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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
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Page 1 of 26 ACS Applied Materials & Interfaces

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Controlled Zn2+-Triggered Drug Release by Preferred
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7 Coordination of Open Active Sites within Functionalization
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10 Indium Metal Organic Frameworks
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Xi Du, Ruiqing Fan,*, Liangsheng Qiang, Kai Xing, Haoxin Ye, Xinya Ran, Yang
15 Song, Ping Wang, and Yulin Yang*,
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21 MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion
22 and Storage, School of Chemistry and Chemical Engineering, Harbin Institute of
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24 Technology, Harbin 150001, P. R. China
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31 * Corresponding Author: Ruiqing Fan and Yulin Yang
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33 E-mail: [email protected] and [email protected]
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4 ABSTRACT: Drug delivery in target regions could make extraordinary progress in
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6 chemo-selective therapies. A novel preferred coordination (PC) strategy referring to
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8 proactive interacting with open active sites to replace previous occupation by
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10 ion-exchange for controlling release of drug molecules is well constructed. Two
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12 topological types of MOF-In1 (Schlfli symbol: (4,8)-connected of (41061583)(456)2)
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14 and MOF-In2 (Schlfli symbol: (4,4)-connected of (66)) show the specific way.
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16 Increasing node connectivity as well as the trapping of guest OH anions,
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18 5-fluorouracil (5-FU) is preferentially captured into the MOF-In1, which exhibits an
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20 outstanding loading capacity around 34.32 wt%. F NMR spectroscopy was further
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22 employed to investigate host-guest interaction and reveal the binding constant (Ka =
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24 3.84 102 M1). Meanwhile, the controlled release of 5-FU in a simulated human
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26 body with liquid phosphate-buffered saline solution by bio-friendly Zn2+-triggered is
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28 realized. With an elevated Zn2+ concentration, the drug release will be enhanced. This
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30 efficient strategy for MOFs as multifunctional drug carrier opens a new avenue for
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32 biological and medical applications.
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34 KEYWORDS: preferred coordination strategy, open active sites, host-guest
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36 interaction, nano-MOFs, Zn2+-triggered drug release
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4 INTRODUCTION
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6 In order to achieve ideal therapeutic effect, traditional small molecule drugs are
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8 usually at a high concentration in the circulation of the blood stream and subsequently
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10 reach a desired final concentration for the target tissue. This practice inevitably brings
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12 about some defects, including poor solubility and nonselective drug distribution,
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14 which may damage the healthy tissues and limit the therapeutic effect. Recently in the
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16 drug delivery field, some chemists are devoted to overcome these negative effects.1-5
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18 Generally, to ensure the efficient therapy, the drug carriers are required not only to
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20 capture drugs with high payloads, but also are hoped to be in nanoscale, which
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22 facilitate the release of drugs to the whole body and absorbed by the specific tissues
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24 by intravenous administration. Different from most of the existing pure organic and
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26 inorganic carrier materials, metal organic frameworks (MOFs) as novel porous
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28 functionality materials6-9 possess the well-defined pore structure and the open active
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30 sites, which are conducive to bind or transport specific guests within the
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32 frameworks.10-14 Thus, it is possible to improve drug solubility issues by choosing
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34 appropriate nano-MOFs as drug carrier to ensure a targeted delivery.
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36 In addition to ensuring above therapeutically level requirements, achieving
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38 sustained release is an important prerequisite for efficient nanoparticulate drug
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40 carriers employed to improve drug efficacy and safety.15-16 Inspired by host-guest
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42 interaction,17-21 anionic nano-MOFs can selectively trap cations through ion exchange
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44 to achieve a controlled drug delivery. Zinc as one of essential trace elements in human
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46 body, plays ubiquitous biological role. Compared with other organs, the zinc
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48 content is the highest in brain. In brain extracellular fluid, zinc concentration is about
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50 500 nM. In some named zinc-containing neurons, zinc concentration might exceed
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52 1 mM through weak coordination interaction with endogenous ligand.22 Thus, zinc
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54 displays a strong influence on central nervous system23 and zinc imbalance may lead
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56 to autism spectrum disorders, Parkinsons disease, epilepsy, schizophrenia and
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58 amyotrophic lateral sclerosis.24-28 The increased Zn2+ concentration in these diseases
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60 offers a new avenue for drug delivery to target regions and reduces the limitation for

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

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Zn2+-triggered. This method provides a platform to deliver the sufficient quantities of
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drugs to a target region accurately (Scheme 2).
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17 [In3O2(CO2)6(OH)4] H3TPO [InO(CO2)3]
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28 8-c node 4-c node 4-c node 4-c node
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46 (4,8)-connected topology (4,4)-connected topology
47 MOF-In1 MOF-In2
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49 Scheme 1. Syntheses route of MOF-In1 and MOF-In2
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56 5-Fu Zn2+
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59 MOF-In1 5-Fu@MOF-In1 Zn2+@MOF-In1
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Scheme 2. Preferred coordination strategy for creating 5-FU@MOF-In1 and Zn2+@MOF-In1

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4 RESULTS AND DISCUSSION
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Structural Description of MOF-In1. The structure of MOF-In1 is determined by
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single crystal crystallography and displays a 3D porous framework. It is crystallized
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11 in the Monoclinic C 2/c space group and its asymmetric unit contains one and a half
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13 In(III) ions, one TPO3 anion, two OH anions, a half H3O+ guest cation and a half
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15 neutral H2O guest molecule (Table 1). After symmetry operation, each 6-coordinated
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17 In(III) cation is coordinated with four independent TPO3 ligands and two OH anions
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19 in a octahedron coordination geometry to form a 8-connected [In3(CO2)6(OH)4]
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21 secondary building unit (SBU) (Figure S1). For the C3-symmetric TPO3 ligands, two
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23 carboxylate groups are coordinated in the chelating mode to link two [In3(CO2)6(OH)4]
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25 SBUs, one remaining carboxylate group and the oxygen atom (O1) from P=O bond
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27 are connected to the other two [In3(CO2)6(OH)4] SBUs in monodentate coordination
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29 mode, in which all the observed bond lengths of InO range from 2.076(4) to 2.183(4)
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31 shown in Table S1.32-34 In this way, the ligands could be deemed to 4-connected
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33 nodes with quadrilateral geometry. As a result, the structure of MOF-In1 displays a
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35 (4,8)-connected topology network with the Schlfli symbol of (41061583)(456)2
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37 (Figure 1b).
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39 In this 3D structure, MOF-In1 exhibits two types of 1D square channels divided by
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41 these [In3(CO2)6(OH)4] SBUs via alternating the organic linker molecules rotational
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43 orientation along the b axis. As depicted in Figure 1a, two types of 1D channels adopt
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45 the ABAB connection mode, with the compositions of four [In3(CO2)6(OH)4] SBUs
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47 (A) and two [In3(CO2)6(OH)4] SBUs (B). Under careful observation, there exist open
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49 Lewis basic oxygen active sites in the Type A channel, H3O+ and H2O guest molecules
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51 in the Type B channel, respectively. Calculated using the PLATON program35-37
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53 shows the overall solvent-accessible volume equal to 2240.6 3 per unit cell, which
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55 accounts for about 37.4% of the cell volume of 5991.0 3 (Figure 1c).
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4 Type A Type B
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33 Figure 1. MOF-In1 showing (a) 3D framework containing two types of channels (left: Type A
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36 Structural Description of MOF-In2. The study reveals MOF-In2 is crystallized
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38 in the Hexagonal R3 space group and features [InO(CO2)3] SBUs based 3D
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40 diamond-like framework. In its asymmetric unit, there is one In(III) ion and one
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42 TPO3 anion. Metal In(III) ion adopts typical 7-coordinated geometry by six oxygen
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44 atoms (chelating coordination mode) from three carboxylate groups of three
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46 individual TPO3 ligands (Figure S2), as well as one oxygen atom (monodentate
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48 coordination mode) from the P=O of the fourth TPO3 ligand to give 4-conneceted
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50 mononuclear [InO(CO2)3] SBUs, in which the observed InO bond lengths are
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52 comparable with those reported.38-40 After symmetry operation, the ligands joint four
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54 [InO(CO2)3] SBUs in four directions and are equal 4-connected nodes. The overall
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56 structure of MOF-In2, integrated in a SBUs-by-SBUs way through these bridging
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58 TPO3 ligands, generates a well-constructed 3D 2-fold interpenetrating diamond-like
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60 topology structure with the Schlfli symbol of (66) (Figure 2). Usually
interpenetrating structure minimizes pore sizes and restricts porosity. The PLATON
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4 calculation shows the overall solvent-accessible volume equal to 296.0 3 per unit
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36 Figure 2. MOF-In2 showing (a) [InO(CO2)3] hexagonal cage; (b) 2D layer; (c) 3D framework; (d)
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39 Table 1 Crystal data and structure refinement for the two MOFs.
40 Identification code MOF-In1 MOF-In2
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42 Empirical formula C42H33O20P2In3 C21H12O7PIn
43 Formula weight 1264.08 522.10
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45 Crystal system Monoclinic Hexagonal
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Space group C 2/c R3
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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
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59 90.00 120.00
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60 Volume( ) 5991(2) 1654.2(2)

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

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

15 0.8

Transittance/%
Absorbance

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21 0.2
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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
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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
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31 drug-carrying material to the nanometer size.46-47 As shown in Figure 4a, the
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33 nanocrystalline MOF-In1 was prepared by a reflux method at low temperature and
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35 characterized by the scanning electron microscope (SEM). The PXRD reflection of
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37 the obtained nanocrystalline MOF-In1 corresponds well with the simulated pattern,
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39 readily indexing high crystallinity of the obtained MOF-In1 nanomaterial (Figure S3).
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41 Due to the open OH sites in the channel of MOF-In1 nanocrystalline and its small
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43 particle size about 190 nm, the MOF-In1 is preferred as drug carrier by conjugation
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45 with the targeted agent 5-FU to form nanocomposite 5-FU@MOF-In1 (Figure 4b).
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47 Further evidence for the uniformly distribution of In and F components in the
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49 5-FU@MOF-In1 is identified by the elemental mapping. As shown in Figure 4c and
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51 d, the elemental mapping images of In and F clearly demonstrate the
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53 5-FU@MOF-In1 nanoparticles are homogeneous distribution in the 3D framework.
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55 The diameters are calculated to be 256 nm for MOF-In1 and 295 nm for
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57 5-FU@MOF-In1 (in methanol solution) by dynamic light scattering (DLS) (Figure
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59 S4), which shows the particle size became larger after encapsulation 5-FU drug
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molecules. The particle diameters of MOF-In1 and 5-FU@MOF-In1 are also larger
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4 than that measured by SEM. This phenomenon can ascribe to the exact real diameter
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6 are replaced by the hydration diameter. Meanwhile, the zeta potentials of MOF-In1
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8 and 5-FU@MOF-In1 are measured to be ca. -30.6 and -21.2 mV, respectively (Table
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10 S2), which indicate that MOF-In1 is capable of encapsulation 5-FU and
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12 5-FU@MOF-In1 can maintain certain stability. The loading procedure followed the
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14 literature to immerse the nanoparticles in a methanol solution of 5-FU for one day.
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16 The structure of MOF-In1 possesses two pores and the pore diameters are
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18 approximately 0.776 and 1.147 nm, respectively (Figure S5). After encapsulation
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20 5-FU molecules, 5-FU@MOF-In1 shows the two pore diameters are 0.498 and 0.848
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22 nm, which are smaller than that of MOF-In1. The smaller pore volume can be
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24 attributed to the aggregation of 5-FU molecules in the framework of MOF-In1. The
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26 loading amount was determined by thermogravimetric analysis (TGA) and the result
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28 showed 34.32 wt% 5-FU uptake, which corresponds to 5 molecules of 5-FU per
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30 formula unit of MOF-In1 (Figure S6).
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100 nm 100 nm
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58 Figure 4. SEM images for (a) MOF-In1 and (b) 5-FU@MOF-In1; Corresponding to the
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60 elemental mapping image of 5-FU@MOF-In1 for (c) the indium element and (d) the fluorine
element.

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

29 Ka
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31

32 l o g n l o gG[ ] n l o gK a
33 1
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35 In the hill equation, the value of 1- can be obtained with divide observed by the
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37 maximum change of chemical shift in 19F NMR spectra. The coefficient value (n)
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39 of MOF-In1 indicates that the guest molecules are independent binding. Derived
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41 from the Hill function plot of the 5-FU@MOF-In1 system (Figure 5c), a Hill
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43 coefficient (n) of 2.74 indicates a strongly positive cooperative binding mode between
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45 5-FU and MOF-In1. The measured apparent association constant Ka is 3.84102 M-1.
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47 In striking contrast, similar titrations of 5-FU into the solution of MOF-In2 showed
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49 no chemical shift of F signals in the 19
F NMR spectra. The finding suggests that the
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51 structure of MOF-In2 is not suitable to capture 5-FU molecules. The window of
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53 MOF-In2 is approximately 16.59816.598 2 in diagonal line, which is larger than
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55 those two windows of MOF-In1 (12.5038.546 and 8.6016.121 2) and results in
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57 less steric hindrance of the guest molecule 5-FU. Moreover, the structure of
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59 MOF-In2 is 2-fold interpenetrating, which minimizes pore sizes and restricts porosity.
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Therefore, the observed binding between 5-FU and MOF-In1 underlines that the size
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4 selectivity may be dependent on the channel window.
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6 (a) (b)
7 0.30
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=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
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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
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log [/(1)]
=0.960
5-Fu -0.8
21 =1.000 -1.0
5-Fu
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-1.2
23 -172.1 -172.2 -172.3 -172.4 -172.5 -172.6 -172.7 -172.8
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/ppm
-1.4

25 -1.6
-3.1 -3.0 -2.9 -2.8 -2.7
26 log[5-Fu]
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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,
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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
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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
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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
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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

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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
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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: [email protected]
18
19 *E-mail: [email protected]
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
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10 Coordination of Open Active Sites within Functionalization
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12 Indium Metal Organic Frameworks
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16 Xi Du, Ruiqing Fan,*, Liangsheng Qiang, Kai Xing, Haoxin Ye, Xinya Ran, Yang
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18 Song, Ping Wang, and Yulin Yang*,
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20 MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion
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and Storage, School of Chemistry and Chemical Engineering, Harbin Institute of
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46 Zn2+@MOF-In1
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48 This preferred coordination strategy based on MOFs as an ideal nanomaterial for
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