26
27
28
This work was supported by National Natural Science Foundation of China (Grant
29
30
21371040 and 21571042), the National Key Basic Research Program of China (973
31
32
Program, No. 2013CB632900).
33
34
35 REFERENCES
36
37 (1) Nicolas, J. Drug-Initiated Synthesis of Polymer Prodrugs: Combining Simplicity
38
39 and Efficacy in Drug Delivery. Chem. Mater. 2016, 28, 1591-1606.
40
41 (2) Lee, J.; Oh, E. T.; Yoon, H.; Woo Kim, C.; Han, Y.; Song, J.; Jang, H.; Joo Park,
42
43 H.; Kim, C. Mesoporous Nanocarriers with a Stimulus-Responsive Cyclodextrin
44
45 Gatekeeper for Targeting Tumor Hypoxia. Nanoscale 2017, 9, 6901-6909.
46
47 (3) Tibbitt, M. W.; Dahlman, J. E.; Langer, R. Emerging Frontiers in Drug Delivery. J.
48
49 Am. Chem. Soc. 2016, 138, 704-717.
50
51 (4) Chen, W.; Zeng, K.; Liu, H.; Ouyang, J.; Wang, L.; Liu, Y.; Wang, H.; Deng, L.;
52
53 Liu, Y. N. Cell Membrane Camouflaged Hollow Prussian Blue Nanoparticles for
54
55 Synergistic Photothermal-/Chemotherapy of Cancer. Adv. Funct. Mater. 2017, 27,
56
57 1605795-1605803.
58
59 (5) Gou, M.; Li, S.; Zhang, L.; Li, L.; Wang, C.; Su, Z. Facile One-Pot Synthesis of
60
Carbon/Calcium Phosphate/Fe3O4 Composite Nanoparticles for Simultaneous

19

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 20 of 26

1
2
3
4 Imaging and pH/NIR-Responsive Drug Delivery. Chem. Commun. 2016, 52,
5
6 11068-11071.
7
8 (6) DeStefano, M. R.; Islamoglu, T.; Garibay, S. J.; Hupp, J. T.; Farha, O. K.
9
10 Room-Temperature Synthesis of UiO-66 and Thermal Modulation of Densities of
11
12 Defect Sites. Chem. Mater. 2017, 29, 1357-1361.
13
14 (7) Guo, L. Y.; Su, H. F.; Kurmoo, M.; Wang, X. P.; Zhao, Q. Q.; Lin, S. C.; Tung, C.
15
16 H.; Sun, D.; Zheng, L. S. Multifunctional Triple-Decker Inverse 12-Metallacrown-4
17
18 Sandwiching Halides. ACS Appl. Mater. Interfaces 2017, 9, 19980-19987.
19
20 (8) Li, X. Y.; Su, H. F.; Kurmoo, M.; Tung, C. H.; Sun, D.; Zheng, L. S. Structure,
21
22 Solution Assembly, and Electroconductivity of Nanosized
23
24 Argento-Organic-Cluster/Framework Templated by Chromate. Nanoscale 2017, 9,
25
26 5305-5314.
27
28 (9) Zhang, Y.; Wang, X.; Li, S.; Song, B.; Shao, K.; Su, Z. Ligand-Directed
29
30 Assembly of Polyoxovanadate-Based Metal-Organic Polyhedra. Inorg. Chem. 2016,
31
32 55, 8770-8775.
33
34 (10) Goswami, S.; Ma, L.; Martinson, A. B.; Wasielewski, M. R.; Farha, O. K.; Hupp,
35
36 J. T. Toward Metal-Organic Framework-Based Solar Cells: Enhancing Directional
37
38 Exciton Transport by Collapsing Three-Dimensional Film Structures. ACS Appl.
39
40 Mater. Interfaces 2016, 8, 30863-30870.
41
42 (11)Zhao, J.; Wang, Q.; Sun, C.; Zheng, T.; Yan, L.; Li, M.; Shao, K.; Wang, X.; Su, Z.
43
44 A Hexanuclear Cobalt MetalOrganic Framework for Efficient CO2 Reduction under
45
46 Visible Light. J. Mater. Chem. A 2017, 5, 12498-12505.
47
48 (12) Sen, U.; Erkartal, M.; Kung, C. W.; Ramani, V.; Hupp, J. T.; Farha, O. K. Proton
49
50 Conducting Self-Assembled Metal-Organic Framework/Polyelectrolyte Hollow
51
52 Hybrid Nanostructures. ACS Appl. Mater. Interfaces 2016, 8, 23015-23021.
53
54 (13) Wang, Z.; Li, X. Y.; Liu, L. W.; Yu, S. Q.; Feng, Z. Y.; Tung, C. H.; Sun, D.
55
56 Beyond Clusters: Supramolecular Networks Self-Assembled from Nanosized Silver
57
58 Clusters and Inorganic Anions. Chem. Eur. J. 2016, 22, 6830-6836.
59
60 (14) Yan, Z. H.; Li, X. Y.; Liu, L. W.; Yu, S. Q.; Wang, X. P.; Sun, D. Single-Crystal to
Single-Crystal Phase Transition and Segmented Thermochromic Luminescence in a
20

ACS Paragon Plus Environment

Page 21 of 26 ACS Applied Materials & Interfaces

1
2
3
4 Dynamic 3D Interpenetrated Ag(I) Coordination Network. Inorg. Chem. 2016, 55,
5
6 1096-1101.
7
8 (15) Cao, F.; Ju, E.; Liu, C.; Li, W.; Zhang, Y.; Dong, K.; Liu, Z.; Ren, J.; Qu, X.
9
10 Encapsulation of Aggregated Gold Nanoclusters in a Metal-Organic Framework for
11
12 Real-Time Monitoring of Drug Release. Nanoscale 2017, 9, 4128-4134.
13
14 (16) Selvakumar, M.; Kumar, P. S.; Das, B.; Dhara, S.; Chattopadhyay, S. Structurally
15
16 Tuned Antimicrobial Mesoporous Hydroxyapatite Nanorods by Cyclic
17
18 Oligosaccharides Regulation to Release a Drug for Osteomyelitis. Cryst. Growth Des.
19
20 2016, 17, 433-445.
21
22 (17)Deng, Y. K.; Su, H. F.; Xu, J. H.; Wang, W. G.; Kurmoo, M.; Lin, S. C.; Tan, Y. Z.;
23
24 Jia, J.; Sun, D.; Zheng, L. S. Hierarchical Assembly of a {Mn II15MnIII4} Brucite Disc:
25
26 Step-by-Step Formation and Ferrimagnetism. J. Am. Chem. Soc. 2016, 138,
27
28 1328-1334.
29
30 (18) Chen, W. M.; Meng, X. L.; Zhuang, G. L.; Wang, Z.; Kurmoo, M.; Zhao, Q. Q.;
31
32 Wang, X. P.; Shan, B.; Tung, C. H.; Sun, D. A Superior Fluorescent Sensor for Al 3+
33
34 and UO22+ Based on a Co(ii) MetalOrganic Framework with Exposed Pyrimidyl
35
36 Lewis Base Sites. J. Mater. Chem. A 2017, 5, 13079-13085.
37
38 (19) Wang, X. P.; Chen, W. M.; Qi, H.; Li, X. Y.; Rajnak, C.; Feng, Z. Y.; Kurmoo, M.;
39
40 Boca, R.; Jia, C. J.; Tung, C. H.; Sun, D. Solvent-Controlled Phase Transition of a
41
42 CoII-Organic Framework: From Achiral to Chiral and Two to Three Dimensions.
43
44 Chem. Eur. J. 2017, 23, 7990-7996.
45
46 (20) Li, Z.; Peters, A. W.; Liu, J.; Zhang, X.; Schweitzer, N. M.; Hupp, J. T.; Farha, O.
47
48 K. Size Effect of the Active Sites in UiO-66-Supported Nickel Catalysts Synthesized
49
50 via Atomic Layer Deposition for Ethylene Hydrogenation. Inorg. Chem. Front. 2017,
51
52 4, 820-824.
53
54 (21) Xu, Z.; Han, L. L.; Zhuang, G. L.; Bai, J.; Sun, D. In Situ Construction of Three
55
56 Anion-Dependent Cu(I) Coordination Networks as Promising Heterogeneous
57
58 Catalysts for Azide-Alkyne "Click" Reactions. Inorg. Chem. 2015, 54, 4737-4743.
59
60 (22) Zotter, A.; Olah, J.; Hlavanda, E.; Bodor, A.; Perczel, A.; Szigeti, K.; Fidy, J.;
Ovadi, J. Zn2+-Induced Rearrangement of the Disordered TPPP/p25 Affects Its
21

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 22 of 26

1
2
3
4 Microtubule Assembly and GTPase Activity. Biochemistry 2011, 50, 9568-9578.
5
6 (23) Robson, M. J.; Quinlan, M. A.; Blakely, R. D. Immune System Activation and
7
8 Depression: Roles of Serotonin in the Central Nervous System and Periphery. ACS
9
10 Chem. Neurosci. 2017, 8, 932-942.
11
12 (24) Zhou, Y.; Tan, L. L.; Li, Q. L.; Qiu, X. L.; Qi, A. D.; Tao, Y.; Yang, Y. W.
13
14 Acetylcholine-Triggered Cargo Release from Supramolecular Nanovalves Based on
15
16 Different Macrocyclic Receptors. Chem. Eur. J. 2014, 20, 2998-3004.
17
18 (25) Johnston, S. B.; Raines, R. T. Conformational Stability and Catalytic Activity of
19
20 PTEN Variants Linked to Cancers and Autism Spectrum Disorders. Biochemistry
21
22 2015, 54, 1576-1582.
23
24 (26) Shi, Y.; Acerson, M. J.; Abdolvahabi, A.; Mowery, R. A.; Shaw, B. F. Gibbs
25
26 Energy of Superoxide Dismutase Heterodimerization Accounts for Variable Survival
27
28 in Amyotrophic Lateral Sclerosis. J. Am. Chem. Soc. 2016, 138, 5351-5362.
29
30 (27) Chen, Y.; Hong, T.; Wang, S.; Mo, J.; Tian, T.; Zhou, X. Epigenetic Modification
31
32 of Nucleic Acids: from Basic Studies to Medical Applications. Chem. Soc. Rev. 2017,
33
34 46, 2844-2872.
35
36 (28) Tan, L. L.; Li, H.; Zhou, Y.; Zhang, Y.; Feng, X.; Wang, B.; Yang, Y. W.
37
38 Zn2+-Triggered Drug Release from Biocompatible Zirconium MOFs Equipped with
39
40 Supramolecular Gates. Small 2015, 11, 3807-3813.
41
42 (29) Li, B.; Ma, D.; Li, Y.; Zhang, Y.; Li, G.; Shi, Z.; Feng, S.; Zaworotko, M. J.; Ma,
43
44 S. Dual Functionalized Cages in MetalOrganic Frameworks via Stepwise
45
46 Postsynthetic Modification. Chem. Mater. 2016, 28, 4781-4786.
47
48 (30)Li, X. Y.; Wang, Z.; Su, H. F.; Feng, S.; Kurmoo, M.; Tung, C. H.; Sun, D.; Zheng,
49
50 L. S. Anion-Templated Nanosized Silver Clusters Protected by Mixed Thiolate and
51
52 Diphosphine. Nanoscale 2017, 9, 3601-3608.
53
54 (31) Song, B. Q.; Wang, X. L.; Zhang, Y. T.; Wu, X. S.; Liu, H. S.; Shao, K. Z.; Su, Z.
55
56 M. Periodic Tiling of Triangular and Square Nanotubes in a Cationic MetalOrganic
57
58 Framework for Selective Anion Exchange. Chem. Commun. 2015 51, 9515-9518.
59
60 (32) Jiang, X. M.; Zhang, M. J.; Zeng, H. Y.; Guo, G. C.; Huang, J. S. Inorganic
Supramolecular Compounds with 3-D Chiral Frameworks Show Potential as Both
22

ACS Paragon Plus Environment

Page 23 of 26 ACS Applied Materials & Interfaces

1
2
3
4 Mid-IR Second-Order Nonlinear Optical and Piezoelectric Materials. J. Am. Chem.
5
6 Soc. 2011, 133, 3410-3418.
7
8 (33) Liu, Y.; Kravtsov, V.; Eddaoudi, M. Template-Directed Assembly of Zeolite-like
9
10 Metal-Organic Frameworks (ZMOFs): A Usf-ZMOF with an Unprecedented Zeolite
11
12 Topology. Angew Chem Int Ed 2008, 47, 8446-8449.
13
14 (34) Qian, J. J.; Jiang, F. L.; Su, K. Z.; Pan, J.; Liang, L. F.; Mao, F. F.; Hong, M. C.
15
16 Constructing Crystalline Heterometallic IndiumOrganic Frameworks by the
17
18 Bifunctional Method. Cryst. Growth Des. 2015, 15, 1440-1445.
19
20 (35) Spek, A. L. Single-Crystal Structure Validation with the Program PLATON. J.
21
22 Appl. Cryst. 2003, 36, 7-13.
23
24 (36) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool; Utrecht University:
25
26 Utrecht, The Netherlands 2006.
27
28 (37) Yao, S.; Wang, D.; Cao, Y.; Li, G.; Huo, Q.; Liu, Y. Two Stable 3D Porous
29
30 MetalOrganic Frameworks with High Performance for Gas Adsorption and
31
32 Separation. J. Mater. Chem. A 2015, 3, 16627-16632.
33
34 (38) Luo, J.; Wang, J.; Cao, Y.; Yao, S.; Zhang, L.; Huo, Q.; Liu, Y. Assembly of an
35
36 IndiumPorphyrin Framework JLU-Liu7: a Mesoporous MetalOrganic Framework
37
38 with High Gas Adsorption and Separation of Light Hydrocarbons. Inorg. Chem. Front.
39
40 2017, 4, 139-143.
41
42 (39) Du, X.; Fan, R.; Qiang, L.; Song, Y.; Xing, K.; Chen, W.; Wang, P.; Yang, Y.
43
44 Unusually Flexible Indium(III) Metal-Organic Polyhedra Materials for Detecting
45
46 Trace Amounts of Water in Organic Solvents and High Proton Conductivity. Inorg.
47
48 Chem. 2017, 56, 3429-3439.
49
50 (40) Bu, F.; Lin, Q.; Zhai, Q. G.; Bu, X.; Feng, P. Charge-Tunable Indium-Organic
51
52 Frameworks Built from Cationic, Anionic, and Neutral Building Blocks. Dalton Trans.
53
54 2015, 44, 16671-16674.
55
56 (41) Gao, X.; Zhai, M.; Guan, W.; Liu, J.; Liu, Z.; Damirin, A. Controllable Synthesis
57
58 of a Smart Multifunctional Nanoscale Metal-Organic Framework for Magnetic
59
60 Resonance/Optical Imaging and Targeted Drug Delivery. ACS Appl. Mater. Interfaces
2017, 9, 3455-3462.
23

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 24 of 26

1
2
3
4 (42) Argyo, C.; Weiss, V.; Bruchle, C.; Bein, T. Multifunctional Mesoporous Silica
5
6 Nanoparticles as a Universal Platform for Drug Delivery. Chem. Mater. 2014, 26,
7
8 435-451.
9
10 (43) Yang, Q.; Zhu, Y.; Luo, B.; Lan, F.; Wu, Y.; Gu, Z. pH-Responsive Magnetic
11
12 Metal-Organic Framework Nanocomposites for Selective Capture and Release of
13
14 Glycoproteins. Nanoscale 2017, 9, 527-532.
15
16 (44) He, W. W.; Li, S. L.; Yang, G. S.; Lan, Y. Q.; Su, Z. M.; Fu, Q. Controllable
17
18 Synthesis of a Non-Interpenetrating Microporous Metal-Organic Framework Based
19
20 on Octahedral Cage-Like Building Units for Highly Efficient Reversible Adsorption
21
22 of Iodine. Chem. Commun. 2012, 48, 10001-10003.
23
24 (45) Singh, P.; Jangir, D. K.; Mehrotra, R.; Bakhshi, A. K. Development and
25
26 Validation of an Infrared Spectroscopy-Based Method for the Analysis of Moisture
27
28 Content in 5-Fluorouracil. Drug Test Anal 2009, 1, 275-278.
29
30 (46) Sahandi Zangabad, P.; Karimi, M.; Mehdizadeh, F.; Malekzad, H.; Ghasemi, A.;
31
32 Bahrami, S.; Zare, H.; Moghoofei, M.; Hekmatmanesh, A.; Hamblin, M. R.
33
34 Nanocaged Platforms: Modification, Drug Delivery and Nanotoxicity. Opening
35
36 Synthetic Cages to Release the Tiger. Nanoscale 2017, 9, 1356-1392.
37
38 (47) Lismont, M.; Dreesen, L.; Wuttke, S. Metal-Organic Framework Nanoparticles in
39
40 Photodynamic Therapy: Current Status and Perspectives. Adv. Funct. Mater. 2017, 27,
41
42 1606314-1606329.
43
44 (48) Takezawa, H.; Murase, T.; Resnati, G.; Metrangolo, P.; Fujita, M. Recognition of
45
46 Polyfluorinated Compounds through Self-Aggregation in a Cavity. J. Am. Chem. Soc.
47
48 2014, 136, 1786-1788.
49
50 (49) Sun, C. Y.; Qin, C.; Wang, C. G.; Su, Z. M.; Wang, S.; Wang, X. L.; Yang, G. S.;
51
52 Shao, K. Z.; Lan, Y. Q.; Wang, E. B. Chiral Nanoporous Metal-Organic Frameworks
53
54 with High Porosity as Materials for Drug Delivery. Adv. Mater. 2011, 23, 5629-5632.
55
56 (50) Xu, W. Q.; Fan, Y. Z.; Wang, H. P.; Teng, J.; Li, Y. H.; Chen, C. X.; Fenske, D.;
57
58 Jiang, J. J.; Su, C. Y. Investigation of Binding Behavior between Drug Molecule
59
60 5-Fluoracil and M4L4-Type Tetrahedral Cages: Selectivity, Capture, and Release.
Chem. Eur. J. 2017, 23, 1-7.
24

ACS Paragon Plus Environment

Page 25 of 26 ACS Applied Materials & Interfaces

1
2
3
4 (51) Bag, P. P.; Wang, D.; Chen, Z.; Cao, R. Outstanding Drug Loading Capacity by
5
6 Water Stable Microporous MOF: a Potential Drug Carrier. Chem. Commun. 2016, 52,
7
8 3669-3672.
9
10 (52) Qin, J. S.; Du, D. Y.; Li, W. L.; Zhang, J. P.; Li, S. L.; Su, Z. M.; Wang, X. L.; Xu,
11
12 Q.; Shao, K. Z.; Lan, Y. Q. N-rich Zeolite-Like MetalOrganic Framework with
13
14 Sodalite Topology: High CO2 Uptake, Selective Gas Adsorption and Efficient Drug
15
16 Delivery. Chem. Sci. 2012, 3, 2114-2118.
17
18 (53) Horcajada, P.; Serre, C.; Vallet-Reg, M.; Sebban, M.; Taulelle, F.; Frey, G.
19
20 MetalOrganic Frameworks as Efficient Materials for Drug Delivery. Angew. Chem.
21
22 2006, 118, 6120-6124.
23
24 (54) Zhao, X.; Mao, C.; Luong, K. T.; Lin, Q.; Zhai, Q. G.; Feng, P.; Bu, X.
25
26 Framework Cationization by Preemptive Coordination of Open Metal Sites for
27
28 Anion-Exchange Encapsulation of Nucleotides and Coenzymes. Angew. Chem. Int.
29
30 Ed. 2016, 55, 2768-2772.
31
32 (55) Wei, W.; Lu, R.; Tang, S.; Liu, X. Highly Cross-Linked Fluorescent
33
34 Poly(cyclotriphosphazene-co-curcumin) Microspheres for the Selective Detection of
35
36 Picric Acid in Solution Phase. J. Mater. Chem. A 2015, 3, 4604-4611.
37
38 (56)Li, H.; Tan, L. L.; Jia, P.; Li, Q. L.; Sun, Y. L.; Zhang, J.; Ning, Y. Q.; Yu, J.; Yang,
39
40 Y. W. Near-Infrared Light-Responsive Supramolecular Nanovalve Based on
41
42 Mesoporous Silica-Coated Gold Nanorods. Chem. Sci. 2014, 5, 2804-2808.
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

25

ACS Paragon Plus Environment

 ACS Applied Materials & Interfaces Page 26 of 26

1
2
3
4 Table of Contents
5
6
7 Controlled Zn2+-Triggered Drug Release by Preferred
8
9
10 Coordination of Open Active Sites within Functionalization
11
12 Indium Metal Organic Frameworks
13
14
15
16 Xi Du, Ruiqing Fan,*, Liangsheng Qiang, Kai Xing, Haoxin Ye, Xinya Ran, Yang
17
18 Song, Ping Wang, and Yulin Yang*,
19
20 MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion
21
and Storage, School of Chemistry and Chemical Engineering, Harbin Institute of
22
23 Technology, Harbin 150001, P. R. China
24
25
26
27
28
29
30
31
32
33
34 5-Fu@MOF-In1
35
36
37
38
39
40
41
42
43
44 MOF-In1
45
46 Zn2+@MOF-In1
47
48 This preferred coordination strategy based on MOFs as an ideal nanomaterial for
49
50
drug delivery, combining physical and natural biochemical treatment in one pot,
51 opens a new avenue, especially in the treatment of central nervous system disease.
52
53
54
55
56
57
58
59
60

26

ACS Paragon Plus Environment