Zr-Based MOFs Shielded with Phospholipid Bilayers: Improved

Article pubs.acs.org/cm

Zr-Based MOFs Shielded with Phospholipid Bilayers: Improved Biostability and Cell Uptake for Biological Applications Jian Yang,† Xiaojing Chen,‡,§ Yongsheng Li,† Qixin Zhuang,† Peifeng Liu,*,‡,§ and Jinlou Gu*,† †

Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, China. ‡ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China § Central Laboratory, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. S Supporting Information *

ABSTRACT: For practical biomedical applications, the stabilization of nanoscale metal−organic frameworks (NMOFs) in the presence of phosphate is of prime importance but remains a significant challenge because of the inevitable and strong driving force between metal clusters and phosphate species to form metalphosphate in physiological environments. Through shielding Zr-NMOFs within the continuous phospholipid bilayers (PBLs), herein, we figured out a unique way to protect the vulnerable coordination bonds in their frameworks from the attack of phosphate. To exemplify the facility of constructing PBLs on Zr-NMOFs core, a porphyrinic NMOF of PCN-223 (standing for a platform with broad biological applications) was elaborated using a triethylamine (TEA)-modulated strategy. TEA could not only control the phase transformation of porphyrinic MOFs to achieve pure-phase PCN-223 crystals but also minimize their particles size down to sub-200 nm. Negative-stained TEM, FT-IR and XPS techniques revealed that PBLs could be closely coated onto the surface of nanoPCN-223, thanks to the strong Zr−O−P chemical complexation between Zr-NMOFs and phospholipid. The resultant coated nanoPCN-223 exhibited significantly enhanced phosphatic-resistance in phosphate buffer solution (PBS) and presented exceptional stability in harsh chemical environments. Furthermore, the MOFs-supported PBLs could effectively provide a stable biocompatible interface for subsequent cell culture and improve their biocompatibility, cellular uptake efficiency and real biostability of NMOFs in cellular environments. This study offers an alternative system for forming stable PBLs supported on NMOFs, and represents the first example of stabilizing Zr-NMOFs free from the attack of phosphate species in biological media. ligands toward the formation of metal-phosphate.25,26 For example, UiO-66(Zr) and UiO-67(Zr) were regarded as highly water-resistant and chemical stable MOFs, but degraded within few hours once dispersed in phosphate buffer solution (PBS).27,28 Such a phosphatic coordination substitution would strongly affect the ordered porous texture of MOFs and consequently result in their structure collapse or the immature release of the cargo before their arrival at target location. Thus, the water stability of MOFs is not enough to predict their performance in the presence of phosphate species for practical biomedical applications. Nevertheless, very little information has been gathered so far to overcome this critical issue. Therefore, it is highly desirable to develop a general and simple approach to avoid the collapse of NMOFs-based platform in the presence of phosphate species, and thus to make them applicable in complex biological media. We notice that enveloping nanomaterials within phospholipid bilayers (PBLs), and thus mimicking cell structure, is a unique way to endow them with common biocompatible

1. INTRODUCTION The past decades have witnessed a rapid development in nanotechnology for its clinical application potentials (e.g., biosensing, imaging, diagnosis, and therapy).1−5 Nanoscale metal−organic frameworks (NMOFs) represent a unique new family of hybrid nanomaterials that readily combine the beneficial characters of organic ligands and metal clusters. Their infinite combination of organic and inorganic building units endows them with structural diversities and tunable chemical properties to satisfy the specific biomedical functions.6−12 The current challenge in the area encompasses not only tailoring the nanoscale morphology but also improving their surface chemistry to meet the proposed applications.12−16 For many biomedical applications, it is a prerequisite to have robust MOFs to be stable in aqueous phase.17,18 Highly waterresistant MOFs have been successfully constructed to expand their working environments through the employment of hard Lewis acidic species, such as Zr4+ and Hf4+.19−24 However, the wide existence of phosphate in biological environments, which exhibits a much stronger affinity toward metal clusters than carboxylic groups in ligands of MOFs, would rapidly destroy the coordination equilibrium between the metal nodes and © 2017 American Chemical Society

Received: March 31, 2017 Published: April 28, 2017 4580

DOI: 10.1021/acs.chemmater.7b01329 Chem. Mater. 2017, 29, 4580−4589

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Chemistry of Materials

Scheme 1. Pictural Illustration for the Formation of MOFs-Supported PBLs on nanoPCN-223 through the Strong Zr−O−P Interaction Between the Zr6 Clusters and DOPC Molecules

interface.29−41 Furthermore, the stability of the fragile PBLs could be significantly improved if chemical bonding between nanoparticles and phospholipid occurred, which could effectively avoid the liposome fusion or detachment from the supported nanoparticle core as exhibited in simple physical absorption.32 Coincidentally, our ongoing researches have been focusing on the host−guest interaction between phosphorcontaining species and Zr-MOFs.42−45 We found that the structural stability of Zr-MOFs was indeed sensitive to inorganic phosphate species in aqueous phase.42 On the other hand, Zr-MOFs presented high affinity toward organophosphorus species and could realize the remarkably enhanced enrichment of phosphonates thanks to the formation of Zr− O−P bonding while maintaining the integrity of the frameworks.43 These strongly inspire us to propose that the abundant superficial Zr−OH sites on NMOFs could also serve as the natural anchorages to strongly complex with the P−O bonds in phospholipid molecules while their pristine structure could be kept intact in the PBLs coating process (Scheme 1). More importantly, the inner hydrophobic region of PBLs could provide a continuous shield around NMOFs, which is particularly impermeable to ions and then might protect the vulnerable coordination bonds in NMOFs from the attack of phosphate (Scheme 1). To exemplify the facility to construct PBLs coating, Zr-based porphyrinic NMOF of PCN-223 was elaborated due to their diverse biological applications such as photodynamic therapy,22,46 bioimaging as well as biosensing.47,48 Interestingly, it was found that porphyrinic Zr-based MOFs existed flexible and diversified coordination modes under the similar reaction conditions.49−51 As a result, it is challenge to directly obtain nanoscale pure-phase structure.52 In the current work, we report a facile triethylamine (TEA)-modulated strategy to prepare nanoPCN-223. The TEA played a crucial role to modulate the deprotonation degree of carboxylic group in porphyrin-containing tetrakis(4-carboxyphenyl)porphyrin (TCPP) ligands and to control the phase transformation. Meanwhile, the particle size of porphyrinic MOFs was minimized to sub-200 nm. The obtained nanoPCN-223 was further employed for PBLs coating, which was first coated a continuous monolayer of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) in organic solvent via the strong Zr−O−P interaction between the surface Zr−OH sites of nanoPCN-223 and DOPC molecules. Then, the nanoPCN-223@DOPC was further coated with DOPC and cholesterol to self-assemble into a tight MOFs-supported PBLs in the hydrophobic system (Scheme 1). As expected, the continuous PBLs could effectively serve as a barrier for NMOFs and dramatically enhance the

chemical stability of nanoPCN-223 against phosphate attack in PBS. Furthermore, the nanoPCN-223@DOPC/DOPC exhibits more favorable biocompatibility, improved cellular uptake efficiency and intracellular biostability than bare nanoPCN223. These excellent features together with the facility to construct PBLs on NMOFs might prefigure their wide application potentials in biological fields.

2. EXPERIMENTAL DETAILS Chemicals and Materials. TCPP, DOPC (97%), and cholesterol were purchased from J&K Scientific Ltd., Beijing, China. Uranyl acetate was obtained from Shanghai Aladdin Bio-Chem Technology Co., LTD, China. 1,4-Phenylenediphosphonic acid (H4PDP) was purchased from TCI, Japan. Zirconyl chloride octahydrate (ZrOCl2· 8H2O), acetic acid, triethylamine (TEA), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetone, and chloroform were obtained from Sinopharm Chemical Reagent Co., Ltd., China. 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and 4′,6-diamidino-2-phenylindole (DAPI) were purchased from Sigma-aldrich. Fetal bovine serum (FBS) was obtained from Gibco, Switzerland. Cell-culture products, unless otherwise mentioned, were purchased from Keygentec, China. All the reagents were of analytical grade and used as received without additional purification. The applied water (18.1 MΩ·cm−1) in the experiments was purified from a NW Ultrapure Water System (Heal Force, China). TEA-Modulated Synthesis of nanoPCN-223 Particles. To modulate the size of porphyrinic MOFs, different contents of TEA were utilized. The starting materials of ZrOCl2·8H2O (225 mg, 0.702 mmol), TCPP (45 mg, 0.0576 mmol), acetic acid (45 mL), TEA (x eq to TCPP; x = 0, 10, 15, 20, 25, 30, 35, and 40; such as 25 eq = 200 μL) and DMF (180 mL) were mixed in a 250 mL vial. Specifically, ZrOCl2· 8H2O was first dissolved in DMF, and the mixture was sonicated for about 30 min. Then, TCPP was added to the mixture (sonicated for 10 min). Various amounts of TEA were introduced into the solution (sonicated for 5 min). Finally, acetic acid was added (sonicated for 5 min), and then the reactor was heated at 65 °C for 5 days. After cooling to room temperature, the obtained red solid was collected by centrifugation and soaked in DMF (3 × 50 mL) for 6 h each time. The DMF was then replaced with acetone (5 × 50 mL) at 65 °C over a 5day period. Finally, half of the particle was activated in vacuo (80 °C, 24 h) for the material characterization, and the rest particle was dispersed in CHCl3 for the following PBLs-coating process. Preparation of the Phospholipid-Coated NanoPCN-223. All the reagents were bubbled with nitrogen for 10 min to drive off the dissolved oxygen before reaction. To synthesize nanoPCN-223@ DOPC/DOPC particles, DOPC solution (0.4 mL, 25 mg/L in CHCl3) was added into nanoPCN-223 suspension (10 mL, 2 mg/ mL). After stirring at 300 rpm for 24 h in the dark condition, the obtained nanoPCN-223@DOPC particles were collected by centrifugation and washed with THF to remove excessive DOPC, redispersing them in 10 mL THF. Then, DOPC (800 μL, 25 mg/L) and cholesterol (200 μL, 25 mg/L) in CHCl3 were added into a 100 mL 4581


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Chemistry of Materials round-bottom flask. After sonication for 3 min under N2 atmosphere and dark condition, CHCl3 was evaporated from the mixture under reduced pressure. Twenty mL H2O/EtOH solution (v/v = 70:30) was added into DOPC/cholesterol mixture and sonicated for 10 min. NanoPCN-223@DOPC (10 mL, 2 mg/mL) in THF was added into the above DOPC/cholesterol solution and sonicated for 10 min again. To form PBLs, the organic solvent was gradually evaporated at progressively increased temperatures (40/45/50 °C) with occasional sonication for 10 min each time under N2 atmosphere and dark condition. With the increasement of hydrophobicity in the nanoPCN223@DOPC/DOPC/cholesterol system, the DOPC molecules are expected to self-assemble into a two-layered structure around the surface of nanoPCN-223 with the hydrophilic headgroup exposing toward the water. The obtained nanoPCN-223@DOPC/DOPC particles were collected by centrifugation (13 000 rpm, 15 min) and washed with H2O for two time to remove free DOPC. Finally, the red particles were dispersed in 10 mL H2O and stored in a refrigerator at 4 °C under dark condition. Preparation of the Uranyl Acetate-Stained Samples for TEM Observation. A drop of nanoparticle suspension (bare nanoPCN-223 and nanoPCN-223@DOPC/DOPC) was placed on a carbon-coated copper grid, and the water was removed through capillary action using a filter paper after 20 min of standing. Then, a drop of 1% uranyl acetate solution was placed on the copper grid for 1 min and the filter paper was used again to blot up the samples. The grid was dried at ambient temperature and observed under a JEM-1400 electron microscope. Size and Surface Charge Analysis of Synthesized Nanoparticles. For long-term particle stability studies, the bare and coated nanoPCN-223 particles were suspended in various media (water, PBS, DMEM and RPMI-1640) at concentration of 200 mg/L, and then were aged for 7 days at 37 °C. The hydrodynamic diameter of nanoparticles were evaluated by the dynamic light scattering (DLS) with a Nicomp TM 380 ZLS zeta-potential/particle sizer (PSS Nicomp particle size system). The zeta potential of samples (200 mg/ L, pH 7.4) suspended in water were measured using Zetasizer (NanoZS) from Malvern Instruments and its software. The pH of suspension was adjusted by adding negligible volumes of 0.01 M HCl or 0.01 M NaOH aqueous solutions before measurement. Cytotoxicity Test. We employed both SMMC-7721 (human hepatocellular carcinoma) and HeLa cells (human cervical cancer) for the cytotoxicity tests through the MTT assay. The SMMC-7721 cells and HeLa cells were cultivated at 37 °C in RPMI-1640 with 10% FCS and DMEM with 10% FCS, respectively. For the cytotoxicity test, the cells were seeded in a 96-well plate at a density of 5000 cells per well and grown for 24 h at 37 °C, 5% CO2 and 95% humidity. The media were then removed and media containing bare nanoPCN-223 or coated nanoPCN-223 at the TCPP dose of 0, 6, 12.5, 25, 50, 100, 200, 400 μM were added to each well. After 24 h of incubation, 5 mg mL−1 MTT was dissolved in media with 10% FCS, and incubated for another 4 h, followed by adding DMSO into each well. Absorption was measured on a microplate reader at 490 nm. Confocal Laser Scanning Microscope (CLSM) Observation and Flow Cytometric Measurements. For CLSM observation, the cells with an amount of 104 cells mL−1 were grown overnight in a 35 mm Petri dish. The TCPP molecule, bare nanoPCN-223 and coated nanoPCN-223 (at the same dose of 50 μM TCPP) were cocultivated with cells for 12 h at 37 °C, 5% CO2 and 95% humidity. Before the CLSM (A1R, Nikon) observation, the cells were rapidly washed for 3 times with PBS buffer (pH = 7.4) to remove the residual materials. Then, 0.5 mL of DAPI solution in methanol (10%) was added, and incubated for 10 min to stain the nuclei and to fix the cells. After the incubation, the cells were washed twice to remove excessive DAPI, and added with 1 mL of PBS for CLSM observation. Blue and red fluorescent emissions from DAPI and NPs were excited at the wavelength of 405 and 561 nm, respectively. The emission wavelengths were collected from 425 to 475 nm for DAPI and 670 to 750 nm for NPs, respectively. To evaluate the cellular uptake of nanoparticles, cells were cultured in a 6-well plate with a density of 2 × 105 cells per well to achieve 80%

confluence. After medium removal and washing with PBS buffer, 1 mL of TCPP molecule, bare nanoPCN-223 and coated nanoPCN-223 (at the same dose of 50 μM TCPP) in media were then added to the dishes. Then the cells were further incubated for 4, 12, and 24 h, respectively. After incubation, the stained cells were rapidly washed three times with PBS buffer and studied by flow cytometry (Becton Dickinson Immunocytometry Systems, San Jose, CA). Bio-TEM Observation. SMMC-7721 cells were incubated with bare nanoPCN-223 and coated nanoPCN-223 (at the same dose of 50 μM TCPP) for 24 h. Then, the cells were rapidly washed twice with PBS and detached by incubation with 0.25% trypsin for 5 min. The cell suspension was centrifuged at 2000 r/min for 3 min. After the removal of incubation medium, the cells were fixed by glutaraldehyde at room temperature, then rinsed with PBS and dehydrated through a graded ethanol series, finally cleared with propylene oxide. Then, the cell samples were embedded in EPOM812 and polymerized in an oven at 37 °C for 12 h, 45 °C for 12 h, and 60 °C for 48 h. Ultrathin sections (70 nm thick) were cut with a diamond knife on a Leica UC6 ultramicrotome and transferred to the copper grid for Bio-TEM observation. Instruments and Methods. UV−vis absorption spectra were measured with a UV-3600 spectrophotometer (Shimadzu). The powder X-ray diffraction (XRD) patterns were obtained on a Bruker D8 instrument using Cu Kα radiation (40 kV, 40 mA). N2 sorption isotherms were recorded with a surface area and pore size analyzer (Micromeritics Tristar 3020). All of the samples were degassed under vacuum for 12 h before measurements. The specific surface area was calculated by the Brunauer−Emmett−Teller (BET) method using adsorption data at a relative pressure lower than 0.15. Transmission electron microscope (TEM) measurements were carried out on a JEM 1400 electron microscope. Field emission scanning electron microscopy (FESEM) was performed on a JEOL JSM6700F electron microscope.

3. RESULTS AND DISCUSSION 3.1. Characterization of Porphyrinic MOFs Synthesized with TEA-Modulated Method. It has been well documented that porphyrinic Zr-based MOFs could perform a broad range of biological applications thanks to their excellent photochemical features derived from the porphyrin-containing ligands. However, the flexible and diverse coordination modes between the same porphyrinic linker and Zr6 cluster frequently bring about the occurrence of many topological derivative structures (e.g., PCN-222, PCN-223, and PCN-224) with various connecting numbers and symmetry under the similar reaction condition.49−51 Thus, many previous attempts in our group to minimize the size of these MOFs to nanoscale by means of varying the synthetic conditions were unsuccessful due to the evolvement of mixed derivative phases. These unwanted phases severely affect their biological applications since various size/morphology/structure of particles present enormously different performances.46,52 It is imperative to find the crucial factor for controlling the phase transformation between various topological structures, realizing to obtain purephase NMOFs crystals for the diverse biological applications. After many efforts, we found that TEA could not only control the phase transformation of porphyrinic MOFs, but also minimize their size from a micrometer scale to nanoscale under a moderate solvothermal reaction. The XRD and SEM techniques were employed to track the structure, morphology and size evolvements of the synthesized MOFs at various feed ratios of TEA to TCPP (0−40 equiv). All the as-synthesized samples exhibit obvious Bragg diffraction peaks and permanent porosity, demonstrating the preservation of high crystallinity and intact porosity upon the introduction of TEA in the MOFs synthesis (Figure 1, SI Figure S1 and Table S1). Interestingly, 4582


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25 eq of TEA to TCPP was utilized. Further increasing the amount of TEA (30 eq and 35 equiv) still yields PCN-223 crystalline but gives rise to serious intergrown aggregates (SI Figures S4 and S5). Therefore, the nanoPCN-223 synthesized with 25 eq TEA was selected for the following PBLs coating to ensure a monodispersed system. The permanent porosity of nanoPCN-223 was measured by N2 sorption measurement at 77 K (SI Figure S1). A type I isotherm is obtained for nanoPCN-223, exhibiting a high surface area of around 1626 m2/g. 3.2. Characterization of MOFs-Supported PBLs. The presence of PBLs on the surface of NMOFs was initially checked by IR spectra. As shown in SI Figure S6, two new bands corresponding to CH2 symmetric (2852 cm−1) and asymmetric (2926 cm−1) stretching modes are obviously visible upon PBLs coating, which could be assigned to the abundant CH2 groups in the two acyl chains of DOPC molecules.56 A relatively low absorption at 2956 cm−1 is associated with CH3 asymmetric stretch due to the presence of only one CH3 group at the end of each acyl chains in DOPC.56 The successful coating of PBLs on NMOFs was further followed by surface potential measurements. The zeta potential of nanoPCN-223@ DOPC/DOPC is determined to be electrically neutral (−2.7 ± 0.2 mV), which matches well with the fact that DOPC is a zwitterionic lipid with a net charge of approximate zero at physiological pH. On the contrast, the surface of bare nanoPCN-223 carries high negative charges (−34.2 ± 1.3 mV) at pH 7.4. We also measured the XPS spectra of O, Zr and P for coated nanoPCN-223 to further confirm the presence of Zr−O−P interaction between nanoPCN-223 and DOPC. After the coating process, the appearance of the P 2p peak verifies that the DOPC is undoubtedly attracted to the nanoparticles (SI Figure S7A) in agreement with the FTIR analysis. The deconvoluted O 1s peaks of coated nanoPCN-223 (SI Figure S7B) also contain the signals assigned to Zr−O−P and PO (531.4 eV) consistent with our previous investigations,43,45 indicating that the Zr−O clusters on the surface of nanoPCN223 show high affinity toward DOPC molecules. Thanks to the chemical complexation of Zr−O−P, the lipid could be strongly adsorbed on the nanoPCN-223 and forms stable MOFssupported PBLs to protect the vulnerable coordination bonds in NMOFs.

Figure 1. Powder XRD patterns for the simulated PCN-222, simulated PCN-223, simulated PCN-224 and the as-synthesized MOFs prepared at different TEA to TCPP feed ratios of (a) 0 eq, (b) 10 eq, (c) 15 eq, (d) 20 eq, (e) 25 eq, and (f) 30 eq.

the applied amount of TEA plays a key role to mediate the phase transformation from six-connected PCN-224 (0 to 10 eq TEA) to eight-connected PCN-222 (20 eq TEA), and finally to 12-connected PCN-223 (25 to 40 eq TEA). The transition state of PCN-224/PCN-222 mixed phases is also observed (15 eq TEA, Figure 1c). The SEM images further reveal that the different morphologies of porphyrinic MOFs are generated in correlated with the applied amount of TEA, corresponding to PCN-224, PCN-222, and PCN-223 crystals in cube, long rod, and short rod shapes, respectively (Figure 2). The addition of TEA would increase the deprotonation degree of carboxylic groups in TCPP ligands and consequently raise their coordination ability to Zr6 clusters, leading to the higher connected number between Z6 clusters and TCPP (Scheme 2). Although it has been reported that a solvent-assisted separation approach is capable to separate pure-phase MOFs isomers from mixed phases, it is quite difficult to find the suitable parent solvent to distinct mixed porphyrinic MOFs on the basis of their density difference.53 This strategy might pave a new way to achieve pure-phase porphyrinic MOFs, and could be helpful to discover other MOFs crystalline in the future. TEA could also increase the speed of nucleation in MOFs synthesis due to the deprotonation of carboxylic groups in TCPP ligands,54,55 leading to gradually reduced length in axial direction of PCN-223 (SI Figures S2 and S3). It could be observed that the monodispersed nanocrystals are mainly shortrod in shape with a mean dimension of ca. 120 × 180 nm when

Figure 2. SEM images of the as-synthesized porphyrinic MOFs crystals synthesized with applied TEA amount of (a) 0 eq, (b) 10 eq, (c) 15 eq, (d) 20 eq, (e) 25 eq, and (f) 30 eq to TCPP ligands to demonstrate the morphology evolvement. 4583


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Chemistry of Materials Scheme 2. Proposed Mechanism of the TEA-Modulated Strategy for the Synthesis of nanoPCN-223a

a

TEA was used to control the phase transformation and particle size.

Figure 3. Negative-stained TEM images of (a, b) the bare nanoPCN-223 and (c, d) the coated nanoPCN-223@DOPC/DOPC particles. Long-term dispersity of (e) bare and (f) coated nanoPCN-223 suspended in H2O, PBS, RPMI-1640 and DMEM media, respectively. The corresponding photographs of (g) bare and (h) coated nanoPCN-223 in H2O and PBS for 7 days, indicating a serious aggregation and precipitation for bare nanoPCN-223 in PBS. (i) Tyndall phenomenon of coated nanoPCN-223 after 7-day aging in PBS solution. (j) A digital picture of coated nanoPCN223 in PBS solution under UV illumination.

To further confirm the existence of PBLs on the surface of NMOFs, we employed TEM with negative staining to directly monitor the evolvement of the morphology and size of the nanoPCN-223 before and after the PBLs coating.57 It can be observed that nanoPCN-223 particles are monodispersed with a mean dimension of ca. 120 × 180 nm (Figure 3a and b) in good agreement with SEM image. Notably, the nanoPCN223@DOPC/DOPC shows a totally different pattern after negative staining with uranyl acetate owing to the strong interaction between uranium and the phosphonate head groups.57 As shown in Figure 3c, the uranium ions uniformly accumulate around the edge of nanoPCN-223@DOPC/ DOPC, indicating the formation of a continuous and dense PBLs in line with the deduction from IR and XPS spectra. Meanwhile, the PBLs could be individually supported on each NMOF without aggregation and still maintain the morphology of nanoPCN-223 core (Figure 3d). Hence, it is expected that the obtained nanoPCN-223@DOPC/DOPC could exhibit favorable phosphatic resistance in simulated physiological environments. It should be noted that directly coating DOPC/cholesterol outer layer onto nanoPCN-223@DOPC in aqueous phase would lead to serious and irreversible aggregation (SI Figure S8). Upon the first coating step of

intimal DOPC, the nanoPCN-223@DOPC was highly hydrophobic and would aggregate in aqueous phase due to the fact that abundant acyl chains of DOPC change the surface property of MOFs.16 Therefore, the second step is necesasry to coat the nanoPCN-223@DOPC in the H2O/EtOH systems to avoid direct aggregation of NMOFs in H2O systems. Long-term particle dispersity of bare and coated nanoPCN223 was measured in water and biological media, including PBS, RPMI-1640 and DMEM. As shown in Figure 3e, the hydrodynamic size of bare nanoPCN-223 in H2O increases over time. More unfortunately, when it was dispersed in PBS solution, their size sharply increases to ∼4.6 μm in the first day. The nanoparticle is seriously aggregated and irreversibly precipitated after 7-day aging in PBS, which could be visible to naked eye in the bottom of the vessel (Figure 3g). On the contrast, the coated nanoPCN-223 in H2O does not increase in size over a 7-day incubation period and shows improved longterm dispersity in PBS solution (Figure 3f and h). The Tyndall phenomenon could be obviously observed for the coated nanoPCN-223 in PBS solution with a 7-day incubation time in good consistence with the DLS measurements (Figure 3i). Furthermore, the red fluorescence of coated nanoPCN-223 is still visible to the naked eyes in PBS after 7-day aging, which 4584


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Figure 4. TEM images of (a) bare nanoPCN-223 and (b) PBLs coated nanoPCN-223 particles in PBS solution with 2-day incubation time. (c) Powder XRD patterns for coated nanoPCN-223 (Black), coated nanoPCN-223 in PBS (Red) and bare nanoPCN-223 in PBS (Blue). (d) Degradation rate of the bare and coated nanoPCN-223 in PBS for a 7-day incubation period.

Figure 5. (a) Displacement of TCPP ligands from the bare and coated nanoPCN-223 by potentially coexistent ions (e.g., phosphate, Na+, Mg2+, NO2− and SO42−; 10 mM and 100 mM each), H4PDP (10 mM and 100 mM), reactive oxygen species (H2O2, 1% and 10%) and serum (1% and 10%) in 2-day incubation time. (b) The corresponding photographs illustrating the changes of bare and coated nanoPCN-223 suspensions under various chemical environments (100 mM or 10% of the above compounds).

the identical morphology of nanoPCN-223@DOPC/DOPC preserves and they maintain monodispersed in PBS solution (Figure 4b) in according to the above DLS measurements. This clearly evidences that the PBLs may function as a barrier to restrain phosphate from approaching the structure of Zr-based NMOFs. Further inspection was performed by XRD measurements (Figure 4c). The bare nanoPCN-223 has completely transformed to amorphous material, disclosing the destruction of the initial MOFs structure after their dispersing in PBS solution. In contrast, the structure and crystallinity of nanoPCN-223@ DOPC/DOPC remain intact after the same treatment. The UV−vis spectra were employed to quantitatively analyze the amount of TCPP ligands released from the bare or coated NMOFs to further evaluate whether nanoPCN-223 would degrade in PBS buffer solutions (SI Figure S9). As shown in Figure 3d, the bare nanoPCN-223 rapidly releases massive TCPP ligands (about 89%) upon its dispersing in PBS at the

could be directly served as an imaging signal for biological applications. These results strongly support our proposal that the additional PBLs on NMOFs could improve the long-term dispersity of untreated nanoPCN-223 particles in biologically relevant media. 3.3. Phosphate-Resistant Property of the Coated NanoPCN-223. An important motivation to coat PBLs is to enhance the phosphatic resistance of Zr-based NMOFs to make them practical for the potential biological applications since phosphate is widely existed in physiological environments. Hence, we explored our system in simulative physiological condition (PBS buffer, pH 7.4) containing a large number of phosphate. The morphology, structure, and degradation processes of all the samples were monitored by TEM, XRD, and UV−vis spectra, respectively. TEM images indicate that bare nanoPCN-223 crystals undergo serious corrosion with plenty of fragments caused by the attack of phosphate, after their keeping in PBS for 2 days (Figure 4a). In sharp contrast, 4585


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Figure 6. (a) The merged confocal image of SMMC-7721 cells after their incubation with TCPP molecules, bare nanoPCN-223, and coated nanoPCN-223 (at a dose of 50 μM TCPP) for 12 h at 37 °C; Bio-TEM images of SMMC-7721 cells incubated with (b, c) bare nanoPCN-223 and (d, e) coated nanoPCN-223. (c) and (e) are the enlarged images correspond to the rectangle sections in images b) and d). The red arrows in the images indicate the degraded fragment of bare nanoPCN-223 in the cytoplasm, whereas the blue one shows the presence of partially degraded nanoPCN-223 before endocytosis.

first hour. It agrees well with the fact that phosphate could easily replace the carboxyl-containing ligands in Zr-based MOFs even at very low concentration of phosphate (5 μM).42 For biomedical applications, this phenomenon will strongly affect their bioimaging signal and chemical sensing performance in the physiological environment if Zr-based MOFs could not maintain intact long enough to complete their functions. Fortunately, the nanoPCN-223@DOPC/DOPC shows almost no TCPP ligands release (less than 3%), after their staying in PBS solution for as long as 7 days (Figure 4d). All the above results unambiguously demonstrate that the MOFs-supported PBLs could effectively resist the attack from phosphate to the vulnerable coordination bonds and ensure the real stability of MOFs in complex biological media. Next, we challenged our system with various chemicals that might be encountered in the physiological conditions (Figure 5). As expected, both samples are very stable when exposing to the common cations, anions and serum due to their high waterresistance and chemical stability of Zr-based MOFs. However, the total different phenomena were observed when harsher conditions were applied. In all the cases, the coated nanoPCN223 system shows much higher stability. When reactive oxygen species of H2O2 was selected, which is widely existed in living organisms, the bare nanoPCN-223 releases approximate 20% of TCPP ligands at a low concentration of H2O2 (1%). While the coated nanoparticles still maintain stable even at H2O2 concentration of as high as 10%. H4PDP molecule possesses two PO33− groups with strong affinity for binding Zr metal centers, which could easily replace carboxylic groups in TCPP ligands of NMOFs through the competitive coordination effect. Actually, almost 35% and 60% of bare nanoPCN-223 degraded upon the addition of H4PDP (10 mM and 100 mM), but no TCPP ligand release was observed for coated particles in 100 mM H4PDP solution (Figure 5a). Correspondingly, the color of bare nanoPCN-223 suspension changes from red to light green, green and yellow green with the attack of H2O2, H4PDP and phosphate, respectively, while the colors keep almost unchangeable for coated NMOFs in all the applied solutions. These results further give an indication that MOFs-supported PBLs are impermeable to most water-soluble molecules, and

thus protect MOFs to survive in harsh chemical media, especially in complex physiological environment. 3.4. Intracellular Bio-Stability Evaluation for the Coated NanoPCN-223. Up until now, the practical using of porphyrinic Zr-based MOFs in biological fields (e.g., imaging agents, biosensors, photodynamic therapeutic agents) has been well explored.22,46−48 Nevertheless, very little information was disclosed to discuss their degradation behavior in cells. Hence, a porphyrinic MOFs platform of nanoPCN-223, covering a broad range of potentials in biological applications, could provide important insight in considering the real biostability of Zr-based MOFs in cells. To determine the implication of PBLs coating on NMOFs, free TCPP molecules, bare nanoPCN-223 as well as coated nanoPCN-223 were applied to incubate with HeLa and SMMC-7721 cells, respectively. According to the CLSM images, free TCPP could image the cancer cells with a weak red fluorescence and uniformly distributes in the whole cell (Figure 6a, top panel), ascribed to the passive diffusion and the active uptake by a number of transport proteins on the cell membrane.58,59 Trace amount of bare nanoPCN-223 is taken into the cancer cells through cell endocytosis, exhibiting as sporadically distributed red fluorescent dots in the lysosomal localization. Meanwhile, a large number of TCPP ligands are found to be released and taken into the cytoplasm and nucleus consistent with the observation in free TCPP molecules (Figure 6a, middle panel). This indicates that bare nanoPCN-223 is partially broken, and TCPP ligands are rapidly leaked from porous framework with the influence of phosphate in RPMI1640 culture medium. Compared with the free TCPP molecules and the bare nanoPCN-223, the coated nanoPCN223 shows remarkably higher cellular uptake and distributes intensively in the lysosome as manifested by the appearance of red fluorescent dots around the nucleus (Figure 6, bottom panel). More importantly, no red fluorescence from the released TCPP ligands is found in the nucleus for coated nanoPCN-223 samples. The same phenomena are also observed in HeLa cells (SI Figure S10). Bio-TEM was further employed to track the change of NMOFs after their endocytosis into the cells. It is found that fragments of nanoPCN-223 in both extracellular and 4586


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Figure 7. (a) Flow cytometric analysis of SMMC-7721 cells after incubation with TCPP molecules (blue), bare nanoPCN-223 (orange) and coated nanoPCN-223 (green) at the same TCPP dose of 50 μM and control sample (red) for 24 h at 37 °C. The inset: the mean fluorescence intensity (MFI) of FL3-H in SMMC-7721. (b) Viability test of SMMC-7721 cells with different concentrations (0−400 μM) of bare and coated nanoPCN223 after 24 h of incubation.

and greatly improved biostability in cellular environments, the coating of PBLs on NMOFs may pave a general way for their widely potential applications in biological fields.

cytoplasmic milieus of SMMC-7721 cells are definitely visible (Figure 6b, c), corresponding to the collapse of bare nanoPCN223 in PBS and intracellular environment. Meanwhile, a large number of nanoPCN-223@DOPC/DOPC particles are observed in the cytoplasm and maintain their intact short-rod morphology (Figure 6d, e). Therefore, the PBLs coating on NMOFs-core could effectively protect nanoPCN-223 from the attack of phosphate in the intracellular and PBS environments, which ensures NMOFs to maintain intact long time enough to complete their functions. For flow cytometric analysis, the TCPP solution, bare nanoPCN-223 and coated nanoPCN-223 suspensions were incubated with SMMC-7721 and HeLa cells for 4, 12, and 24 h, respectively. All the samples could enter into cancer cells, demonstrating that not only the nanoparticles could be effectively internalized but also the free TCPP molecules could enter into cancer cells via a passive diffusion path.58,59 With the increasing of incubation time, the fluorescent intensity for bare nanoparticles gradually enhances (SI Figure S11 and S12). However, it is found that the coated nanoPCN-223 particles are rapidly endocytosized into cancer cells in the first 4 h of incubation, according to the fact that only slight increase of fluorescence intensity could be observed with incubation time prolonging to 12 and 24 h (SI Figure S11 and S12). Additionally, the cells incubated with coated nanoPCN-223 show a much higher fluorescence intensity than those incubated with bare nanoPCN-223 and free TCPP molecules at the same incubation times (Figure 7a, SI Figures S13 and S14). For the samples incubated with SMMC-7721 cells for 24 h (Figure 7a), the mean intensities for bare nanoPCN-223 and free TCPP samples are only approximate 59% and 58% of that for coated nanoPCN-223 sample. This indicates that the existence of PBLs would benefit to a more effective cell endocytosis in consistency with the results deduced from CLSM images.60,61 MTT cell viability assay was employed to evaluate the cellular cytotoxicity of nanoPCN-223 in SMMC-7721 and HeLa cells. The cytotoxicity of nanoparticles depends on the dose and is improved with the existence of PBLs. As shown in Figure 7b (SMMC-7721 cells) and SI Figure S15 (HeLa cells), both bare and coated nanoPCN-223 show almost no toxicity to cells at a common drug dose (0−50 μM based on TCPP concentration) after incubation for 24 h. However, with a higher treatment dose (50−400 μM TCPP concentration), the bare nanoPCN-223 leads to much higher amounts of cell deaths than coated nanoPCN-223, indicating an enhanced biocompatibility with the biointerface of PBLs on NMOFs. Taking the good biocompatibility, high cell uptake efficiency,

4. CONCLUSIONS In summary, a general and reproducible triethylamine (TEA)modulated approach has been successfully developed for the preparation of monodispersed porphyrinic Zr-NMOFs. This method not only successfully minimizes the particle size of porphyrinic MOFs to sub-200 nm, but also achieves the purephase crystals via modulating the phase transformation. In virtue of Zr−O−P complexation between Zr-NMOFs and phospholipid, closely packed PBLs are successfully assembled onto NMOFs, which effectively protect NMOFs from the attack of phosphate and other potentially coexisted species in complex biological media. The obtained NMOFs@PLBs nanosystem exhibits more favorable biocompatibility, improved cellular uptake, and intracellular biostability. Given the facility to construct the PBLs on various Zr-MOFs and their diversity for further modification with functional biomolecules, this strategy could pave a new way for the fabrication of nanosystems inheriting both the merits of Zr-NMOFs and PBLs with extended functions for practical biological applications (e.g., triggered release, targeting to certain cells).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemmater.7b01329. N2 sorption isotherms and Table S1, XRD patterns, SEM images, FT-IR and XPS spectra, TEM image, Quantitative analysis of TCPP degradation rate in MOFs, Confocal images, Cell viabilities for HeLa and Flow cytometric analyses (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*(P. F. L.) E-mail: [email protected]. *(J. L.G.) E-mail: [email protected]. ORCID

Jinlou Gu: 0000-0002-3190-573X Notes

The authors declare no competing financial interest. 4587


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ACKNOWLEDGMENTS This work was financially supported by the Natural Science Foundation of China (Grants 51372084, 81472842, and 81502560) and the 111 Project (Grant B14018).

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Zr-Based MOFs Shielded with Phospholipid Bilayers: Improved

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