An ATP-Responsive Autocatalytic Fenton Nanoparticle for Tumor

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An ATP-Responsive Autocatalytic Fenton Nanoparticle for Tumor Ablation with Self-Supplied H2O2 and Acceleration of Fe(III)/Fe(II) Conversion Lu Zhang, Shuang-Shuang Wan, Chu-Xin Li, Lu Xu, Han Cheng, and Xian-Zheng Zhang Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.8b03178 • Publication Date (Web): 01 Nov 2018 Downloaded from http://pubs.acs.org on November 1, 2018

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An ATP-Responsive Autocatalytic Fenton Nanoparticle for Tumor Ablation with Self-Supplied H2O2 and Acceleration of Fe(III)/Fe(II) Conversion

Lu Zhang,† Shuang-Shuang Wan,† Chu-Xin Li, Lu Xu, Han Cheng, and Xian-Zheng Zhang*

Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China

* Corresponding author E-mail address: [email protected] (X.-Z. Zhang) †

L. Zhang and S.-S. Wan contributed equally to this work.

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Abstract Chemodynamic therapy (CDT) can efficiently destroy tumor cells via Fenton reaction in the presence of H2O2 and a robust catalyst. However, it has faced severe challenges including the limited amounts of H2O2 and inefficiency of catalysts. Here, an ATPresponsive autocatalytic Fenton nanosystem (GOx@ZIF@MPN), incorporated with glucose oxidase (GOx) in zeolitic imidazolate framework (ZIF) and then coated with metal polyphenol network (MPN), was designed and synthesized for tumor ablation with self-sufficient H2O2 and TA-mediated acceleration of Fe(III)/Fe(II) conversion. In the ATP overexpressed tumor cells, the outer shell MPN of GOx@ZIF@MPN was degraded into Fe(III) and tannic acid (TA) while the internal GOx was exposed. Then GOx reacted with the endogenous glucose to produce plenty of H2O2, while TA reduced Fe(III) to Fe(II) that is a much vigorous catalyst for Fenton reaction. Subsequently, selfproduced H2O2 was catalyzed by Fe(II) to generate highly toxic hydroxyl radical (∙OH) and Fe(III). The produced Fe(III) with low catalytic activity was quickly reduced to reactive Fe(II) mediated by TA, forming an accelerated Fe(III)/Fe(II) conversion to guarantee efficient Fenton reaction mediated CDT. This autocatalytic Fenton nanosystem might provide a good paradigm for effective tumor treatment.

Keywords: glucose oxidase, metal polyphenol network, Fenton reaction, Fe(III)/Fe(II) conversion, chemodynamic therapy, starvation therapy

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As an alternative strategy for traditional cancer treatment, chemodynamic therapy (CDT) has received increasing attention in recent years due to its unique way of Reactive oxygen species (ROS) generation independent of local oxygen.1-3 During CDT process, ∙OH can be directly produced by endogenous chemical energy (H2O2) through a metal ions-mediated Fenton reaction.4-5 And ∙OH (E(∙OH /H2O) = 2.80 V) is a stronger oxidizing ROS than H2O2 ((E(H2O2/H2O) = 1.78 V), which can cause more detrimental oxidative damage to tumor cells.6 Hence, it is an effective strategy to convert endogenous H2O2 into highly toxicity ∙OH by catalysts for cancer treatment. Importantly, such a process substantially avoids non-specific side effect (toxicity to normal tissues) as well as low efficiency (limited light penetration and oxygen dependence) brought by traditional cancer treatments like chemotherapy and photodynamic therapy (PDT).7-9 However, limited amounts of H2O2 in vivo and inefficient catalysts have restricted the further application of CDT in some degree.10-11 Thus, it is urgent to develop a Fenton nanosystem with excellent catalytic performance for highly efficient and specific cancer treatment. In order to solve the problem of insufficient endogenous H2O2 in tumor region, strategies like directly wrapping exogenous H2O2 or stimulating the production of endogenous H2O2 were proposed.11-12 However, the leakage of H2O2 from wrapping materials might be inevitable and thus cause damage to normal tissues.13 Therefore, it may be a better way to stimulate H2O2 production in situ, and the stimulus should be designed to achieve the purpose of specific response and dosage control.14 It is known that glucose oxidase (GOx) could catalyze β-D-glucose to produce gluconic acid and 3


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H2O2, which would meet the requirement of H2O2 generation in situ.15 What’s more, the consumption of glucose (GO) in tumor cells may also disorder glucose metabolism, resulting in starvation therapy of tumor cells.16-17 As described by Warburg, the proliferation of tumor cells mainly depends on aerobic glycolysis, which make tumor cells more sensitive to glucose concentration change.18-20 Thus, the way of altering tumor glucose metabolic pathways becomes a kind of attractive cancer therapy strategy.21 To date, although several studies have applied metal ions like Mn(II) and Cu(II) to initiate a Fenton-like reaction,22-24 the most widely used is still Fe(II), which usually comes from Fe3O4 and ferrocene.25-26 In Fe(II)-mediated Fenton reaction systems, Fe(II) catalyzes H2O2 to produce ∙OH and itself could be oxidized into Fe(III). Fe(III) exhibits lower catalytic performance than Fe(II) and the conversion rate (0.002−0.01 M−1 s−1) from Fe(III) to Fe(II) is very slow,27 which will retard the efficiency of Fenton reaction.28 In catalytic field, many strategies have been proposed to accelerate Fe(III)/ Fe(II) conversion for enhanced Fenton reaction, such as combing semiconductor materials or reductive substances with Fe-containing materials.29-31 However, the way that light-excited semiconductors transfer electron to reduce Fe(III) was limited by the poor penetration of ultraviolet (UV) light. Hence, introducing a reductive substance into the Fenton system may be a more attractive approach. As far as we know, it is rarely reported to improve the effect of Fenton reaction by accelerating Fe(III)/Fe(II) conversion for CDT. Therefore, enhancing the effect of CDT with reductive substance is greatly possible to achieve better cancer treatment. 4


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An excellent drug carrier should specifically respond to the tumor environment, which avoided damage of normal tissues.32-33 It is well known that adenosine triphosphate (ATP) in tumor cells is upregulated as compared to that in normal cells,34 which provides a target for cancer therapy.35-36 Hence, we designed an ATP-responsive autocatalytic Fenton nanosystem GOx@ZIF@MPN for tumor ablation by the enhanced CDT and starvation therapy. As illustrated in Scheme 1, GOx was encapsulated in ZIF by one pot synthesis, and then it was used as a template for formation of GOx@ZIF@MPN (Scheme 1A). Once administrated into mice by tail vein, GOx@ZIF@MPN could not only avoid the toxicity to normal tissues caused by GOx leakage but also realize long blood circulation and effective accumulation in tumor site. When internalized by tumor cells (Scheme 1B), the overexpressed ATP made the external MPN coating degrade to release Fe(III) and TA, accompanied with exposure of GOx. On one hand, the released TA could reduce Fe(III) into Fe(II) due to its reductive ability. On the other hand, the exposed GOx consumed glucose to cut off the nutrient supply of tumor cells and produce H2O2 for ∙OH generation by subsequent catalysis of Fe(II). Thus, the enhanced Fenton reaction combined with aggravated starvation of cells could be achieved simultaneously in vivo, which showed excellent antitumor

ability

against

4T1

tumor-bearing

mice.

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Scheme 1. Schematic illustration of GOx@ZIF@MPN as an ATP-responsive autocatalytic Fenton nanosystem for tumor ablation. (A) The preparation of GOx@ZIF@MPN. (B) Detailed processes of glucose consumption, self-sufficient H2O2 and acceleration of Fe(III)/Fe(II) conversion for enhanced CDT and starvation therapy.

Firstly, GOx@ZIF nanoparticles were synthesized by one-pot method to embed GOx into ZIF matrix,37-38 which showed a nanosize geometric spherical particle with positive charge (Figure 1A-1C). Then TA and Fe(III) were added into GOx@ZIF solution to form the GOx@ZIF@MPN according to the procedures in the literature.3941

The size distribution and ζ-potential of GOx@ZIF@MPN studied by dynamic light

scattering (DLS) (Figure 1A and 1B) revealed NPs had a narrow size distribution with an average size of 180 nm and the ζ-potential of NPs changed from positive potential (14.6 mV) to negative potential (-17.9 mV). And the change of ζ-potential indirectly indicated the formation of MPN coating. From the scanning electron microscope (SEM) image (Figure 1D), GOx@ZIF@MPN was spherical nanoparticles and had the same 6


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size as measured by DLS (Figure 1A). And the accurate morphology and structure could be further observed by the image of TEM (Figure 1E). Obviously, GOx@ZIF@MPN exhibited a uniform hollow sphere structure which had a shell with a thickness of about 15 nm. This was attributed to etching of MPN coating. As a control, ZIF@MPN had similar structure and morphology to that of GOx@ZIF@MPN (Figure 1F). As shown in Figure 1G and Figure S1, TEM mapping images and EDX result exhibited a clear distribution of Zn, Fe and N elements in the shell, which not only further confirmed successful formation of MPN but also indicated the template effect of GOx@ZIF. And the same conclusion could also be drawn from spectrum of X-ray photoelectron spectroscopy (XPS) (Figure 1H and Figure S2). Particularly, all modifications did not change the crystal structure of the nanoparticles based on the fact that characteristic peaks of all nanoparticles were almost identical to that of simulated ZIF (Figure 1I). Here, the ZIF structure could mineralize GOx enzyme to improve the tolerance of the enzyme while provided a template for the formation of the MPN. It was worth mentioning that all the synthesis processes were carried out in aqueous phase, which could shield inactivation of organic solvents against GOx. Moreover, thermogravimetric analysis (TGA) confirmed the successful encapsulation of GOx in GOx@ZIF@MPN with 2% of loading (Figure 1J), which was consistent with the results measured by BCA protein assay (Figure S3). And the total iron content in GOx@ZIF@MPN was about 12.8% determined by ICP-AES. In addition, after soaking GOx@ZIF@MPN in water, phosphate buffered saline (PBS) and cell medium for 24 h, the solutions were still uniform and translucent. This indicated good dispersion and stability of GOx@ZIF@MPN in stock solution (Figure S4).

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Figure 1. Characterizations of GOx@ZIF@MPN. (A) Hydrodynamic size distribution and (B) Zeta potential of ZIF@MPN, GOx@ZIF and GOx@ZIF@MPN. (C) SEM and TEM (insert) of GOx@ZIF. The scale bar of insert images were 20 nm. (D) SEM and TEM (insert) of ZIF@MPN. (E) SEM and (F) TEM of GOx@ZIF@MPN. (G) Mapping image of GOx@ZIF@MPN. (H) XPS spectra of GOx@ZIF@MPN. (I) PXRD patterns of ZIF, GOx@ZIF, ZIF@MPN and GOx@ZIF@MPN. (J) TGA of ZIF, GOx@ZIF, ZIF@MPN and GOx@ZIF@MPN.

Detailed mechanism process of self-sufficient H2O2 and acceleration of Fe(III)/Fe(II) conversion in GOx@ZIF@MPN was illustrated in Figure 2A. Briefly, upon responding to ATP, GOx@ZIF@MPN could release TA, Fe(III) and expose GOx. GOx could decompose glucose to provide sufficient H2O2 for subsequent Fenton reaction. And TA could accelerate the conversion from Fe(III) (low catalytic efficiency) into Fe(II) (high catalytic efficiency), resulting in highly efficient Fenton reaction. Each 8


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step in this process was verified in detail. In order to verify ATP-responsive disassembly behavior of GOx@ZIF@MPN, a series of experiments were designed. As observed in images of SEM and TEM (Figure S5), morphology and dimensions of GOx@ZIF@MPN had undergone serious changes after soaking in ATP solution for half-hour. This manifested the degradation ability of GOx@ZIF@MPN in the presence of ATP. Since it has been reported that bare MPN can be used as MRI contrast agent,42 we observed the MRI imaging of GOx@ZIF@MPN in the presence and absence of ATP to confirm whether ATP would affect the imaging performance. Both T1-weighted and T2-weighted imaging were conducted. As shown in Figure 2B and 2C, both longitudinal relaxivity coefficient (r1) and transverse relaxivity coefficient (r2) were increased with the addition of ATP, indicating that GOx@ZIF@MPN was an ATP-sensitive MRI contrast agent. The enhanced relaxation value might be attributed to the improved interaction between protons and Fe(III) release from GOx@ZIF@MPN. Thus, this result indicated that NPs had great potential as T1 contrast agent for tumor diagnosis in vivo because of the higher value compared with commercial contrast agents.43 In addition, the enhanced MRI signal in the presence of ATP also confirmed that NPs could respond to ATP. Then, we proceed to investigate the release profile of iron following ATPresponsive degradation of GOx@ZIF@MPN. The release of iron at different time points and different ATP concentrations was quantified by classic method of 1,10phenanthroline (Figure S6). As expected, in the absence of ATP, iron released from GOx@ZIF@MPN was almost undetectable, while it increased as time prolonged in groups containing ATP, and as ATP dosage elevated, it reached maximum as quick as within 2 h (Figure 2D). These results again demonstrated the stability as well as ATPresponsive character of our nanoplatform, which should be attributed to strong binding 9


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affinity of ATP to Fe(III). Indeed, these results showed that release of Fe(III) from GOx@ZIF@MPN could be triggered by ATP. This could attribute to the strong binding affinity of ATP to Fe(III).34 The ATP-triggered disassembly process was sensitive and fast, which was an attractive to achieve “burst release” of drug at targeting site for drug delivery. Moreover, such “burst release” of GOx was indirectly proved by detecting release Zn2+ of GOx@ZIF@MPN (Figure S7) in view of interference of direct detection and synchronization of and Zn2+ release. According to the literature, Fe(III) could be reduced to Fe(II) by reductive agent,3031

which could be helpful for enhancing the efficiency of Fenton reaction. In order to

verify the reduction of TA against Fe(III), we first mixed Fe(III) and TA in the ATPcontaining solution and monitored the concentration of Fe(II) without additional reductive agent. As shown in Figure 2E, nearly 50% of Fe(III) could be reduced within 30 minutes and the Fe(II) concentration slightly increased in the later 4 hours. Contrastively, almost no Fe(II) was detected in the solution with Fe(III) only because Fe(III) could not react with phenanthroline without reductive substances. These results demonstrated that TA could effectively reduce Fe(III) to Fe(II) in the aqueous solution. Further, to confirm the TA from GOx@ZIF@MPN could accelerate the conversion Fe(III) to Fe(II), the Fe(II) concentration was measured in the presence of ATP by using the same method above. And the group mixed of GOx@ZIF and Fe(III) was served as control in the same conditions. As shown in Figure 2F, more Fe(II) was detected in the experimental group than that in the control group and the Fe(II) concentration increased with time. More importantly, electron transfer between TA and Fe(III) originated from degradation of GOx@ZIF@MPN could effectively reduce Fe(III) into Fe(II). After degradation of the outer shell of GOx@ZIF@MPN under ATP, the internal encapsulated GOx was exposed. In the presence of glucose, GOx could catalyze the 10


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decomposition of glucose to generate H2O2 and gluconic acid.13 Therefore, the decomposition product (H2O2 and gluconic acid) could be used to evaluate the catalytic performance of GOx. Here, GOx@ZIF was chosen to accurately quantify the acid changes and the amount of produced H2O2. As expected, the pH value gradually decreased as the initial glucose concentration increased and then kept at about pH = 3.5 (Figure S8). It was worth noting that acidification caused by the enzyme could create a favorable acid environment for the Fenton reaction in the entire nanocatalytic system. This would ultimately improve the Fenton reaction efficiency. Further, H2O2 production was detected to assess catalysis of GOx@ZIF. The ammonium titanyl oxalate was chosen as an indicator due to the good linear relationship between maximum absorption of H2O2/Ti(IV) and concentration of H2O2 (Figure S9).44 The generated H2O2 concentration increased with the increase of glucose concentration (Figure S10) and the extension of time (Figure S11), indicating that the modification did not have much effect on the activity of GOx. Importantly, it could be inferred that the sufficient H2O2 catalyzed by GOx could ensure the success of subsequent reactions. Based on the above premise, we proceed to investigate the overall ∙OH production of our integrated nano-platform GOx@ZIF@MPN as well as the decisive factors behind. The effects of each component in our nanoparticles on ∙OH production were verified. Here, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) was served as a spin trap to detect ∙OH by electron spin-resonance (ESR) spectrometer, in which DMPO/∙OH adduct displays a typical 1:2:2:1 four-line characteristic spectrum with a hyperfine splitting constant (αN = αH = 14.95 G).45 Firstly, we examined the ATP-responsive ∙OH production capacity of GOx@ZIF@MPN. As shown in Figure 2G, GOx@ZIF@MPN showed robust ∙OH generation ability once mixed with ATP, while almost no signals could be detected in the absence of ATP, demonstrating the superior 11


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ATP-responsive intelligence. Subsequently, we conducted experiments to prove that TA-mediated conversion of Fe(III) into Fe(II) could enhance ∙OH production in Fenton reaction. The generation of ∙OH was detected in mixed solution of H2O2, Fe(III) and ATP in the presence and absence of TA. It was found that the signal of ∙OH in mixture of Fe(III) and TA was stronger than that in Fe(III) solution (Figure S12). Thus, we suggested that TA released from degrading GOx@ZIF@MPN could serve as a beneficial role. As shown in Figure 2H, GOx@ZIF@MPN could produce more abundant ∙OH by itself, as compared with GOx@ZIF + Fe(III). This result demonstrated the intelligent integration of our self-catalytic nanoplatform, where the reductive TA as well as the entire construction of nanoparticle did not provide burden in ∙OH production but instead present a significantly higher efficiency. We proceeded to investigate the effect of H2O2 production catalyzed by GOx on the overall efficiency of Fenton reaction in our nano-platform. As shown in Figure S13, GOx + Fe(II) + GO could produce ∙OH, demonstrating that H2O2 produced in GOx-catalyzed GO consumption could efficiently participate in Fenton reaction. What’s more, encapsulation into ZIF did not impair the catalytic activity of GOx and GOx@ZIF could effectively couple with Fe(II) to produce ∙OH on the consumption of GO (Figure S14). Therefore, it is not surprise to find that GOx@ZIF@MPN showed highest ∙OH production as compared with GOx@ZIF and ZIF@MPN (Figure 2I). Since Fe(III) and TA from MPN insure sufficient Fe(II) while GOx insure abundant H2O2, which are both essential in Fenton reaction and this was also reflected in Figure S12. The ATPresponsive character as well as high efficiency in Fenton reaction demonstrate the rational design and intelligent integration of our nano-platform. On the contrary, the characteristic peaks of ∙OH were much stronger in the group containing GOx@ZIF@MPN, indicting plenty of ∙OH was produced. In addition, the 12


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corresponding Methylene Blue (MB) decolorization experiments (Figure S15) also showed the maximum MB degradation in GOx@ZIF@MPN group, which was consistent with the ESR results. All above results had clearly proved the process of mechanism in Figure 2A. As response to ATP, GOx@ZIF@MPN released Fe(III) and TA while GOx reacted with glucose to produce H2O2. TA-mediated Fe(III) reduction into highly catalytic Fe(II) coupled with GOx-catalyzed H2O2 production to realize a highly efficient Fenton reaction and abundant ∙OH generation in our nano-platform, revealing preferable autocatalytic as well as self-accelerated characters.

Figure 2. (A) Illustration of mechanism of self-sufficient H2O2 and acceleration of Fe(III)/ Fe(II) conversion in GOx@ZIF@MPN nanosystem. (B) T1- and (C) T2weighted image (top) and corresponding relaxation rate (r1 and r2) (bottom) of GOx@ZIF@MPN solution at different concentrations in the presence or absence of ATP. (D) Time-dependent release of Fe(III) from GOx@ZIF@MPN at various ATP 13


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concentrations. Detection of Fe(II) after treated with (E) Fe(III) and Fe(III) + TA, (F) GOx@ZIF + Fe(III) and GOx@ZIF@MPN. (G) ∙OH detection in the sample containing GOx@ZIF@MPN in the presence and absence of ATP. (H) Detection of ∙OH in samples treated with GOx@ZIF@MPN and GOx@ZIF + Fe(III) respectively at same concentration of H2O2 and ATP. (I) ∙OH detection in samples treated with GOx@ZIF@MPN, GOx@ZIF and ZIF@MPN respectively in the presence of ATP.

We next investigate the anti-cancer effect of GOx@ZIF@MPN. To better destroy the tumor cells, it was necessary to understand the best internalization time of FITC labeled GOx@ZIF@MPN by tumor cells. Hence, the difference of endocytosis caused by incubation times (2 h, 4 h and 8 h) was studied by flow cytometry analysis. As observed in Figure S16, the uptake amount of GOx@ZIF@MPN by 4T1 cells increased significantly over time. Comparing semiquantitative data of internalization experiment at 4 h and 8 h, it could be observed that the MFI at 8 h was slightly higher than that at 4 h, attributing to the saturated endocytosis of GOx@ZIF@MPN by 4T1 cells at 4 h. Based on this, we chose 4 h as the optimal culturing time of samples for follow-up cell experiments. Furthermore, uptake mechanism of FITC GOx@ZIF@MPN was studied with three inhibitors. In Figure S17, cells incubated with genistein (an inhibitor of caveolae-mediated endocytosis) and amiloride (an inhibitor of micropinocytosis) exhibited strong intracellular fluorescence similar to the control group. While a significant decrease uptake of GOx@ZIF@MPN was observed group with chlorpromazine (an inhibitor of clathrin-mediated endocytosis), demonstrating that clathrin-mediated endocytosis was the primary cellular uptake pathway. After clarifying endocytic mechanism of GOx@ZIF@MPN, it was necessary for us to figure out how to escape endosomes. Obviously, fluorescence of calcein (a membrane14


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impermeant fluorophore) changed from a punctuate distribution of control group to spreading throughout the cell after incubating with ZIF@MPN and GOx@ZIF@MPN (Figure S18A), implying endosomal escape mode by increasing the permeability of endosomal membrane. The phenomena could be ascribed to the “proton sponge” effect caused by outer shell MPN, since protonation of TA from MPN would absorb H+ in an acid endosomal environment. This explanation was further confirmed by increasing endosomal pH in ZIF@MPN and GOx@ZIF@MPN group (Figure S18B). Then the catalytic behavior of GOx@ZIF@MPN against 4T1 tumor cells was explored. After 4 h co-cultured different concentrations of GOx@ZIF with cells, the H2O2 level in cells was detected. The H2O2 content in cells treated with GOx@ZIF was higher than cells without treatment and it showed a positive correlation with the concentration of GOx@ZIF (Figure S19). This result indicated that NPs could still achieve catalytic function in complex cell environment and provided a prerequisite for ∙OH

generation

catalyzed

by

MPN.

Subsequently,

∙OH

production

of

GOx@ZIF@MPN in tumor cells was measured using the fluorescent probe, DCFHDA. A weak DCFH fluorescence was observed in the group treated with DCFH-DA only (Figure 3A1), probably due to the ROS produced by the metabolism of the cells themselves. Similarly, the fluorescence was weak in the group after treatment of ZIF@MPN (Figure 3A2). That was because the endogenous H2O2 was not enough for ZIF@MPN to generate high amount of ∙OH. For the cells treated with GOx@ZIF, it had a slightly enhanced fluorescence intensity compared with the first two groups (Figure 3A3). This phenomenon could be explained by low concentration of GOx@ZIF used, considering concentration dependence of H2O2 production and interference of H2O2 on the detection of ∙OH. A significantly enhanced DCFH fluorescence was found in 4T1 cells after incubation with GOx@ZIF@MPN (Figure 3A4), which revealed 15


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much more generation of ∙OH. This was attributed to production of ∙OH which was highly active to oxidize DCFH. In addition, flow analysis showed the similar results (Figure 3B and 3C), which further verified GOx@ZIF@MPN could effectively produce ∙OH and illustrated nearly 4-fold increase of ∙OH generated in GOx@ZIF@MPN group compared with other groups. In short, GOx@ZIF@MPN exhibited great ability to converse the energy (glucose) of tumor cells into highly toxic ∙OH by aid of Fenton reaction. Encouraged by excellent catalytic performance of GOx@ZIF@MPN, its anticancer ability against 4T1 cells was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay. It is known that glucose is a very important energy supply for cell proliferation, which was proportional to glucose concentration (Figure S20). Moreover, tumor cells are more sensitive to change of glucose concentration because their main energy supply depend on aerobic glycolysis. Therefore, consuming glucose by GOx could significantly reduce the viability of tumor cells (Figure S21) compared with that of normal cells, which could serve as a target for tumor treatment while avoiding damage to normal cells.11 The same conclusion could be obtained from Figure S22 and Figure S23. Compared with normal COS7 cells, the proliferation of 4T1 cells was obviously inhibited at the same concentration of GOx@ZIF and GOx@ZIF@MPN. Simultaneously, the catalytic process of GOx was accompanied by the production of H2O2 which could slightly aggravate death of tumor cells (Figure S24). However, H2O2 could be converted to more toxic ∙OH catalyzed by Fe(II), which could cause oxidative damage to tumor cells. As shown in Figure 3D, cytotoxicity of 4T1 cells treated with ZIF@MPN was higher than that without addition of ZIF@MPN at the same concentration of H2O2, demonstrating the stronger cytotoxicity of ∙OH than H2O2. And the cell viability of 4T1 cells decreased with the 16


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increased Fe(II) produced by ZIF@MPN at the same H2O2 level. This illustrated the good catalytic ability of MPN. Further, the cytotoxicity of GOx@ZIF@MPN in vitro was explored where GOx@ZIF and ZIF@MPN acted as controls. In a medium supplemented with glucose (300 μg/mL) (Figure 3E), cells treated with ZIF@MPN showed a negligible cytotoxicity, because intracellular H2O2 level was not enough to produce excessive ∙OH for killing tumor cells. This could be also verified by almost no cytotoxicity against cells incubated with pure Fe(II) (Figure S25). The cell viability in GOx@ZIF group was decreased to 52%, which indicated the effects of starvation therapy of GOx@ZIF by blocking the glucose supply. Sharply, the group of GOx@ZIF@MPN showed the highest toxicity against 4T1 cells than all control groups, demonstrating synergistic effect of starvation therapy and CDT on tumor cell inhibition. In detail, tumor cell death caused by GOx@ZIF@MPN was attributed to the metabolic disorder caused by consumption of glucose and generation of highly toxic ∙OH via Fenton reaction. The same toxicity trend showed in cells cultured in glucose-free medium (Figure 3F). Due to the limited intracellular glucose concentration, the cytotoxicity of GOx@ZIF@MPN was decreased compared with that in the presence of glucose, illustrating the cytotoxicity was glucose concentration dependent. Hereafter, fluorescence live/dead cell assay was conducted to directly visualize the ratio of live and dead cells (Figure S26). The significant red fluorescence (referred to dead cells) was observed in the cells treated with GOx@ZIF@MPN compared with other groups. An attenuated red fluorescence showed in cells incubated with GOx@ZIF and no obvious red fluorescence was found in ZIF@MPN group. These observations matched well with the results of cytotoxicity, which further testified excellent killing ability of GOx@ZIF@MPN against tumor cells among all groups. Deeply, in order to explore the mechanism of cell death, the cells treated with different samples were 17


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collected and analyzed by flow cytometry after dying with annexin V-FITC and PI. In Figure S27A, the more cells were detected in Q2 and Q3 region in GOx@ZIF@MPN group in the presence and absence of glucose (Q1, Q2, Q3 region represents necrosis, late apoptosis and early apoptosis cells respectively while Q4 region represents live cells), which clarified that lethal mechanism of cells induced by GOx@ZIF@MPN was mainly depended on apoptosis pathway rather than necrosis. And in view of starvation therapy caused by disorders of glucose metabolism, we could find small amounts of apoptotic cells in GOx@ZIF group. As shown in the column chart in Figure S27B, the statistical data was clear and intuitive to display the difference of different treatment. All results showed the superior anticancer ability of GOx@ZIF@MPN compared with the single starvation therapy of GOx@ZIF, attributing to the efficient and enhanced ∙OH production of GOx@ZIF@MPN.

Figure 3. (A) Intracelluar ROS detection after 4T1 cells treatment with (A1) PBS, (A2) 18


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ZIF@MPN, (A3) GOx@ZIF and (A4) GOx@ZIF@MPN. The scar bar was 20 μm. (B) Flow cytometry analysis of ROS generation after treatment with ZIF@MPN (blue line), GOx@ZIF (orange line), GOx@ZIF@MPN (green line) and PBS (red line) and (C) the corresponding MFI values. (D) The cytotoxicity of ZIF@MPN in the presence of H2O2 (75 μM or 125μM). The viability of 4T1 cells after incubating with different samples in the (E) presence and (F) absence of glucose. **P < 0.01, ***P < 0.001.

To evaluate the targeting ability of GOx@ZIF@MPN in vivo, a 4T1 tumor-bearing mice model was built to examine in vivo tumor fluorescence imaging by a small animal imaging system. Cy5.5-doped NPs were obtained by loading Cy5.5 in GOx@ZIF@MPN. After intravenous injection of Cy5.5-doped NPs to 4T1 tumor bearing mice, the accumulated fluorescence was observed at different time in tumor site. As shown in Figure 4A and 4B, the fluorescence gradually enhanced over time and reached a maximum within 2 h. Then fluorescence intensity weakened but still retained after 24 h, which indicted long retention of GOx@ZIF@MPN, favorable for long-term treatment. 24 h later, the mice were sacrificed and the tumor and all main organs were harvested for imaging. Clearly, the fluorescence intensity was the highest at tumor site compared with other organs from the image (Figure 4C). And the semiquantitative data further proved the great tumor tissue enrichment of GOx@ZIF@MPN (Figure 4D). Fluorescence observed in liver was due to liver metabolism of nanoparticles.46 From which, it could draw a conclusion that GOx@ZIF@MPN preferentially and effectively accumulated in tumor region, which was benefit from suitable size distribution for passive target via EPR effect. Moreover, negative charge of GOx@ZIF@MPN was also 19


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helpful for avoiding clearance by the mononuclear phagocyte system (MPS),47-48 which was certified by pharmacokinetic of GOx@ZIF@MPN in blood (Figure S28). In additon, it had been proved that GOx@ZIF@MPN could act as an excellent T1weighted MRI contrast agent and had ATP-enhanced MRI image performance in solution (Figure 2B). Thus, T1-weighted contrast effect of GOx@ZIF@MPN was further studied in vivo. After intratumoral injection of GOx@ZIF@MPN, MRI signal at the injection site was detected by MRI imaging system. As observed in Figure 4E, T1-weighted imaging signal was obvious after 10 min post-injection and gradually enhanced over time, indicating that NPs rapidly degraded in response to ATP at tumor site and possessed an excellent T1-weighted imaging effect for tumor diagnosis.

Figure 4. (A) In vivo fluorescence images of tumor-bearing mice after intravenous injection of Cy5.5-doped GOx@ZIF@MPN at different times and (B) the 20


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corresponding MFI values. (C) Ex vivo tissue imaging after 24 h post-injection. He: heart, Li: liver, Sp: spleen, Lu: lung, Ki: kidney and Tu: tumor. (D) The corresponding MFI values of tissues after 24 h post-injection. (E) T1-weighted MRI imaging after intratumoral injection of GOx@ZIF@MPN at different times.

As shown in Figure 5A, Fe ion concentration was increased over time after intratumorally injection with GOx@ZIF@MPN, implying time-related Fe release in response to high expression of ATP at tumor site. Additionally, we also demonstrated in vivo GOx@ZIF@MPN-induced the consumption of intratumoral glucose (Figure 5B), which indicated that GOx@ZIF@MPN could achieve starvation therapy by reducing glucose supply. Encouraged by the efficient accumulation and response of GOx@ZIF@MPN as well as excellent performance of cascade catalysis at tumor site, the antitumor ability in vivo was further evaluated against 4T1 tumor-bearing mice. When the tumor reached 100 mm3, the tumor-bearing mice were randomly divided into four groups (6 mice per group) and treated with GOx@ZIF@MPN, GOx@ZIF, ZIF@MPN and PBS, respectively. From tendency of relative body weights showed in Figure 5C, there was no obvious body weights changes of the mice in all experimental groups, indicating negligible systemic toxicity of GOx@ZIF@MPN. Additionally, hemolysis test (Figure S29) also reflected the biosafety of the NPs even at high concentrations. Further, the relative tumor volume was monitored to evaluate the therapeutic effect every day (Figure 5D). Obviously, the tumor grew rapidly in the mice treated with ZIF@MPN, implying that ZIF@MPN could not suppress tumor growth 21


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because of the limited H2O2 inside tumor. But in group treated with GOx@ZIF, tumor growth was inhibited to some extent, which could be ascribed to the role of starvation therapy caused by GOx in GOx@ZIF. Unsurprisingly, the mice treated with GOx@ZIF@MPN exhibited the best tumor suppression effect, which was due to the increased accumulation and the prolonged retention time. More importantly, this result indicated that cascade catalysis of GOx@ZIF@MPN significantly enhanced the treatment by enhanced CDT combined with the starvation therapy. After treatment for 14 days, all mice were sacrificed and the tumors were harvested to take the pictures of excised tumors (Figure 5E). The smallest tumor was obtained from GOx@ZIF@MPN, confirming its excellent antitumor ability. Additionally, hematoxylin and eosin (H&E) staining was carried out to investigate the antitumor activity at cellular level (Figure 5F). It displayed maximum dead cells in the GOx@ZIF@MPN group, further demonstrating its effective antitumor activity. Moreover, no obvious physiological morphology changes were observed in major organs (liver, heart, lung, spleen and kidney) in all groups, further certifying the great biocompatibility of these nanoparticles.

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Figure 5. In vivo antitumor effect of GOx@ZIF@MPN. (A) Fe concentration and (B) glucose concentration of tumor ex vivo over time after intratumoral administration with GOx@ZIF@MPN. The picture on the right showed the color change of a colorimetric reaction at different treated times. **P < 0.01. (C) Relative body weight and (D) relative tumor volume of mice in different groups. Red arrow refers to the time of administration. ***P < 0.001. (E) Photographs of 4T1 tumor tissues in different groups after 14 days treatment. (F) H&E staining of major organs and tumors in different groups. F1-F4 stand for GOx@ZIF@MPN, GOx@ZIF, ZIF@MPN and PBS, respectively. 23


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In

summary,

an

ATP-responsive

autocatalytic

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Fenton

nanosystem

GOx@ZIF@MPN, was constructed to suppress tumor growth by enhanced chemodynamic therapy and starvation therapy. Once injected by tail vein, the negative charge and nanoscale of GOx@ZIF@MPN made it avoid being cleared by reticuloendothelial system and accumulate in tumor region by EPR. After uptake by tumor cells, GOx@ZIF@MPN was degraded to release Fe(III) and TA as well as to expose GOx in response to the overexpressed ATP. Then TA accelerated the conversion of Fe(III) into Fe(II), which reacted with H2O2 derived from catalysis of GOx to produce ∙OH. The process disordered glucose metabolism by GOx and produced great amount of ∙OH by Fenton reaction. Consequently, tumor growth was significantly suppressed. This unique self-enhanced CDT strategy will find great potential for effective clinical anti-tumor treatment.

The Supporting Information is available free of charge on the ACS Publications website at DOI: xxxxxx. Details of experimental procedures and supplementary results (PDF).

Acknowledgments L. Zhang and S.-S. Wan contributed equally to this work. This work was supported by the National Natural Science Foundation of China (51690152, 51573142 and 21721005).

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An ATP-Responsive Autocatalytic Fenton Nanoparticle for Tumor

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