Heterodimers Made of Upconversion Nanoparticles and Metal

Sep 12, 2017 - CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center...
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Heterodimers Made of Upconversion Nanoparticles and Metal− Organic Frameworks Yifan Li,†,# Zhenghan Di,†,# Jinhong Gao,† Ping Cheng,† Chunzhi Di,† Ge Zhang,‡ Bei Liu,† Xinghua Shi,† Ling-Dong Sun,‡ Lele Li,*,† and Chun-Hua Yan‡ †

CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China ‡ Beijing National Laboratory for Molecular Sciences, State Key Lab of Rare Earth Materials Chemistry and Applications, PKU-HKU Joint Lab in Rare Earth Materials and Bioinorganic Chemistry, Peking University, Beijing 100871, China S Supporting Information *

ABSTRACT: Creating nanoparticle dimers has attracted extensive interest. However, it still remains a great challenge to synthesize heterodimers with asymmetric compositions and synergistically enhanced functions. In this work, we report the synthesis of high quality heterodimers composed of porphyrinic nanoscale metal−organic frameworks (nMOF) and lanthanide-doped upconversion nanoparticles (UCNPs). Due to the dual optical properties inherited from individual nanoparticles and their interactions, absorption of low energy photons by the UCNPs is followed by energy transfer to the nMOFs, which then undergo activation of porphyrins to generate singlet oxygen. Furthermore, the strategy enables the synthesis of heterodimers with tunable UCNP size and dual NIR light harvesting functionality. We demonstrated that the hybrid architectures represent a promising platform to combine NIR-induced photodynamic therapy and chemotherapy for efficient cancer treatment. We believe that such heterodimers are capable of expanding their potential for applications in solar cells, photocatalysis, and nanomedicine.

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INTRODUCTION The past decade has witnessed shifting of the focus of nanoscience from the synthesis of single-component nanoparticles (NPs) to the construction of multicomponent hybrid NPs.1 In particular, NP dimers, in which two equivalent NPs (for homodimers) or two NPs of distinct nature (for heterodimers) are connected through controlled junction areas, are emerging as an important family of hybrid nanostructures that enable special optic, electronic and magnetic communication between two components and thus lead to cooperative functions not observed either for single component or their physical mixtures. 2,3 Furthermore, heterodimers can provide anisotropic surface platforms and offer technological potential for site-specific functionalization,2g electrical connections,1b and programmable assembly of NPs,3h which facilitate diverse applications in solar energy conversion,2d catalysis,2h and cancer therapy.2g Despite such promise, most of the reported NP dimers are limited to pure inorganic components, such as metal−metal,2a,b,3a−e metal− semiconductor,2c,d,3f and metal−metal oxide combinations.2e−i In addition, preparation of NP dimers with controlled structures and compositions remains a formidable challenge because of the difficulty in tuning the surface chemistry of NPs for the controlled assembly and/or growth of different NPs. For example, the self-assembly of premade NPs using biomolecular linkers has proven especially useful for construction of such NP dimers.3 This strategy is conceptually simple, yet requiring complex control of the “valency” of the NPs (i.e., modification © 2017 American Chemical Society

of NP with a single DNA molecule) and often have low yields that need additional step of purification.3 Among the various types of building blocks, metal−organic frameworks (MOFs), synthesized by self-assembly of metal ions/clusters and organic ligands through coordination bonds, are becoming an exciting candidate, due to their unique properties including chemical and structural versatility, high surface area, tunable crystalline pores, and multiple coordination sites.4 In particular, porphyrin-based MOFs, in which porphyrin ligands can be isolated from each other to prevent self-quenching, have attracted extensive interest for the construction of light-harvesting systems with diverse applications such as solar cell, photocatalysis, and cancer therapy.5 Unfortunately, since the efficiency of these systems depends on the fraction of photons MOFs can absorb, the relatively narrow absorption spectra of porphyrinic MOFs in visible light region limited such applications significantly.5a Considering the nearinfrared (NIR) light that accounts for more than 50% of solar spectrum has several advantages over visible light, including deeper penetration and higher sensitivity and resolution, the synthesis of MOF-based nanostructures that can harvest NIR light is extremely attractive for various applications. Most recently, triplet−triplet annihilation (TTA)-based photon upconversion, which can convert low-energy photons into light of high-energy, has been introduced as a promising wavelength-shifting technique to tune the light-harvesting Received: July 13, 2017 Published: September 12, 2017 13804

DOI: 10.1021/jacs.7b07302 J. Am. Chem. Soc. 2017, 139, 13804−13810

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Journal of the American Chemical Society properties of MOFs.6 Such upconversion mechanism involves the energy transfer from a sensitizer molecule to an emitter molecule.7 However, efficient TTA-based upconversion MOFs with NIR-light harvesting capability have not been achieved yet, since this strategy often requires controlled organization of multiple chromophores, decreasing aggregation-induced quenching, and improving photostability.8 Lanthanide-doped upconversion nanoparticles (UCNPs), another promising platform to enable anti-Stokes emission upon excitation by low-power light, have attracted substantial attention in fields such as biosensing, bioimaging, therapeutics, and photovoltaics.9 In particular, UCNPs can absorb NIR light and convert it into tunable shorter-wavelength emissions spanning from UV to NIR regions. Such fascinating photoconversion ability along with other unique properties, including tunable multicolored emissions, high photostability, and suppression of autofluorescence, allow UCNPs to be used for the construction of novel energy transfer systems.9d,10 For example, dye-sensitized UCNPs were recently designed to enhance the upconversion efficiency, in which NIR dyes act as antennas to absorb incident light and transfer their energy to the UCNPs.10a,b UCNPs were also applied for NIR-induced triggering photoreactions of photosensitive materials by functioning as donors for energy transfer.9e,10c,d Herein, we report the synthesis of heterostructural nanoparticle dimers in high yields through the selective anisotropic growth of Zr-based porphyrinic nanoscale MOFs (nMOFs) onto UCNPs (Figure 1). Such MOF-based asymmetric

Figure 2. (a) TEM image of the original UCNPs. (b,c) TEM and (d,e) HRTEM images of UCMOFs. The dimers in (b) are highlighted with red ellipses. (f) HAADF-STEM image and corresponding elemental mapping images (green for Zr and red for Gd) of a single UCMOF. (g) EDS line scan profiles of a single UCMOF along the arrowed line shown in HAADF-STEM image (inset). (h) Powder XRD pattern of UCMOFs.

UCNPs exhibit single-crystalline nature, and possess the (001) facets at the top faces and (100) facets at the side faces (Figure S2). These hydrophobic nanocrystals were then coated with polyvinylpyrrolidone (PVP) to convert them into hydrophilic ones and to facilitate subsequent growth of MOFs on their surface (Figure S3). In a typical synthesis of UCNP-MOF heterodimers (UCMOFs), an optimal amount of PVP-coated UCNPs was added into a DMF solution of 5,10, 15, 20Tetrakis (4-carboxyphenyl)porphyrin, ZrOCl2·8H2O, and benzoic acid. This mixture was stirred for 5 h at 90 °C, and the solution turned from transparent to opaque. The resulted purple solid was collected by centrifugation and washed several times with DMF. Figure 2b and c present representative TEM images of the as-synthesized UCMOFs without any further purification. The heterodimer is clearly identified as the appearance of nMOF domain with lower contrast on UCNPs, implying anisotropic growth of MOF onto the surface of each UCNP. The diameter of the nMOF domain ranges from 40 to 80 nm. Statistic analysis by counting a total of 300 particles from the TEM micrographs revealed that the heterodimer was obtained in approximately 81% yield with the remaining 19% having either monomers or hybrid nanostructures with multiple NPs. The optimization of synthesis condition indicated that the amount of UCNPs used for the growth of heterodimers played an important role for achieving such a high yield. A decrease in the amount of the UCNP seeds leads to an increased population of isolated MOF NPs, while increasing the concentration of the UCNP seeds yields MOF NP with multiple UCNPs on its surface (Figure S4). Further evidence for the growth of nMOF onto single UCNP is provided by high-resolution TEM (HRTEM) images in Figure 2d and 2e, which indicates that

Figure 1. Schematic showing the synthesis of UCMOF heterodimers through the anisotropic growth of nMOFs onto UCNPs (red dots in UCNP represent doped lanthanide sensitizer (e.g., Yb3+ and Nd3+) and activator (e.g., Er3+, Tm3+ and Ho3+) ions).

nanostructures showed a different photon upconversion mechanism in comparison with aforementioned TTA-based upconversion MOFs. The heterodimers can harvest photons beyond the absorption spectra of the native porphyrinic MOFs through the resonance energy transfer from the UCNPs to nMOFs, which facilitates production of singlet oxygen under NIR light irradiation. To the best of our knowledge, this is the first example of a MOF-based heterodimer with NIR light harvesting behaviors. We further demonstrated that the heterogeneous NPs provide a potential platform for NIRinduced synergetic therapy of tumors.

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RESULTS AND DISCUSSION Oleate-capped NaGdF4:Yb,Er@NaGdF4 core−shell UCNPs were synthesized using the thermal decomposition method combined with a seed-mediated shell growth strategy.11 The core−shell design could efficiently avoid environmental quenching effect and thus ensure high upconversion efficiency.9d TEM showed that the nanoplates had an average size of ∼19 × 8 nm (Figure 2a, Figure S1 and Figure S2). The 13805

DOI: 10.1021/jacs.7b07302 J. Am. Chem. Soc. 2017, 139, 13804−13810

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spectrum of UCNPs over a broad wavelength range (Figure 3a). Such spectra overlap and the close proximity between the two nanodomains in the UCMOFs make possible the resonance-based energy transfer between the pair. As shown in Figure 3b, the UCL spectrum measured at room temperature without removing of oxygen suggests that an efficient energy transfer process has occurred from the UCNPs to the nMOFs, as evidenced by the strong depression of the Er3+ emission bands after forming heterodimers. The increase in the ratio of red to green UCL intensity (I654/I541 = 0.9) of the UCMOFs in comparison with that of UCNPs (I654/I541 = 0.4) could be attributed to relative less overlap of the absorption spectrum of nMOFs with the red UCL band of UCNPs. Time-resolved photoluminescence measurements were employed to provide more definitive evidence for the energy transfer process. The UCL decay curves of PVP-coated UCNPs and UCMOFs are shown in Figure 3c, which reveals a significant shortening in the lifetime of Er3+ emission at 541 nm (from 379 to 156 μs) upon the formation of the heterodimers. The energy transfer efficiency can be calculated as 1 − τDA/τD, where τDA and τD is the UCL lifetime of the particle donor in the presence and absence of energy acceptor, respectively.10d The calculation shows that the hybrid systems provide more than 58% energy transfer efficiency from Er3+ (4S3/2 to 4I15/2) to nMOF. The absolute photoluminescent quantum yield of the UCMOFs was determined to be 0.2% at an excitation wavelength of 980 nm (3.2 W/cm2), which is in good agreement with the reported values.10a Next, the ROS generation induced by the UCMOFs under NIR light irradiation was evaluated using SOSG (an indicator of 1O2), which can be rapidly oxidized by 1O2 to increase their fluorescence and therefore provides a means for assessment of 1O2 production. Note that the fluorescence intensity of SOSG in heterodimers solution increased upon the irradiation with 980 nm laser, but remained unchanged without NIR irradiation (Figure 3d). This set of experiments demonstrates that, the photon energy absorbed by UCNP domain is efficiently transferred to the nMOF, thereby generating 1O2 with surrounding oxygen molecules. As a control, the porphyrin-based nMOFs itself could not produce 1O2 upon the 980 nm laser irradiation (Figure S8). Since ultrasmall UCNPs (less than 10 nm) often possess weak upconversion luminescence,9d we selected 19 nm UCNPs for the synthesis of the heterodimers. To investigate the versatility of our approach, NaGdF4:Yb,Er@NaYF4@NaYF4:Yb,Tm@NaYbF4:Nd@NaYF4 core−multishell structured UCNPs with larger size were synthesized for the growth of UCMOFs (Figure 4a). Lanthanide activators (Tm3+ and Er3+) and sensitizers (Nd3+ and Yb3+) were doped in separate shells in such UCNPs to realize orthogonal UCL through harvesting two NIR light of different wavelengths (808 and 980 nm) (Figure 4b).12 As shown in Figure 4c and Figure S9, the asprepared nanoplates display uniform size of ∼55 × 29 nm. The interplanar spacing of 0.52 nm in the HRTEM image (the inset in Figure 4c) was indexed as (100) lattice fringe of the hexagonal phase. Further characterization indicated that the multishelled UCNP is also single-crystal with planes of top (001) and side planes of (100) (Figure S10). The multishelled structure was also confirmed by HAADF-STEM images (Figure 4d), in which the darker regions correspond to the lighter element (Y) and the brighter parts correspond to heavier elements (Gd, Yb, and Nd). The successful formation of the multishelled UCNPs with the designed compositions was

the two nanoscale domains were connected together with the lattice distance of 0.32 nm for the UCNPs, corresponding to the (110) plane of the hexagonal NaGdF4. The observation of multiple lattice fringe sets for the UCNP in Figure 2e may because that the NP surface is at different heights in terms of the beam optics. Further analysis confirmed that the singlecrystalline nature of UCNPs was retained after the formation of UCMOFs (Figure S5). According to the statistical analyses from TEM images, ∼77% of the heterodimers exhibit selective growth of nMOFs on the top faces of the UCNPs. Detailed information on the composition of the heterostucture was investigated with high-angle annular dark-field scanning transmission electron microscopy−energy dispersive X-ray spectroscopy (HAADF-STEM-EDS) elemental mapping and line scan. In Figure 2f, elemental mapping study of Zr and Gd on a single UCMOF confirms the asymmetry of the dimers in term of both geometrical and compositional distributions. Figure 2g shows EDS line scan analysis of single UCMOF with the corresponding elemental concentration profiles along the arrowed line, demonstrating the counts for Zr element is nearly steady in the nMOF domain, while there is a drastic rise for the level of Gd element at the location of the UCNP part. The powder X-ray diffraction (XRD) data in Figure 2h provides evidence that crystalline MOFs is formed on the UCNPs, which show sharp peaks that correspond to a pure hexagonal phase of NaGdF4 UCNPs,11 along with cubic crystalline PCN-224 MOFs,5j and no peak assigned to other impurities is detected. It shows that the UCMOFs remain intact in water and buffer (0.1 M HEPES, pH 7.4) at 37 °C for 24 h (Figure S6). We subsequently measured the upconversion luminescence (UCL) spectra of the PVP-coated UCNPs with and without the anisotropic growth of nMOFs on their surface. When the PVPUCNPs were illuminated with 980 nm continuous wave laser, the Yb3+ ions transfer energy to Er3+ and results in characteristic emission bands from Er3+ centered around 522 nm, 541 and 654 nm (Figure 3a), corresponding to the transitions from 2 H11/2 and 4S3/2 to 4I15/2, and from 4F9/2 to 4I15/2, respectively (Figure S7).9d The UV−vis absorption spectrum of the UCMOFs shows typical four Q-bands of porphyrinic MOFs at 519, 554, 589, and 646 nm, which overlaps with the emission

Figure 3. (a) UCL spectrum of the PVP-coated UCNPs and UV−vis absorption (Abs.) spectrum of the UCMOFs. The spectral overlapping is highlighted in orange. (b) UCL spectra and (c) UCL decay curves of the emission at 541 nm of PVP-coated UCNPs and UCMOFs. (d) Singlet oxygen generation by UCMOFs with and without NIR irradiation, detected by SOSG assay. 13806

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UCMOFs synthesized from 19 nm UCNPs could be attributed to the increased distance between the Er3+ donor and nMOF acceptor in this system. Similarly, the much lower energy transfer efficiency of Er3+ to nMOFs compared with that of Tm3+ to nMOFs in the UCMOFs synthesized from fourshelled UCNPs was also due to the distance difference: the distance from the surface of Er3+-doped core (NaGdF4:Yb,Er) and the outer surface of Tm3+-doped shell layer (NaYF4:Yb,Tm) to the surface of the four-shelled UCNPs were 7−13 nm and 3−7 nm, respectively (Figure S15). All together, these results demonstrated that this strategy not only could be applied to synthesis of UCNP-MOF heterodimers with controlled size of UCNPs, but also allows for dual NIR light harvesting with tunable energy transfer from the UCNPs to the MOFs. Typically, the growth of NP heterodimers are processed through the nucleation of a secondary NP onto the surface of a premade NP.1b,c,2i The synthesis is inherently complicated and often required a judicious choosing of reaction parameters to promote the heterogeneous nucleation.1b,2l We were curious about the underlying mechanism for the formation of such UCMOF heterodimers under our experimental conditions and were motivated to explore it. Since PVP can bind to metal ions (e.g., Zr ions) with carbonyl O atoms in the repeating unit via coordination interaction,13 we speculate that PVP on the surfaces of UCNPs not only stabilizes the NPs in the reaction solution, but also promote the adsorption of Zr ions onto the UCNP surface for heterogeneous nucleation and subsequent MOF growth. To prove this, we performed the synthesis by using UCNPs without PVP-coating and no heterodimers were observed, instead, significant self-nucleation of MOF NPs occurred. There were two types of NPs in the final reaction mixture: spherical nMOFs of ∼40−100 nm in diameter and seed UCNPs (Figure S16). The results confirm that the PVP on the UCNPs surface is critical for the formation of the heterodimers. As is known that PVP can selectively bind certain crystal facets of nanocrystals, and thus are widely used as a capping agent for the synthesis of a variety of anisotropic nanostructures.14 Thus, we set out to investigate whether PVP have preferential adsorption to specific crystal facets of the UCNPs used here by density functional theory (DFT). The simulation indicates that the repeat unit of PVP preferentially binds to (001) facet of the UCNPs, with a higher binding energy (−13.82 meV/Å2) than on the (100) facet (−9.12 meV/Å2) (Figure S17), similar results has been reported for the binding of oleic acids on UCNPs.15 Therefore, we strongly suggest that the anisotropic structure of UCNP and facetselected binding of PVP play key roles for the formation of UCNOF heterodimers in a controllable fashion and Zr-PVP interaction is the driving force for the preferential nucleation and growth of nMOFs on the top (001) facets of UCNPs. Our results are consistent with the general rules for the formation of the heterodimers reported in literature, which shows that the attachment of a secondary material onto a seed NP often occurs on the crystal facets that have a large binding affinity for the first atomic layer of this secondary material.21 Recently, much effort has been devoted to the growth of ZIF-8 MOFs on various types of NPs (e.g., gold NPs, QDs), which often produced isotropic heterostructures (e.g., core@ shell geometry).16 We used our PVP-UCNPs as seeds to induce the growth of ZIF-8 on their surface according to the reported synthetic methods,16a however, only the hybrid nanostructure with UCNPs encapsulated in ZIF-8 was achieved (Figure S18).

Figure 4. (a) Schematic showing the structure of UCMOFs synthesized by the growth of nMOFs onto multishelled UCNPs. (b) Schematic illustration of the energy-transfer mechanism for the fourshelled UCNPs with excitation orthogonalized multicolor UCL. (c) TEM, HRTEM (the inset) and (d) HAADF-STEM images of the four-shelled UCNPs. (e) TEM image of UCMOFs (the dimers are highlighted with red ellipses). Inset: HAADF-STEM image of a single UCMOF. UCL spectra of PVP-coated four-shelled UCNPs and resulted UCMOFs upon excitation with (f) 808 nm NIR laser and (g) 980 nm NIR laser.

further confirmed by characterization of the NPs after each shell layer growth (Figure S11). The four-shelled UCNPs were then coated with PVP for subsequent MOFs growth on their surface (Figure S12). The TEM image in Figure 4e shows that UCMOFs were successfully achieved with nMOF domain ranging in size from 30 to 80 nm. The heterodimer morphology was obtained in approximately 63% yield (n = 200), with nMOF growing mainly on the top faces of the UCNPs (80%). We then proved that these UCNPs with different shell layers could serve as the seeds for the synthesis of UCNP-MOF heterodimers (Figure S13). As shown in Figure 4f and g, the four-shelled UCNPs exhibited orthogonal UCL under NIR light excitations at 808 and 980 nm, respectively. The UCNPs display characteristic Er3+ dominated visible green (522 and 541 nm) and red (654 nm) UCL upon excitation by 980 nm and Tm3+ dominated visible blue (450 nm, 1D2 to 3F4 transition) and ultraviolet (360 nm, 1D2 to 3H6 transition) UCL under excitation at 808 nm. The UCL profile of the UCMOFs shows the strong depression of Tm3+ emission and moderate decrease of Er3+ emission. The time-resolved UCL investigation of PVP-coated UCNPs and UCMOFs reveals a significant shortening in the lifetime of Tm3+ emission at 450 nm from 107 to 63 μs, whereas the lifetime of the Er3+ emission at 541 nm shows a slight change from 419 to 376 μs (Figure S14). The calculated efficiency for the energy transfer from Tm3+ (1D2 to 3F4) and Er3+ (4S3/2 to 4 I15/2) to nMOFs is 41% and 10%, respectively. Since the resonance-based energy transfer is dependent on the distance of energy donor and acceptor, the decreased Er3+-based energy transfer efficiency of this hybrid NPs compared with that of the 13807

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Journal of the American Chemical Society The result suggested that the synthesis of NPs-MOF heterostructures was affected by many factors, including type of precursors, nature of the MOFs, and the synthetic conditions. A systematic study is needed to achieve a comprehensive understanding of the synthesis mechanism for such hybrid nanostructures. Inspired by the NIR light-triggered generation of cytotoxic 1 O2 from the UCMOFs, we explored the use of them for PDT. It is worth noting that although the usage of porphyrin-based MOFs for PDT has been reported recently,5h,i their limited absorption in the deep-tissue-penetrable NIR region hindered their use for PDT in the NIR window. We took advantage of the porous structure of the nMOF domain in the heterodimers to encapsulate a small-molecule drug (doxorubicin (Dox)) for combining chemotherapy with NIR-induced PDT. The loading content of Dox was determined to be 32 wt %. The Dox release profile for the system was pH-dependent, exhibiting increased release rate at increased acidities (Figure S19). First, the cellular uptake of the heterodimers was investigated by incubating UCMOFs with 4T1 breast cancer cells at 37 °C for 2 h. The resulting cells exhibited green UCL, which colocalized well with the fluorescence of MOFs in cells (Figure 5a), indicating efficient internalization of the hybrid NPs. The colocalization of the UCMOFs with lysosomes stained with lysotracker was observed (Figure S20), meaning that the UCMOFs were mainly transported to lysosomes. We then examined 1O2 production by the heterodimers inside cells by using dichlorofluorescein diacetate (DCF-DA) as a cell permeable fluorescent probe. DCF-DA is nonfluorescent and can be oxidized to a bright green fluorophore (dichlorofluorescein, DCF) in the presence of 1O2. As shown in Figure 5b, the 4T1 cells treated with the UCMOFs without NIR light irradiation showed negligible fluorescence of DCF. After NIR irradiation, cells treated with the UCMOFs showed strong green fluorescence of DCF, whereas negligible fluorescence was observed in the cells that were pretreated with UCNPs or nMOFs followed by NIR irradiation (Figure S21 and S22). The fluorescence of DCF induced by ROS partially colocalized with the fluorescence of MOFs (Figure S23), which may attribute to the diffusion of 1O2 in cells.17 The UCMOFs-mediated generation of 1O2 inside the cells upon NIR light irradiation was further quantitatively measured by the flow cytometry assays (Figure 5c). The cells treated with UCMOFs and a NIR irradiation displayed 1.8-fold higher DCF fluorescence when compared with cells treated with UCMOFs but without NIR irradiation. In addition, control studies using PBS, nMOFs and UCNPs exerted much less effect on NIR induced 1O 2 production. The in vitro cytotoxicity of the system against 4T1 cells was then evaluated by using CCK-8 assay. Treatment with only NIR irradiation, UCNPs, nMOFs or UCMOFs did not result in a significant decrease in the cell viability (Figure 5d), implying the negligible toxicity of light irradiation and these NPs to 4T1 cells. In contrast, UCMOFs under NIR irradiation showed significant cytotoxicity compared with nMOFs and UCNPs with irradiation, confirming their effect as NIR-based PDT agents. Notably, incubation of the cells with Dox-loaded UCMOFs (Dox/UCMOFs) following NIR irradiation led to higher cytotoxicity than that of the cells treated with Dox/ UCMOFs without irradiation or UCMOFs with irradiation, indicating an enhanced potency could be achieved through the combination of chemotherapy and NIR-induced PDT. These results were further supported by the Annexin V-FITC/PI

Figure 5. (a) Confocal fluorescence images of 4T1 cells treated with UCMOFs. (b) Confocal fluorescence images of 4T1 cells treated with UCMOFs and DCF-DA, with or without NIR irradiation. Nuclei is stained with Hohcest. Scale bar = 50 μm. (c) Flow cytometry analysis of generation of 1O2 in 4T1 cells with different treatments. (d) Cell viability of 4T1 cells with different treatments. Data are means ± SD; N = 4. (e) Flow cytometry analysis of 4T1 cell apoptosis induced by different treatments using the Annexin V/PI staining. (+) and (−) refer to with and without NIR irradiation, respectively. For NIR irradiation, cells were exposed to 980 nm laser at 1.2 W/cm2 for 10 min.

apoptosis detection assay. Dox/UCMOFs with NIR irradiation evoked the least level of healthy cells (13.44%) among all of the groups (Figure 5e). The good performance of this system in vitro motivated us to further investigate its in vivo antitumor activity. The 4T1 breast tumor-bearing mice were treated with different samples, including saline, free Dox, nMOFs, Dox/nMOFs, UCMOFs, or Dox/UCMOFs. In the NIR-treated groups, the tumor site was irradiated with a 980 nm laser for 20 min (1.2 W/cm2) 3 h postinjection. As shown in Figure 6a,b and Figure S24, there was no statistically significant difference in final tumor size or weight for saline, saline + NIR, nMOF, nMOFs + NIR, and UCMOFs treated groups, indicating that these treatments had no effect on tumor growth. Treatment of Dox/nMOFs or Dox/ UCMOFs had moderate antitumor capability because of 13808

DOI: 10.1021/jacs.7b07302 J. Am. Chem. Soc. 2017, 139, 13804−13810

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Lele Li: 0000-0001-8593-9292 Chun-Hua Yan: 0000-0002-0581-2951 Author Contributions #

Y.L. and Z.D. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Yan Guan and Dr. Mingxing Chen (Peking University) for their assistance with measurement of photoluminescent lifetime and quantum yield. This work was financially supported by the Young Thousand Talented Program and the start-up supports from CAS.

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Figure 6. (a) The tumor growth curves after exposure to different treatments. (b) Final weights of tumor tissues 14 days after treatment. Inset: representative images of the tumors for the seven groups of mice at day 14 (1: saline, 2: NIR, 3: Dox, 4: UCMOFs, 5: Dox/UCMOFs, 6: UCMOFs + NIR, 7: Dox/UCMOFs + NIR). Data are means ± SD; N = 5. *P < 0.05, **P < 0.01. (c) Representative H&E stained tumor sections after different treatments. Scale bars = 100 μm.

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chemotherapy. The tumor growth of mice treated with UCMOFs + NIR was efficiently delayed due to PDT effect, while in the Dox/UCMOFs + NIR treated group, the tumor growth was completely suppressed, implying that the combination of chemotherapy and PDT was more effective than either modality alone. Dox/UCMOFs + NIR showed no significant change in mice body weight during the treatment (Figure S25). The hematoxylin and eosin (H&E) stained sections of tumors further confirm that the combined treatment can lead to significantly higher level of nucleus dissociation and necrosis than control groups (Figure 6c).

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CONLUSIONS In summary, asymmetric UCNP-MOF heterodimers have been successfully prepared through the anisotropic growth of nMOFs on UCNPs. Due to their spectra overlap and the close proximity of the two nanodomains, the heterodimers support NIR light harvesting by the UCNPs and followed energy transfer to the nMOFs, which then transfer their energy to surrounding oxygen molecules and produce cytotoxic reactive oxygen species. By loading Dox into the porous channels of the nMOF domain, the heterodimer nanoplatform enables an efficient cancer treatment strategy by combining chemotherapy and NIR-induced PDT. In addition, we should emphasize that such systems could have applications beyond the field of nanomedicine, like enhancement of the photon harvesting ability of chromophore-based MOFs, and thus may potentially increase the efficiency of solar energy conversion.

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DOI: 10.1021/jacs.7b07302 J. Am. Chem. Soc. 2017, 139, 13804−13810

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