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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

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ACS Applied Materials & Interfaces

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*,†

†

MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion and Storage, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, P. R. China

* Corresponding Author: Ruiqing Fan and Yulin Yang E-mail: [email protected] and [email protected]

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ABSTRACT: Drug delivery in target regions could make extraordinary progress in chemo-selective therapies. A novel preferred coordination (PC) strategy referring to proactive interacting with open active sites to replace previous occupation by ion-exchange for controlling release of drug molecules is well constructed. Two topological types of MOF-In1 (Schläfli symbol: (4,8)-connected of (410·615·83)(45·6)2) and MOF-In2 (Schläfli symbol: (4,4)-connected of (66)) show the specific way. Increasing node connectivity as well as the trapping of guest OH– anions, 5-fluorouracil (5-FU) is preferentially captured into the MOF-In1, which exhibits an outstanding loading capacity around 34.32 wt%.

19

F NMR spectroscopy was further

employed to investigate host-guest interaction and reveal the binding constant (Ka = 3.84 × 102 M–1). Meanwhile, the controlled release of 5-FU in a simulated human body with liquid phosphate-buffered saline solution by bio-friendly Zn2+-triggered is realized. With an elevated Zn2+ concentration, the drug release will be enhanced. This efficient strategy for MOFs as multifunctional drug carrier opens a new avenue for biological and medical applications. KEYWORDS: preferred coordination strategy, open active sites, host-guest interaction, nano-MOFs, Zn2+-triggered drug release

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



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treatment central nervous system disease. Herein, a novel preferred coordination (PC) strategy referring to proactive interacting with open active sites to replace previous occupation by ion-exchange for controlling release of drug molecules is constructed. Two topological types of MOF-In1 ({H[In3(TPO)2(OH)4]·2H2O}n) and MOF-In2 ([In(TPO)]n) are selected to specify the implementation effect of the PC strategy (Scheme 1). MOF-In1 is built on 8-connected [In3(CO2)6(OH)4] SBUs to form two kinds of 1D square channels with windows size of about 12.503×8.546 and 8.601×6.121 Å2, respectively, which displays a (4,8)-connected topology network with the Schläfli symbol of (410·615·83)(45·6)2. While MOF-In2 possesses 4-connected [InO(CO2)3] SBUs and integrates

in

a

SBUs-by-SBUs

way

through

bridging

tris-(para-carboxylphenyl)phosphine oxide (H3TPO) ligands, generating a 2-fold interpenetrating (4,4)-connected diamond-like topology structure with the Schläfli symbol of (66). The first type (MOF-In1) consists of 8-connected SBUs and open active site is occupied by OH– anion, making entire host framework is negatively charged. In the second type (MOF-In2), carboxylate TPO3− ligand provides all 4-coordination sites in a regular mode to interact with metal source and the resulting structure exhibits the dia net as a neutral framework. As a result of the node connectivity increasing from (4,4)-connected to (4,8)-connected, as well as the trapping of guest OH– anions, the framework contains different pore sizes with the overall charge negative or neutral, which could encapsulate or remove guest molecules based on the shape and charge.29-31 Driven by the above mentioned host-guest interaction, 5-fluorouracil (5-FU) as one of the broad-spectrum drug molecule is preferentially captured into the MOF-In1 (loading capacity around 34.32 wt%) as a novel drug delivery system in comparison to the MOF-In2. 19F NMR spectroscopy was employed to investigate host-guest interaction and reveal the binding constant (Ka = 3.84 × 102 M–1). Meanwhile, MOF-In1 exhibited outstanding behavior for the controlled release of 5-FU in a simulated human body with liquid phosphate-buffered saline solution by appropriate 4


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Zn2+-triggered. This method provides a platform to deliver the sufficient quantities of drugs to a target region accurately (Scheme 2).

[In3O2(CO2)6(OH)4]

8-c node

H3TPO

4-c node

[InO(CO2)3]

4-c node

(4,8)-connected topology MOF-In1

4-c node

(4,4)-connected topology MOF-In2

Scheme 1. Syntheses route of MOF-In1 and MOF-In2

Zn2+

5-Fu

MOF-In1

5-Fu@MOF-In1

Zn2+@MOF-In1

Scheme 2. Preferred coordination strategy for creating 5-FU@MOF-In1 and Zn2+@MOF-In1 5



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RESULTS AND DISCUSSION Structural Description of MOF-In1. The structure of MOF-In1 is determined by single crystal crystallography and displays a 3D porous framework. It is crystallized in the Monoclinic C 2/c space group and its asymmetric unit contains one and a half In(III) ions, one TPO3− anion, two OH− anions, a half H3O+ guest cation and a half neutral H2O guest molecule (Table 1). After symmetry operation, each 6-coordinated In(III) cation is coordinated with four independent TPO3− ligands and two OH− anions in a octahedron coordination geometry to form a 8-connected [In3(CO2)6(OH)4] secondary building unit (SBU) (Figure S1). For the C3-symmetric TPO3− ligands, two carboxylate groups are coordinated in the chelating mode to link two [In3(CO2)6(OH)4] SBUs, one remaining carboxylate group and the oxygen atom (O1) from P=O bond are connected to the other two [In3(CO2)6(OH)4] SBUs in monodentate coordination mode, in which all the observed bond lengths of In–O range from 2.076(4) to 2.183(4) Å shown in Table S1.32-34 In this way, the ligands could be deemed to 4-connected nodes with quadrilateral geometry. As a result, the structure of MOF-In1 displays a (4,8)-connected topology network with the Schläfli symbol of (410·615·83)(45·6)2 (Figure 1b). In this 3D structure, MOF-In1 exhibits two types of 1D square channels divided by these [In3(CO2)6(OH)4] SBUs via alternating the organic linker molecules rotational orientation along the b axis. As depicted in Figure 1a, two types of 1D channels adopt the ABAB connection mode, with the compositions of four [In3(CO2)6(OH)4] SBUs (A) and two [In3(CO2)6(OH)4] SBUs (B). Under careful observation, there exist open Lewis basic oxygen active sites in the Type A channel, H3O+ and H2O guest molecules in the Type B channel, respectively. Calculated using the PLATON program35-37 shows the overall solvent-accessible volume equal to 2240.6 Å3 per unit cell, which accounts for about 37.4% of the cell volume of 5991.0 Å3 (Figure 1c).

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(a)

Type A

Type B

(c)

(b)

Figure 1. MOF-In1 showing (a) 3D framework containing two types of channels (left: Type A and right: Type B); (b) 3D topology structure; (c) natural tiling structure.

Structural Description of MOF-In2. The study reveals MOF-In2 is crystallized in the Hexagonal R3 space group and features [InO(CO2)3] SBUs based 3D diamond-like framework. In its asymmetric unit, there is one In(III) ion and one TPO3− anion. Metal In(III) ion adopts typical 7-coordinated geometry by six oxygen atoms (chelating coordination mode) from three carboxylate groups of three individual TPO3− ligands

(Figure S2), as well as one oxygen atom (monodentate

coordination mode) from the P=O of the fourth TPO3− ligand to give 4-conneceted mononuclear [InO(CO2)3] SBUs, in which the observed In–O bond lengths are comparable with those reported.38-40 After symmetry operation, the ligands joint four [InO(CO2)3] SBUs in four directions and are equal 4-connected nodes. The overall structure of MOF-In2, integrated in a SBUs-by-SBUs way through these bridging TPO3− ligands, generates a well-constructed 3D 2-fold interpenetrating diamond-like topology structure with the Schläfli symbol of (66) (Figure 2). Usually interpenetrating structure minimizes pore sizes and restricts porosity. The PLATON 7



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calculation shows the overall solvent-accessible volume equal to 296.0 Å3 per unit cell, which accounts for about 17.9% of the cell volume of 1654.2 Å3.

(a)

(b)

(c)

(d)

Figure 2. MOF-In2 showing (a) [InO(CO2)3] hexagonal cage; (b) 2D layer; (c) 3D framework; (d) 3D 2-fold interpenetrating diamond-like topology structure. Table 1 Crystal data and structure refinement for the two MOFs. Identification code

MOF-In1

MOF-In2

Empirical formula

C42H33O20P2In3

C21H12O7PIn

Formula weight

1264.08

522.10

Crystal system

Monoclinic

Hexagonal

Space group

C 2/c

R3

28.825(6)

14.1755(8)

11.472(2)

14.1755(8)

18.905(4)

9.5058(11)

90.00

90.00

106.62(3)

90.00

90.00

120.00

5991(2)

1654.2(2)

a(Å) b(Å) c(Å) α(°) β(°) γ(°) 3

Volume(Å )

8


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Z

4

3

1.402

1.572

μ (Mo Kα)/mm

1.260

1.182

F(000)

2488

774

Crystal size/mm

0.28 × 0.26 ×0.24

0.30 × 0.24 ×0.23

 range (°)

1.47 to 27.52

2.71 to 27.52

Limiting indices

-36

Controlled Zn2+-Triggered Drug Release by ... - ACS Publications

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