Metal-Organic Framework-Assisted Nanoplatform with Hydrogen

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Metal-Organic Framework-Assisted Nanoplatform with Hydrogen Peroxide/Glutathione Dual-Sensitive on-Demand Drug Release for Targeting Tumors and Their Microenvironment Yalei Miao, Xubo Zhao, Yudian Qiu, Zhongyi Liu, Wenjing Yang, and Xu Jia ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.8b00741 • Publication Date (Web): 22 Jan 2019 Downloaded from http://pubs.acs.org on January 26, 2019

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ACS Applied Bio Materials

Metal-Organic Framework-Assisted Nanoplatform with Hydrogen Peroxide/Glutathione Dual-Sensitive on-Demand Drug Release for Targeting Tumors and Their Microenvironment Yalei Miao#, Xubo Zhao*#, Yudian Qiu#, Zhongyi Liu*#, Wenjing Yang†, Xu Jia§ # College

of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China

† Department §School

of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450002, China

of Materials and Chemical Engineering, Zhongyuan University of Technology, Zhengzhou 450007, China

* E-mail address: [email protected]

[email protected]

ABSTRACT Hydrogen peroxide (H2O2)/glutathione (GSH) dual-sensitive nanoplatform holds great promise to alleviate the side effects of chemo drugs and improve their therapeutic efficacy against cancer. The site-specific release of chemo drugs with low premature release still remains a challenge in the field of chemotherapy. In the present work, a novel and multifunctional drug delivery system (DDS) based on polymethylacrylic acid core with cross-linked structure of disulfide bond (PMAABACy), metal-organic framework (MOF) interlayer and biologically inspired polydopamine (PDA) coating was developed, serving as a vehicle for on-demand drug release. The dual-responsive nanoplatform not only prevents the premature leakage of chemotherapeutic drug but also is sensitive to biologically relevant GSH and H2O2 for the precise delivery of chemotherapeutic drug. Considering the transmission route to DDS at the tumor site, the DDS might first respond to the extracellular H2O2 and then to the intracellular GSH, exhibiting a tunable release of chemotherapeutic drug. Through incubation using tumor cells, the growth of tumor cells could be significantly inhibited. Overall, by integrating these different building modules, this research demonstrates the advantages of MOF-assisted regulate strategy to DDS for precise site-specific release against tumor cells with much reduced side-effect on normal tissues.

KEYWORDS: Metal-organic framework, Drug delivery system, Low premature leakage, H2O2/GSH dual-sensitive property, Cancer therapy

1. INTRODUCTION Recently, cancer has attracted extensively attention because of its perniciousness. The ever-growing difficulty from cancer incidence and mortality even has bad influence on society.1 Until now, there have been numerous great progresses in cancer therapy to reduce the mortality of cancer patients, including surgery, radiotherapy, and chemotherapy. So far, for chemotherapy, there are many difficulties and problems because of the systemic side effects, high recurrence rate, and low therapy efficiency in cancer therapeutics.2,3 With developments in nanotechnology and nanomaterials, the nanocarries for loading chemotherapeutic drug have attracted much attention to deal with such ever-growing difficulty from cancer incidence and mortality. Among them, the DDS has effectively enhanced therapy efficiency and improved systemic side effects to inhibit the growth of solid tumor.4-6 However, there have been still some challenges that needed to be overcome before the ideal DDS could start appearing on the

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biomedical market. One of challenges mainly was the premature release of as-loaded chemotherapeutic drug to result in the severe systemic side effects because of the inferior physiological stability in blood circulation.7,8 Therefore, the enhanced stability of DDS is of particular importance to evade this disadvantageous leakage of chemo drugs. The physiological stability upon large dilution in blood circulation is of fundamental importance for an ideal DDS to chemotherapy. For nanocarriers, MOF has served as a new pathway for this purpose.9 MOF was been crafted through the assembly from the exclusively by strong bonds between readily tunable organic linkers and inorganic clusters.10 Because of tunable pore size and connectivities as well as same hydrophobic and hydrophilic entities, MOF could be intensively investigated as vehicles for loading chemotherapeutic drug in medical application.9 Most importantly, the high structural flexibility to MOF-based carriers have enabled the adaptation of their porosity to the shape of the hosted molecule.11 Tsung and coworkers prepared a monodisperse zeolitic imid-azolate framework-8 (ZIF-8) nanosphere to encapsulate small molecules through a general synthetic route for drug delivery. This MOFbased carrier with the average diameter of 70 nm facilitated cellular uptake, and the endosomal release of the asloaded cargo was accelerated through the pH-responsive dissociation of the ZIF-8 framework.12 In addition, Jimenez’s groups developed a biological MOF-based carrier to encapsulate active pharmaceutical ingredient and further delay the release of a model drug in cancer therapy.13 It is noted that the MOF-based carriers not only have tunable pore size for loading chemotherapeutic drug, but also possess outstanding structural stability to restrict the premature release of as-loaded chemotherapeutic drug in blood circulation. Currently, for delivery, the biocompatibility of DDS also play a crucial role for ensuring an efficient therapy. Most of DDSs described in previous publications were compatible in the field of biomedical application.5,9 Most importantly, the compatible materials usually have been chosen as important building units to modify the nanocarriers for altering its fate after the deposition within the human body.14-16 The PDA is usually chosen as an external coating to craft an ideal DDS because of its no long-term toxicity, favorable biocompatibility and good biodegradability.17,18 Therefore, Zhang and coworkers designed a novel multifunctional Mn3O4@polydopamine hybrid as a drug carrier for cancer. Because of the introduction of biodegradable and biocompatible polydopamine, these hybrids exhibited favorable biocompatibility and good biodegradability.17 Zeng also reported a pH-sensitive polydopamine-based DDS for controlled release of desipramine, which exhibited higher cytotoxicity and inhibitory effects on acid sphingomyelinase.19 Along this line, constructing a DDS based on MOF and PDA, which not only displays a favorable biocompatibility, good biodegradability and stability, but also provides a tunable pore size for loading chemotherapeutic drug, could effectively decrease systemic side effects and improve therapeutic effectiveness. As a consequence, it is highly desirable to design and fabricate a DDS with high stability and favorable biocompatibility based on MOF and PDA to control drug delivery for cancer therapy, but it remains a great challenge. Notably, both internal and external stimulus hold great promise to trigger the intelligent DDSs. Among these reported DDSs with sensitive properties, due to the differentiated heterogeneous redox potential gradient between tumor tissue and normal environment, redox potential has been applied in the field of cancer therapy.20 The intracellular cytoplasma is reductive as a result of an elevated GSH concentration, while the extracellular media is oxidative because of the overproduction of H2O2 at tumor sites.21 However, a smart DDS with redox potential property simultaneously responded to GSH and H2O2 are rarely mentioned in the field of chemotherapy.


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Scheme 1. Schematic illustration of the preparation of PMAABACy@(MOF)10@PDA and its disintegration and drug release upon tumor-microenvironmental triggers. Herein, we have designed and synthesized a H2O2/GSH dual-sensitive PMAABACy@(MOF)10@PDA hybrid consisting of the polymethylacrylic acid core with cross-linked structure of disulfide bond, PMAABACy/Fe3+-based MOF interlayer and biologically inspired PDA coating, which has not been reported until now to our best knowledge as illustrated in Scheme 1. Among these building materials, PMAABACy core with cross-linked structure of disulfide bond endowed this PMAABACy@(MOF)10@PDA hybrid with reduction-sensitive property, which could be used to adsorb DOX molecules and anchor Fe3+ ions. Then the introduction of PMAABACy/Fe3+-based MOF interlayer not only further encapsulate chemotherapeutic drug, but also provide a high stability to control drug delivery. The PDA coating was subsequently coated on the surface of PMAABACy@(MOF)10 hybrid via the self-polymerization of dopamine at alkaline environment for the sake of biocompatibility.22 In this study, MIL-100 (Fe)-based MOF interlayer were composed of trimesic acid (TMA) ligands and iron(III) metal centers. What’s more, iron(III) in MOF interlayer could catalyze the decomposition of H2O2. During the process, the structure of MIL-100 (Fe) could be readily destroyed owing to the dissociation of the coordination between iron(III) and TMA breaks. On the basis of the decomposition, the dissociated MIL-100 (Fe) would selectively accelerate the release of the as-loaded chemotherapeutic drug in the presence of H2O2 at pathological concentration, such as the tumor site.24 Subsequently, the PMAABACy core within DDS also could be disintegrated at the pathological concentration of GSH in endosomes.23 Accordingly, H2O2/GSH dual-sensitive PMAABACy@(MOF)10@PDA hybrid was prepared, which could simultaneously respond to H2O2 and GSH at the biological level, destroying their structure. The on-demand release performance validated that DOX-loaded PMAABACy@(MOF)10@PDA could selectively release DOX at the pathological concentration of H2O2 and GSH, demonstrating that this PMAABACy@(MOF)10@PDA hybrid could achieve the precise on-demand drug release upon tumor microenvironment as shown in Scheme 1.



2. MATERIALS AND METHODS Materials and Reagents. 2, 2′-Azobisisobutyronitrile (AIBN) was obtained from Sinopharm Chemical Reagent Co. Ltd and recrystallized from methanol. Methacrylic acid (MAA) was also provided by Aldrich. FeCl3·6H2O and benzene-1,3,5-tricarboxylic acid (H3TBC) were obtained from Sinopharm Chemical Reagent Co. Ltd. DOX·HCl (DOX), dopamine, and cystamine dihydrochloride were provided by Fluorochem Ltd. GSH was obtained from Tianjin Heowns Biochemical Technology Co. Ltd. All other reagents from Tianjin Chemical Co. Ltd were analytic reagent grade. Preparation of PMAABACy Hydrogel. The as-reported procedure was utilized to prepare the typical PMAABACy hydrogel according to the previous reports.26,27 And the resulting product was then lyophilized at room temperature. Fabrication of PMAABACy@(MOF)10. The MOF-coated PMAABACy hybrid was prepared by a layer-by-layer self-assembly strategy. PMAABACy (100 mg) were dispersed in an ethanol solution of FeCl3·6H2O (2 mM, 4 mL) for 30 min to anchor Fe3+ at room temperature. And then PMAABACy/Fe3+ was obtained via centrifugation. Thereafter, PMAABACy/Fe3+ was dispersed in an ethanol solution of H3TBC (2 mM, 4 mL) for 30 min at room temperature. After centrifugation, PMAABACy@(MOF)1 was collected. By above the same procedures, the PMAABACy@(MOF)10 was fabricated via alternately absorption between Fe3+ and H3TBC through repeated rounds of the self-assembly for 10 times. Finally, the resulting PMAABACy@(MOF)10 was lyophilized and stored at room temperature. PDA-coated of PMAABACy@(MOF)10. To obtain the favor biocompatibility, the biologically inspired dopamine was utilized to modify the surface of PMAABACy@(MOF)10, 60 mg of PMAABACy@(MOF)10 was added in 40 mL of Tris-HCl buffer (pH 8.5, 10 mM). Subsequently, 25 mg of hydrochloride dopamine was introduced to the above-dispersion. The reaction was performed in darkness at 25 °C for 24 h. Thereafter, PMAABACy@(MOF)10@PDA was collected through centrifugation and washed several times with abundant water to remove the unpolymerized dopamine.19 In the end, the resulting PMAABACy@(MOF)10@PDA hybrid was also lyophilized and stored at room temperature. Disintegration of PMAABACy@(MOF)10@PDA. To investigate the disintegration of PMAABACy@(MOF)10@PDA, 20 mg of PMAABACy@(MOF)10@PDA was dispersed in 20 mL of buffer solution (pH 5.0, 10 mM GSH) to etch the PMAABACy core with the aid of slightly magnetic stirring. The (MOF)10@PDA hollow microsphere then was collected through centrifugation. Subsequently, 50 μM of H2O2 was introduced to study the disintegration of (MOF)10@PDA hollow microsphere for the different periods of time. Drug Loading and Triggered Release. The PMAABACy@(MOF)10@PDA hybrid was chosen to evaluate its behavior of drug-loading and release according to the previous report.28 To evaluate the influence of MOF interlayer and PMAABACy on drug release, the drug release performance of DOX-loaded PMAABACy@(MOF)10@PDA hybrid was investigated in different buffer solution (pH 7.4 with 10 μM GSH, 50 μM H2O2, 50 mM H2O2, pH 7.4 with 10 mM GSH, and pH 5.0 with 10 mM GSH). More importantly, the dual-stage release of DOX-loaded PMAABACy@(MOF)10@PDA was performed to evaluate its release behavior at simulate tumor microenvironment. Briefly, DOX-loaded PMAABACy@(MOF)10@PDA (10 mg) was transferred to 80 mL PBS 7.4 with 50 mM H2O2. After 9 h, the dialysis solution was fleetly removed by


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centrifugation to obtain the residual precipitate. And the residual precipitate was also immersed in 80 mL of PBS (pH 5.0 with 10 mM GSH) to further perform its drug release for surplus 36 h. Cell Toxicity Assays. The MTT assay and fluorescence inversion microscope system (FIMS) were performed to investigate the biocompatibility of samples using PC-3 cell according to our previous report.26,28 Intracellular Release of DOX-Loaded PMAABACy@(MOF)10@PDA Hybrid. The confocal laser scanning microscopy (CLSM) was used to evaluate the intracellular release of DOX-loaded PMAABACy@(MOF)10@PDA using PC-3 cells according to our previous report.5 Analysis and Characterization. The morphology of PMAABACy, PMAABACy@(MOF)10, and PMAABACy@(MOF)10@PDA was traced by using both transmission electron microscope (TEM) and scanning electron microscopy (SEM). The FT-IR spectra of PMAABACy, PMAABACy@(MOF)10, and PMAABACy@(MOF)10@PDA was recorded with a Bruker infrared spectrometer. A dynamic light scattering (DLS, BI-200SM device) was used to detect the average hydrodynamic diameter (Dh) and the stability of samples. An Elementar Vario EL instrument was used to investigate the X-ray photoelectron spectroscopy (XPS) of samples. A

Micromeritics

ASAP

2420

apparatus

was

utilized

to

detected

the

unique

porosity

of

the

PMAABACy@(MOF)10@PDA at 77 K. The drug-loading of PMAABACy@(MOF)10@PDA and the triggered release profile of DOX-loaded PMAABACy@(MOF)10@PDA were validated using a Lambda 35 UV-vis spectrometer. The drug encapsulation efficiency (DEE) and drug-loading capacity (DLC) could be assessed according to our previous report.5 3. RESULTS AND DISCUSSION Synthesis of PMAABACy@(MOF)10@PDA. As illustrated in Scheme 1, the overall synthetic steps to PMAABACy@(MOF)10@PDA were exhibited. Briefly, the distillation-precipitation polymerization of MAA and BACy was used to prepare the PMAABACy hydrogel with disulfide cross-linked structure. Subsequently, the PMAABACy@(MOF)10 hybrid was crafted via the layer-by-layer self-assembly of Fe3+ and H3TBC on the surface of PMAABACy core to tune drug release. Finally, the PDA coating was introduced on the surface of PMAABACy@(MOF)10 hybrid via the self-polymerization of dopamine at alkaline environment for the sake of biocompatibility. Not only the existence of PMAABACy core and MOF interlayer enhanced the DLC and DEE of PMAABACy@(MOF)10@PDA, but these existence were disintegrated upon the elevated H2O2 and GSH, suggesting that the site-specific release of DOX being facilitated at the tumor site (Scheme 1). Meanwhile, the existence of MOF was applied to control the release of DOX to improve therapeutic effect.



Figure 1. The SEM images of PMAABACy (A), PMAABACy@(MOF)10 (C), and PMAABACy@(MOF)10@PDA (G); and the TEM images of PMAABACy (B), PMAABACy@(MOF)10 (D), and PMAABACy@(MOF)10@PDA (H); the highmagnification SEM (E) and TEM (F) images of PMAABACy@(MOF)10, respectively. As shown in Figure 1A and B, both SEM and TEM images exhibited the PMAABACy core with uniform size and morphology, respectively. And its morphology displayed spherical shape with the average diameter of approximately 86 nm. Owing to the existence of abundant carboxyl (-COOH) within PMAABACy, which could serve as a desired template to efficiently anchor Fe3+ and H3TBC through a layer-by-layer self-assembly. As illustrated in Figure 1C and D, the morphology of PMAABACy@(MOF)10 displayed a rough state compared to the smooth surface of PMAABACy core. Most importantly, the rich small embossing was found on the surface of PMAABACy@(MOF)10 as the number of MOF layers increasing to 10, indicating that the successful introduction of MOF on the surface of PMAABACy hydrogel. This phenomenon was attributed to the introduction of inorganic clusters resulting in a rough surface. Furthermore, as the introduction of MOF interlayers, the average diameter of spherical PMAABACy@(MOF)10 hybrid increased to around 126 nm. Subsequently, the PDA coating was introduced on the surface of PMAABACy@(MOF)10 hybrid to improve favorable biocompatibility. As depicted in Figure 1E and F, there was no small embossing being found in the visible area, revealing the existence of PDA coating compared to that of PMAABACy@(MOF)10 hybrid. As a consequence, we believed that the MOF interlayer and PDA coating were successfully introduced on the surface of PMAABACy hydrogel, displaying a new strategy to the fabrication of PMAABACy@(MOF)10@PDA.


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Figure 2. The FT-IR spectra of PMAABACy, PMAABACy@(MOF)10, and PMAABACy@(MOF)10@PDA (A); and the XPS spectra of PMAABACy, PMAABACy@(MOF)10, and PMAABACy@(MOF)10@PDA (B). To endow the PMAA hydrogel with GSH-sensitive property upon tumor microenvironment, BACy was adopted to cross-link the PMAA chains to obtain the PMAABACy hydrogel with reductive property. PMAABACy hydrogel therefore was synthesized using a mild one-pot distillation-precipitation polymerization according to the previous report.29 As shown in Figure 2A, The FT-IR data of PMAABACy hydrogel showed that the typical amide I (1644 cm-1) bands of BACy crosslinker and the C=O stretching vibration (1712 cm-1) of MAA.29 It’s demonstrated that the PMAABACy hydrogel contained both MAA monomer and BACy crosslinker, rather than only MAA monomer. After been coated with MOF interlayer, the FT-IR spectrum of PMAABACy@(MOF)10 displayed two new adsorption peaks at 1752 cm-1 and 715 cm-1 as depicted in Figure 2A. And these two new adsorption peaks were assigned to the stretching vibration of C=C of H3TBC and out-of-plane blending vibration of H3TBC,30 respectively. After modification with PDA, a new peak appeared in the FT-IR spectrum of PMAABACy@(MOF)10@PDA at 1623 cm-1 compared to that of PMAABACy hydrogel and PMAABACy@(MOF)10 hybrid. Furthermore, the obvious typical amide I bands of BACy crosslinker at 1644 cm-1and the C=O stretching vibration of MAA at 1712 cm-1 disappeared in the FT-IR spectrum of the PMAABACy@(MOF)10@PDA. It demonstrated that the PDA coating has been introduced on the surface of PMAABACy@(MOF)10 to obtain the PMAABACy@(MOF)10@PDA hybrid. To further confirm the successful preparation of PMAABACy@(MOF)10@PDA hybrid, the X-ray photoelectron spectroscopy (XPS) was performed to track the overall procedures. The Figure 2B displayed the bands at 227.17 eV and 399.75 eV in XPS spectrum of PMAABACy, respectively, revealed the existence of S and N components on the surface of PMAABACy hydrogel. These results demonstrated that BACy monomer was introduced in PMAA hydrogel. Furthermore, the two unique bands at 712 eV and 726 eV were found in the spectrum of PMAABACy@(MOF)10 hybrid, revealing that the existence of MOF interlayer, as well as confirming the successful generation of MOF interlayer. After the modification with PDA coating, these aforementioned typical binding-energy peaks disappeared in the spectrum of PMAABACy@(MOF)10@PDA hybrid, suggesting the introduction of PDA coating.



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Figure 3. The typical Dh distribution (A) of PMAABACy (a), PMAABACy@(MOF)10 (b), PMAABACy@ (MOF)10@PDA (c), (MOF)10@PDA with treatment of pH 5.0 with10 mM GSH (d), and the disintegration to PMAABACy@(MOF)10@PDA

by

H2O2

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triggers

(e);

the

pore

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within

PMAABACy@(MOF)10@PDA through BET experiment (B); the stability of PMAABACy@(MOF)10@PDA in DMEM with PBS (10%, v/v) (C); and fluorescent emission spectra of PMAABACy@(MOF)10@PDA and DOX-loaded PMAABACy@(MOF)10@PDA in neutral medium (D). To trace the preparation process of PMAABACy@(MOF)10@PDA, the Dh of PMAABACy, PMAABACy@(MOF)10 and PMAABACy@(MOF)10@PDA was detected using DLS technique. These aforementioned three samples exhibited a narrow unimodal size distribution as depicted in Figure 3A. As the introduction of MOF interlayer and PDA coating, the Dh of PMAABACy@(MOF)10 and PMAABACy@(MOF)10@PDA increased to around 152 nm and 224 nm compared to 224 nm of PMAABACy, respectively. The difference between PMAABACy and PMAABACy@(MOF)10 implied the introduction of MOF interlayer. Meanwhile, the difference between PMAABACy@(MOF)10 and PMAABACy@(MOF)10@PDA also implied the introduction of PDA coating. Additionality, the as-prepared PMAABACy@(MOF)10@PDA exhibited the pore size distribution of approximately 2 nm (Figure 3B), which could be served as a desired tunnel for loading and unloading of DOX molecules. Furthermore, after dispersion for 72 h, the as-prepared PMAABACy@(MOF)10@PDA displayed better stability in DMEM with PBS (10%, v/v) (Figure 3C), indicating its excellent stability in a physiological medium. Meanwhile, these DLS results of PMAABACy hydrogel, PMAABACy@(MOF)10 and PMAABACy@(MOF)10@PDA hybrid have kept consistent with FT-IR, TEM and SEM results from the three samples, indicating the successful preparation of PMAABACy@(MOF)10@PDA hybrid.


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Figure 4. The TEM images of PMAABACy@(MOF)10@PDA with treatment of 10 mM GSH for 2 h (A), and then the 50 μM H2O2 introduced into the above media under magnetic stirring for 1 h (B), 2 h (C), and 3 h (D). Disintegration of PMAABACy@(MOF)10@PDA Hybrid. To evaluate whether such a responsive PMAABACy core within PMAABACy@(MOF)10@PDA hybrid was suitable for decomposition at the pathological concentration of H2O2 and GSH, both DLS and TEM were performed to investigate its related behavior. As we know, the vigorous metabolism of tumor tissues would not only lead to the existence of GSH in high concentration in endosomes, but also result in the slightly acidic H2O2 microenvironments.25 Considering the reactivity of GSH toward PMAABACy hydrogel with reduction-sensitive property, the decomposition performance of the PMAABACy core within PMAABACy@(MOF)10@PDA

hybrid

was

adequately

evaluated

in

typical

environment.

Briefly,

PMAABACy@(MOF)10@PDA hybrid was dispersed into acetate buffer solution (pH 5.0 with 10 mM GSH) with the aid of slightly stirring. After 2 h, the related TEM image exhibited hollow structure in the field of vision (Figure 4A), which was ascribed to the decomposition of PMAABACy core by the function of acidic GSH trigger to obtain the (MOF)10@PDA hybrid with hollow structure compared to that of PMAABACy@(MOF)10@PDA hybrid, suggesting that the PMAABACy core was removed. Furthermore, DLS technique was also applied to track the decomposition. As shown in Figure 3A-d, the average hydrodynamic diameter (Dh) of (MOF)10@PDA hybrid was approximately 209 nm compared to that of PMAABACy@(MOF)10@PDA hybrid. The decomposition of PMAABACy core has resulted in the shrinkage of (MOF)10@PDA hybrid with hollow microspheres. Notably, this decomposition of PMAABACy core at typical environment contribute to tune the site-specific release of the as-loaded drug at focus site. Meanwhile, the elevated H2O2 level was introduced to further disturb the structure of (MOF)10@PDA hybrid. After the treatment with 50 μM H2O2 for different periods of time, the structure of (MOF)10@PDA hybrid was destroyed over 3 h (Figure 4B, C, and D), demonstrating that the activation of MOF layer in the presence of 50 μM H2O2.20 Since the reaction between H2O2 and MIL-100 (Fe) was accompanied by the degradation of MOF layer,23 the collapse of PDA coating was found in the vision of Figure 4D, which was consistent with the DLS results (Figure 3A-e). This phenomenon was attributed the revocation of MOF layer to trigger the collapse of PDA coating. As expected, after fulfilling its delivering task, this PMAABACy@(MOF)10@PDA would be disintegrated into biocompatible byproducts, including the iron(III), PMAA chain, PDA segment, and trimesic acid ligands. These byproducts exhibited excellent biocompatibility and were chosen as building block to fabricate nanocarriers.17,23,26 From the above findings, the introduction of GSH-sensitive PMAABACy core and H2O2-sensitive MOF layer endow this PMAABACy@(MOF)10@PDA hybrid with GSH/H2O2 dual-sensitive properties upon tumor-microenvironmental triggers, indicating that the PMAABACy@(MOF)10@PDA hybrid can be potential to effectively deliver drug to focus



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1.5 1.0 0.5 Y=0.8579X-0.9654

0.0

1000 1500 2000 2500 3000

R2=0.9868

1.0

Time (min)

1.5

2.0 2.5 3.0 Log of time

3.5

Figure 5. Cumulative DOX release from DOX-loaded PMAABACy@(MOF)10@PDA in different buffer solution (50 μM H2O2, 50 mM H2O2, pH 7.4 with 10 μM GSH, pH 7.4 with 10 mM GSH, and pH 5.0 in the presence of 10 mM GSH) (A and B). Additionally, the dual-stage release was performed to study cumulative DOX release (C). Curves of Korsmeyer-Peppas models for the dual-stage release from PMAABACy@(MOF)10@PDA at different periods of time (D). Drug Loading and Controlled Release. For a perfect nanocarrier, the encapsulation efficiency and loading capacity of chemo drugs to itself are of fundamental importance for cancer therapy. It is expected that the DDS exhibits a desired drug loading capacity (DLC) and drug encapsulation efficiency (DEE). Briefly, 50.0 mg of PMAABACy@(MOF)10@PDA hybrid was added in 50.0 mL of 1.0 mg/mL DOX solution under magnetic stirring with the help of ultrasonic wave at pH 7.4. The mixtures were subsequently centrifuged to obtain the DOX-loaded PMAABACy@(MOF)10@PDA hybrid. As we know, the modal DOX molecule was adsorbed into PMAA hydrogel through the electrostatic interaction.31,32 As a result of this interaction, DOX molecule could be noncovalently adsorbed onto the PMAABACy@(MOF)10@PDA hybrid. Furthermore, the MOF layer was also applied to loaded DOX molecule due to the existence of the desired pore size distribution. After the loading of DOX, a UV-vis spectrometer was performed to evaluate the drug-loading capacity and drug encapsulation efficiency of PMAABACy@(MOF)10@PDA hybrid. The high drug-loading capacity (0.9134 mg/mg ± 0.6421 mg/mg) and efficient drug encapsulation efficiency (91.34% ± 6.42%) to PMAABACy@(MOF)10@PDA hybrid were obtained because of the

existence

of

both

PMAA

hydrogel

and

MOF

layer.

Additionally,


as

compared

with

the

Page 11 of 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 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


PMAABACy@(MOF)10@PDA hybrid, the significant fluorescence of DOX-loaded PMAABACy@(MOF)10@PDA hybrid

was

detected,

indicating

PMAABACy@(MOF)10@PDA

that

hybrid

DOX

(Figure

molecules 3D).

As

were

successfully

a

consequence,

adsorbed the

into

the

DOX-loaded

PMAABACy@(MOF)10@PDA hybrid with the desired DLC and DEE was crafted. To investigate the in vitro controlled release performance of DOX-loaded PMAABACy@(MOF)10@PDA, the typical conditions of pH 7.4 with 10 μM GSH, 0.5 μM H2O2, 50 μM H2O2, pH 7.4 with 10 mM GSH, and pH 5.0 with 10 mM GSH were chosen to trigger the release of the as-loaded drug, respectively. As illustrated in Figure 5A, in the presence of H2O2 at normal physiological concentration (0.5 μM), the cumulative release ratio to DOX-loaded PMAABACy@(MOF)10@PDA was only 7.84% after 48 h. However, when the H2O2 level was increased to its pathological concentration (50 μM), over 22.5% of the as-loaded DOX was released (Figure 5A). These results demonstrated that the MOF layer within PMAABACy@(MOF)10@PDA could be selectively destroyed in the presence of H2O2 at pathological concentration rather than that at physiological condition. After MOF layer decomposition, the as-loaded DOX was released. However, most of the as-loaded DOX molecules still were encapsulated within PMAABACy@(MOF)10@PDA because of the existence of PMAABACy. Meanwhile, the cumulative release ratio to DOX-loaded PMAABACy@(MOF)10@PDA was only 2.84% at pH 7.4 in the presence of 10 μM GSH for 48 h (Figure 5B), mimicking the extracellular trafficking pathway. By contrast, when the GSH level was increased to 10 mM, the cumulative release ratio to DOX-loaded PMAABACy@(MOF)10@PDA was increased to 8.76% (Figure 5B). The increased cumulative release ratio was attributed to the breakage of disulfide bond within PMAABACy core at the pathological concentration of GSH (10 mM ).33 With the release condition of media further changed to pH 5.0 in the presence of 10 mM GSH, the cumulative release ratio to DOX-loaded PMAABACy@(MOF)10@PDA hybrid was over 25.86 % as displayed in Figure 5B. However, most of the as-loaded DOX molecules still were encapsulated within PMAABACy@(MOF)10@PDA because of the existence of both MOF interlayer and PDA coating, which hindered the cumulative release of DOX from the DOX-loaded PMAABACy@(MOF)10@PDA hybrid. To further investigate the DOX release performance of DOX-loaded PMAABACy@(MOF)10@PDA hybrid at intracellular environment of tumor tissues, the typical media (50 μM H2O2) were conducted at 37 °C. With the increasing of release time to 9 h, an obviously cumulative release profile of DOX was observed as shown in Figure 5C. At the moment, the abovementioned dispersion system was centrifuged to remove the entire solvent and 80 mL of PBS solution (pH 5.0 with10 mM GSH ) was introduced to further trigger the release of DOX molecules. Notably, a rapidly cumulative release profile of DOX was observed at 24 h postaddition, then its release exhibited a sustained release profile in the final 15 h, and then 78.52 wt % of cumulative release ratio was achieved as illustrated in Figure 5C. Because of the elevated H2O2 level disturbed the structure of MOF interlayer and the decomposition of PMAABACy core was subsequently caused by the function of acidic GSH trigger to destroy the structure of DOX-loaded PMAABACy@(MOF)10@PDA hybrid, which accelerated the diffusion of DOX. On the basis of the above analysis, we therefore supposed that the combination of H2O2-sensetive MOF interlayer and GSH-sensitive PMAABACy core synergistically tuned the DOX release profile at typical media (first responding to 50 μM H2O2, and then to pH 5.0 with 10 mM GSH), mimicking the trafficking pathway at the tumor sites. As a desired nanocarrier, the PMAABACy@(MOF)10@PDA hybrid could efficiently restricted the premature leakage of DOX to decease the side effects. Especially in mimicking the trafficking pathway at the tumor sites, most of DOX molecules could be readily released to enhance the therapeutic effect. As a consequence, we believed that the PMAABACy@(MOF)10@PDA



hybrid could offer aforementioned significant merits to enhance therapy efficiency and improve severe side effects. As illustrated in Figure 5D, the semiempirical Korsmeyer-Peppas equation was applied to analyze the accumulative release data at typical media (first responding to 50 μM H2O2, and then to pH 5.0 with 10 mM GSH). The linearly dependent coefficient (R2) of 0.99 and release exponents (n) of 0.85 were obtained from the above equation, indicating that release mechanism of DOX was anomalous.34,35 This release mechanism of drug could be considered to accord with pseudo-Fickian or a Case III mechanism at the typical media. Considering the hindrance of the MOF interlayer and PMAABACy core within PMAABACy@(MOF)10@PDA hybrid, which efficiently restricted the release of DOX at the first time. Subsequently, the decomposition of both MOF interlayer and PMAABACy core exhibited a positive effect to enhance DOX release, which synchronously yielded anomalous mechanism. From the above, the hindrance effect of MOF interlayer within PMAABACy@(MOF)10@PDA hybrid restricted the premature release at physiological conditions, whereas the burst release of DOX could be realized in mimicking the intracellular environment in the tumor tissues because of the decomposition of MOF interlayer and PMAABACy core. 0 100

Cell Viability (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 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

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Concentrationof PMAA@MOF10@PDA (g/mL) 40 80 120 160 200 240

A

a

B

C

D

80 60

b c

40 20 0

1.2

2.4

9.6 4.8 6.0 DOX equivalent dose (g/mL)

Figure 6. Cell viability assay in PC-3 cells with the treatment of PMAABACy@(MOF)10@PDA (A-a), DOX-loaded PMAABACy@(MOF)10@PDA (A-b), and free DOX (A-c) at 37 °C for 24 h. Data were presented as the mean ± standard deviation (SD; n = 5). In addition, typical micrographs of the PC-3 cells after incubation with PMAABACy@(MOF)10@PDA (B), free DOX at pH 7.4 (C), and DOX-loaded PMAABACy@(MOF)10@PDA (D) at neutral condition for 24 h. Scale bar, 100 µm.

Biocompatibility and Cell Toxicity. The biocompatibility of DDS is also of fundamental importance for cancer therapy. To evaluate the significance, the biocompatibility of PMAABACy@(MOF)10@PDA hybrid was conducted by MTT assay using PC-3 cells with an inherently higher level of H2O2. After incubation for 24 h, the viability of the PC-3 cells treated with the PMAABACy@(MOF)10@PDA hybrid exceeded approximately 90% in the range of testing concentrations as depicted in Figure 6A, indicating that PMAABACy@(MOF)10@PDA exhibited better biocompatibility to PC-3 cells. We supposed that the favorable viability was ascribed to the introduction of PDA and PMAA. To further investigate the inhibition against cancer cells, PC-3 cells were incubated with DOX-loaded PMAABACy@(MOF)10@PDA at different concentrations. The DOX-loaded PMAABACy@(MOF)10@PDA hybrid toward PC-3 cells displayed obvious cytotoxicity as illustrated in Figure 6A-b. With the increasing of DOX concentration, the cytotoxicity toward PC-3 cells exhibited obvious enhancement in the range of testing concentrations, indicating that DOX-loaded PMAABACy@(MOF)10@PDA could be able to effectively deliver DOX into tumor cell, further inhibited the growth of PC-3 cells. It likely may be due to the tumor microenvironment triggering the DOX delivery from DOX-loaded PMAABACy@(MOF)10@PDA after cell internalization. As we know, the intracellular environment inside lysosomes and endosomes exhibited a relative high level of GSH and obviously


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acidic feature,5 which could trigger the dissociation of PMAABACy core within PMAABACy@(MOF)10@PDA hybrid to facilitate DOX release. Additionally, the viability of PC-3 cells with the treatment of free DOX (Figure 6A-c) at neutral condition exhibited the similar trend compared to that of DOX-loaded PMAABACy@(MOF)10@PDA. With the help from the control experiment of free DOX, we supposed that DOX-loaded PMAABACy@(MOF)10@PDA has exhibited same effect toward PC-3 cells compared to that of free DOX. To visualize the procedures of the inhibition against cancer cells, the relevance of the morphologies of PC-3 cells with the treatment of PMAABACy@(MOF)10@PDA, free DOX and DOX-loaded PMAABACy@(MOF)10@PDA could be directly exhibited using FIMS (Figure 6B, C, and D), respectively. It is very interesting that whole PC-3 cells died after the treatment of DOX-loaded PMAABACy@(MOF)10@PDA or free DOX at neutral condition, whereas a large proportion of the PC-3 cells survived with the treatment of PMAABACy@(MOF)10@PDA. We found that these aforementioned results were agree with the design objective of PMAABACy@(MOF)10@PDA, namely that the PMAABACy@(MOF)10@PDA could effectively delivered DOX into tumor cell, further inhibited the growth of tumor cell.

Bright Field

Hoechst

DOX

Merged Image

A

B

Figure 7. Intracellular release of the as-loaded DOX exhibited by CLSM in PC-3 cells after 1 h (A) and 24 h (B) of incubation. Scale bar, 50 μm. Intracellular Release. To further confirm the intracellular release of the as-loaded DOX molecules, the CLSM technique was applied to visualize the intracellular distribution of DOX from the DOX-loaded PMAABACy@(MOF)10@PDA using PC-3 cells as displayed in Figure 7. After incubation for 1h, the DOX fluorescence was hard to detect, implying that the drug release was not triggered. Notably, the obvious DOX red fluorescence were observed in cell nuclei of PC-3 cells for 24 h incubation (Figure 7B), suggesting that the cell internalization of the DOX-loaded PMAABACy@(MOF)10@PDA was realized and the as-released DOX was delivered to cell nuclei. Furthermore, a great mass of dead tumor cells were found in Figure 7B, which kept consistent with the previous reports.36,37 It revealed that PMAABACy@(MOF)10@PDA efficiently delivered DOX to cell nucleus. Additionally, the aforementioned result was also accordance with the results of FIMS as shown in Figure 6. As a consequence, these findings verified the engineering-hypothesis of PMAABACy@(MOF)10@PDA hybrid, namely that PMAABACy@(MOF)10@PDA could efficiently deliver DOX into tumor cell, inhibiting the growth of tumor cell. 4. CONCLUSIONS



In summary, we developed a simple and multifunctional vehicle based on PMAABACy@(MOF)10@PDA hybrid that was prepared through the combination of distillation-precipitation polymerization, layer-by-layer self-assembly and self-polymerization of dopamine. Among its components, the PMAABACy core was able to adsorb chemo drug (DOX) and anchor Fe3+ ions; the MOF layer also could be used to encapsulate chemo drug, simultaneously provided a high stability to control drug delivery; the PDA coating subsequently was introduced for the sake of biocompatibility. Notably, the PMAABACy core and MOF interlayer within this DDS were disintegrated in the presence of H2O2 and GSH at tumor microenvironment. As a consequence, the dual-responsive PMAABACy@(MOF)10@PDA hybrid could respond to H2O2 and GSH at the biological level, further destroying its structure. The performance appraisement validated that DOX-loaded PMAABACy@(MOF)10@PDA could selectively release DOX in the presence of H2O2 and GSH, demonstrating that this PMAABACy@(MOF)10@PDA hybrid could achieve the precise on-demand drug release upon tumor microenvironment. Therefore, this multifunctional vehicle displays the advantages of MOFassisted regulate strategy to DDS for future chemotherapy.

ACKNOWLEDGEMENTS We thank these following funding sources: China Postdoctoral Science Foundation (No. 2018M632795), National Natural Science Foundation of China (No. 21704093), Science & Technology Innovation Talent Plan of Henan Province (No. 174200510018), and Technology Innovation Team of Henan Province (No. 16IRTSTHN001).

NOTES

The authors declare no competing financial interest.

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Metal-Organic Framework-Assisted Nanoplatform with Hydrogen

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