Multifunctional Supramolecular Materials Constructed from

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Multifunctional Supramolecular Materials Constructed from Polypyrrole@UiO-66 Nanohybrids and Pillararene Nanovalves for Targeted Chemophotothermal Therapy Ming-Xue Wu,† Hong-Jing Yan,‡ Jia Gao,† Yan Cheng,§ Jie Yang,† Jia-Rui Wu,† Bai-Juan Gong,‡ Hai-Yuan Zhang,§ and Ying-Wei Yang*,†,∥ ACS Appl. Mater. Interfaces 2018.10:34655-34663. Downloaded from pubs.acs.org by UNIV OF TEXAS SW MEDICAL CTR on 10/12/18. For personal use only.

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State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, P. R. China ‡ Hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun 130012, P. R. China § Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China ∥ Department of Chemistry & Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles, California 90095, United States S Supporting Information *

ABSTRACT: Multifunctional supramolecular nanomaterials capable of targeted and multimodal therapy hold great potential to improve the efficiency of cancer therapeutics. Herein, we report a proof-of-concept nanoplatform for effective chemophotothermal therapy via the integration of folic acid-based active targeting and supramolecular nanovalves-based passive targeting. Inspired by facile surface engineering and designable layer-by-layer assembly concept, we design and synthesize PPy@UiO-66@WP6@PEI−Fa nanoparticles (PUWPFa NPs) to achieve efficient synergistic chemophotothermal therapy, taking advantage of the desirable photothermal conversion capability of polypyrrole nanoparticles (PPy NPs) and high drug-loading capacity of hybrid scaffolds. Significantly, pillararene-based pseudorotaxanes as pH/temperature dual-responsive nanovalves allow targeted drug delivery in pathological environment with sustained release over 4 days, which is complementary to photothermal therapy, and folic acidconjugated polyethyleneimine (PEI−Fa) at the outmost layer through electrostatic interactions is able to enhance tumortargeting and therapeutic efficiency. Such PUWPFa NPs showed efficient synergistic chemophotothermal therapy of cervical cancer both in vitro and in vivo. The present strategy offers not only the distinctly targeted drug delivery and release, but also excellent tumor inhibition efficacy of simultaneous chemophotothermal therapy, opening a new avenue for effective cancer treatment. KEYWORDS: cancer treatment, dual targeting, pillar[n]arene, polypyrrole nanoparticles, synergistic chemophotothermal therapy

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INTRODUCTION Cervical cancer has always been a threat to human health.1 Increasing drug resistance and limitations of monotherapy have stimulated the rapid development of multitherapy that could improve cancer treatment efficiency with the assistance of materials science.2−15 At present, traditional chemotherapy is still the main anticancer manner in clinics; however, its nonspecific treatment causes severe toxicity concerns and lifethreatening side effects.16 Photothermal therapy, as a promising local noninvasive approach that could selectively kill cancer cells through photothermal effect induced by employing optical absorbing agent to convert near-infrared (NIR) light into thermal energy, is a potential adjuvant treatment of cancer with reduced side effects.17−21 Thus, many photothermal agents have received increasing attention, among © 2018 American Chemical Society

which inorganic nanomaterials, such as gold nanoparticles (NPs)22,23 and copper sulfide nanoparticles,24−26 are commonly used photothermal agents. However, these inorganic nanomaterials are either unstable or highly toxic, and are not easy to degrade.27,28 Compared to the widely used but limited inorganic photothermal agents, organic photothermal agents such as polypyrrole nanoparticles (PPy NPs) with good biocompatibility, high conductivity, and excellent photothermal conversion efficiency have become potential polymeric optical absorbing agents, 29−31 which could be easily engineered to integrate multifunctional hybrids as well as to Received: August 11, 2018 Accepted: September 18, 2018 Published: September 18, 2018 34655

DOI: 10.1021/acsami.8b13758 ACS Appl. Mater. Interfaces 2018, 10, 34655−34663

Research Article

ACS Applied Materials & Interfaces

Figure 1. Schematic illustration of the preparation of PUWPFa nanoplatform (A) and such nanoplatform for dual targeted chemophotothermal therapy of cervical cancer and the structures of representative building blocks (B).

have attracted wide attention due to their facile synthesis, accessible derivatizations, and dynamic host−guest chemistry.61−64 In recent years, pillar[6]arenes have developed rapidly in the field of biomedicine, especially in the field of controllable drug delivery with great potential.65−70 Tumortargeted chemotherapeutics is another essential factor for enhancing tumor inhibition ability. Folic acid-mediated targeted identification of cancer cells has always been of particular concern due to the overexpressed folic acid receptors on most cancer cells in view of their working mechanisms of folic acid receptor-meditated endocytosis.71,72 In this regard, the development of targeted therapy under dual mechanism of cancer cell recognition and controllable drug release will significantly improve the selectivity and efficacy of anticancer nanomaterials. In light of the above annotations, we first show a proof-ofconcept dual targeted highly effective synergistic chemophotothermal anticancer nanoplatform based on PPy and UiO66 MOF nanoparticles (PU NPs) equipped with water-soluble pillar[6]arene-based pseudorotaxanes (WP6) as nanovalves and folic acid-modified polyethyleneimine (PEI−Fa) as another major targeting entity (PUWPFa NPs). As expected, the core of PPy NPs guaranteed the desired photothermal efficiency under the irradiation of 808 nm laser, the hybrid

preserve their intrinsic properties, thus providing a variety of possibilities for combinatorial treatments. Metal−organic frameworks (MOFs), as increasingly mature biomedical materials32−38 with good biocompatibility, easy functionalization, tunable compositions, and desirable loading capacity, provide a huge development potential for the construction of MOF-containing nanohybrids for high-performance multimodal therapies.21,39−43 Nonspecific treatments hinder the further improvement of multimodal anticancer efficiency.44−46 Fabricating facile and efficient delivery platforms with precise tumor localization and controllable drug release has been a hot research subject.47−53 Supramolecular switches with tunable host−guest interactions54 can serve as nanovalves of nanovehicles to selectively modulate the drug release at the desired site of action. The host−guest interactions between supramolecular macrocycles and “stalk” components on nanocarrier surfaces can be altered in response to specific stimulus of pathological environment and then minimize the nonspecific toxicity and enhance therapeutic efficiency;55−60 therefore, the installation of supramolecular nanovalves is beneficial to enhance the efficiency and controllability of drug delivery due to the selective “unlocking” and controlled release of drugs. Among them, pillar[n]arenes as a new generation of macrocyclic hosts 34656


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Figure 2. (A) Powder X-ray diffraction (PXRD) patterns of PU NPs, PU−Py NPs, 5-Fu-loaded PUWP NPs, and 5-Fu-loaded PUWPFa NPs. (B) Fourier transform infrared (FT-IR) spectra of PPy, PU NPs, PU−Py NPs, 5-Fu-loaded PUWP NPs, and 5-Fu-loaded PUWPFa NPs. (C) Transmission electron microscopy (TEM) image of PUWPFa NPs. The inset shows an enlarged high-resolution TEM (HR-TEM) image of the nanoscaffolds. (D) Dynamic light scattering (DLS) of PUWPFa NPs, showing the average size. (E) ζ-Surface potential values of PPy NPs, PU NPs, PUWP NPs, PUWPFa NPs, and 5-Fu-loaded PUWPFa NPs. (F) Thermogravimetric analysis (TGA) of PU NPs, PU−Py NPs, PUWP NPs, and PUWPFa NPs.

scaffolds ensured the high loading of chemotherapeutics, and the postmodification of WP6 nanovalves induced pH/temperature-responsive drug release, minimizing collateral damage to normal organs. Furthermore, the outmost targeting layer of PEI−Fa not only enhanced the biocompatibility of the nanoplatform, but also ensured sufficient tumor localization. The effective anticancer experiments both in vitro and in vivo further demonstrated the satisfactory therapeutic ability of this newly developed nanoplatform. The fabrication and application details of the nanoplatform are demonstrated in Figures 1 and S1.

modification and drug loading (Figure 2A). Fourier transform infrared (FT-IR) spectrum further verified the fabrication process of the nanohybrids (Figure 2B). The characteristic peaks at 3461 and 3338 cm−1 correspond to the −NH2 stretching vibrations of UiO-66-NH2, indicating the successful growth of UiO-66 MOF on the surface of PPy NPs, and their disappearance suggests the successful installation of stalk component, i.e., 1-(6-bromohexyl)pyridinium bromide (Py). The corresponding peaks at ca. 3400 cm−1 and its widening as well as the differences in the fingerprint region can be attributed to the nanovalve formation via the threading of WP6 on stalks and the loading of 5-fluorouracil (5-Fu) drug. The characteristic peaks at 2947 and 2837 cm−1 can be attributed to the −CH2− vibration of PEI, and the variations at 1647 and 1097 cm−1 are due to the presence of folic acid. The homogeneous spherical morphology of the as-prepared nanohybrids with an average hydrodynamic diameter of 150 nm was determined by transmission electron microscopy (TEM) (Figure 2C) and dynamic light scattering (DLS) (Figure 2D). Furthermore, TEM images of PPy NPs and PU NPs revealed that the thickness of MOF coating is ca. 10 nm

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RESULTS AND DISCUSSION Characterization. The new synergistic treatment nanoplatform was fabricated by traditional hydrothermal method and postmodification strategy for the growth of MOF and the installation of nanovalves and folic acid identification entity. The presence of the characteristic peaks of UiO-66 MOF in PU NPs in its powder X-ray diffraction (PXRD) pattern confirmed the successful growth of UiO-66 MOF on PPy NPs and its crystallinity was maintained despite the layer-by-layer 34657


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ACS Applied Materials & Interfaces (Figure S2). However, as we continued to increase the concentration of MOF precursor solutions to 1.1 times and kept other conditions unchanged, the morphology of the material became inhomogeneous. Therefore, the PU NPs prepared under the optimized conditions were used for subsequent experiments. In addition, the surface ζ-potential values changed from positive to negative upon installation of the WP6-based nanovalves and then turned into positive due to the modification of PEI−Fa targeting ligand, further confirming the successful construction of nanohybrids (Figure 2E). Thermogravimetric analysis (TGA) showed a plateau region until 320 °C, where the PU NPs began decomposing. The TGA of PU−Py NPs showed that Py stalk components accounted for ca. 18% of weight loss between 160 and 320 °C compared to the different weight loss between PU NPs and PU−Py NPs, and 12% of weight loss difference between PU− Py NPs and PUWP NPs was ascribed to the loss of WP6 in PUWP NPs in the range of 37−320 °C. The difference (10%) between PUWP NPs and PUWPFa NPs was due to the weight loss of PEI−Fa entities (Figure 2F). Photothermal Effects of PUWPFa NPs. To demonstrate the photothermal effects of the as-synthesized hybrid nanomaterials, temperature elevation was monitored in the presence of different concentrations of PUWPFa NPs (0, 50, 100, and 200 μg/mL) under the irradiation of NIR laser (1, 2, and 3 W/ cm2). The temperature rose with the increased concentration of PUWPFa NPs (Figure 3A) and the elevation of NIR energy density (Figure 3B). In comparison, the temperature increased only 3 °C after exposing an equal amount of water to the NIR laser for 10 min. Moreover, the photothermal conversion efficiency of PUWPFa NPs was calculated to be 38.69% (Figure 3C,D). All of these experiments verified that PUWPFa NPs could serve as a potential photothermal nanoplatform. Passive Targeted Drug Delivery. To clarify the importance of the supramolecular nanovalves in passive targeted drug delivery, the release behaviors of 5-Fu-loaded PUWPFa nanoplatform were investigated under the influence of two crucial factors (pH and temperature). As shown in Figure 3E, the higher the temperature, the faster the drug release due to the weakened host−guest interactions between WP6 and Py stalk at high temperature, that is, higher temperature tend to decrease the stability of host−guest system because of the unfavorable entropy term in the process of supramolecular recognition.73−75 Similarly, the lower the pH, the faster the drug release because the protonation of carboxylate groups of WP6 decrease the negative charges and further weaken the electrostatic interactions between the WP6 macrocycles and Py motif. As expected, when the as-fabricated nanoplatform serves as therapeutic system in the pathological environment of cancer (pH 5), increasing temperature will promote the opening of the nanovalves and accelerate the release of drug (Figure 3F), suggesting that the presence of pillararene-based nanovalves endows the PUWPFa nanoplatform with targetable and controllable chemotherapy, which is also complementary to photothermal therapy. Then, the 808 nm NIR-induced controllable drug release performance was further investigated. With the “turn-on” and “turn-off” of 808 nm laser, 5-Fu-loaded PUWPFa NPs exhibited ladder pulsatile release of drug, further illustrating that the photothermal therapy and chemotherapy could cooperate and the temperature responsiveness of nanovalves playes an essential role (Figure 3G). Moreover, 5-Fu-loaded PU NPs released about 25% of the drug in the physiological environment within 2 h,

Figure 3. (A) Temperature changes of the aqueous solutions of PUWPFa NPs (1 mL) in different concentrations under 808 nm laser irradiation (2 W/cm2, 1 mL) for 10 min. (B) Temperature changes of the aqueous dispersions of PUWPFa NPs (200 μg/mL, 1 mL) under 808 nm laser irradiation at various power densities (1, 2, and 3 W/ cm2) for 10 min. (C) Heating and cooling curves of the aqueous dispersion of PUWPFa NPs (200 μg/mL, 1 mL). (D) Plot and linear fit of time versus negative natural logarithm of the temperature increment for the cooling rate of PUWPFa NPs aqueous dispersion. (E) Release profiles of 5-Fu from 5-Fu-loaded PUWPFa NPs and PU NPs (pH 7 aqueous media) at different temperatures. (F) Monitoring of 5-Fu release in the case of temperature change in a simulated pathological environment (pH 5). (G) “Ladder” pulsatile release profile of 5-Fu from 5-Fu-loaded PUWPFa NPs (pH 7 aqueous media) under periodic 808 nm NIR laser on/off irradiation (2 W/ cm2).

while 5-Fu-loaded PUWPFa nanoplatform released only 4%, ensuring a sustained drug release for 4 days and a higher encapsulation capacity of 5-Fu (0.61 μmol/mg) compared to that of the nanovalve-free system (0.33 μmol/mg) due to the presence of gatekeeper, which reduced the drug loss due to premature release and pretreatment. Meanwhile, 5-Fu-loaded PU nanoplatform showed no pH responsiveness although high temperature could accelerate the release of 5-Fu, further indicating that the pH/temperature-responsive and sustained drug release of 5-Fu-loaded PUWPFa nanoplatform was mainly dependent on the nanovalve motifs (Figure S3). All of the experimental results indicated that 5-Fu-loaded 34658


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Figure 4. (A) Cytotoxicity assay of L02 and HeLa cells in the presence of PUWPFa NPs. (B) Cytotoxicity assay of HeLa cells in the presence of 5Fu, 5-Fu-loaded PUWP NPs, and 5-Fu-loaded PUWPFa NPs. (C) Cell viability of HeLa cells after incubation with PUWPFa NPs (200 μg/mL), 5Fu, and 5-Fu-loaded PUWPFa nanoplatforms at the same concentration of 5-Fu (15.9 μg/mL) under 808 nm laser irradiation (2 W/cm2) for 10 min.

Figure 5. In vivo anticancer efficiency. (A) Body weight changes of mice in different groups. (B) Tumor growth curves of different groups in a period of 12 day. (C) H&E staining of the heart, liver, spleen, lung, and kidneys (left to right) harvested from control group of mice and mice at the end of treatment. The scale bars is 200 μm.

PUWPFa nanoplatform possesses the ability of pH/temperature-responsive drug release in cancerous microenvironment with higher loading capacity and sustained release capability due to the updating of the nanovalve entity, providing a great possibility for the targetable and controllable synergistic chemophotothermal therapy. In Vitro Performance. Subsequently, experiments on human hepatocyte cells (L02) and human cervical cancer cells (HeLa cells) were carried out to prove that the PUWPFa nanoplatform could indeed selectively kill cancer cells. As shown in Figure 4A, PUWPFa NPs demonstrated negligible cytotoxicity on both L02 cells and HeLa cells even at a high concentration of 300 μg/mL with expected biocompatibility. More importantly, 5-Fu loaded PUWPFa nanoplatform showed a better killing effect on HeLa cells with the increase of drug loading compared to that of single 5-Fu or PUWP NPs without the targeting group of PEI−Fa (Figure 4B), further illustrating that the PUWPFa nanoplatform is highly effective

in chemotherapy. Significantly, 5-Fu-loaded PUWPFa system showed better treatment efficiency than the 5-Fu-loaded PUWP system, confirming that the presence of PEI−Fa targeting ligands accelerated the folic acid-mediated endocytosis and improved the therapeutic efficiency. Then, the synergistic anticancer efficiency of the 5-Fuloaded PUWPFa nanoplatform was evaluated in vitro by (3(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) (MTT) assay. As in Figure 4C, the viabilities of HeLa cells possess obvious differences upon incubation with PUWPFa NPs, 5-Fu, and 5-Fu-loaded PUWPFa nanoplatform, along with 808 nm irradiation for 10 min. Significantly, under the cooperative effect of 808 nm NIR irradiation and chemodrug, the 5-Fu-loaded PUWPFa nanoplatform reflects the greatest ability to kill HeLa cells in comparison to the single PUWPFa NPs or 5-Fu, which can be attributed to the cooperation of photothermal effect of PUWPFa NPs and chemotherapy effect of 5-Fu. All of these experimental results indicated that such 34659


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Then, 1-(6-bromohexyl)pyridinium bromide (Py) was obtained by reduced pressure distillation. Postsynthesis of PU NPs. For the synthesis of PU−Py nanoparticles, ZrCl4 (23.15 mg) and NH2-BDC (18.16 mg) were dissolved in 5 mL of DMF and then reacted with 1 mL of the abovementioned PPy NPs at 100 °C for 12 h to obtain the crude product of PU NPs. Thereafter, the yellowish product was separated by concentrifugation and washed with DMF and ethanol to remove unreacted impurities. After that, the as-prepared Py served as the stalk of WP6 nanovalves anchored on the surface of PU NPs by postmodification strategy at 80−150 °C for 3 days to obtain PU− Py nanoparticles. To obtain PU NPs with a thicker UiO-66 MOF layer (herein defined as PU1.1 NPs), the amounts of ZrCl4 and NH2BDC were increased to 25.17 and 19.74 mg with other conditions remaining unchanged. Preparation of 5-Fu-Loaded PUWPFa Nanoplatform. 5Fluorouracil (5-Fu), as a representative of chemotherapeutics, was encapsulated in the above synthesized PU−Py nanoparticles by simple encapsulation. Concretely, 3 mg of PU−Py nanoparticles was added into 1 mL of 5-Fu solution (3.3 mM) and the mixture was stirred at room temperature for 1 day, followed by the capping of WP6 nanovalves (30 mg) with continuous stirring at room temperature through host−guest interactions between WP6 and outside Py on PU−Py nanoparticles to obtain 5-Fu-loaded PUWP NPs. Then, enough polyethyleneimine−folic acid conjugate (PEI− Fa) synthesized by the covalent interactions between polyethyleneimine and folic acid under the assistance of 1-ethyl-3-(3dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide was added in the above reaction system and stirred for another 12 h to obtain 5-Fu-loaded PUWPFa nanoplatform. Similarly, unloaded PUWPFa NPs were prepared by replacing 5-Fu solution with water as reaction medium. Controlled Drug Release. Drug release measurements were recorded by the UV−vis absorption spectra. Concretely, 1 mg of 5Fu-loaded PUWPFa or 5-Fu-loaded PU nanoplatform in a dialysis bag was immersed into the cuvette containing 3 mL of deionized H2O under the stimuli of pH/temperature and the real-time release of 5-Fu was recorded by UV−vis absorption spectra. The amount of released drug was quantified by the Beer−Lambert law. To calculate the encapsulation efficiency of PUWPFa NPs and PU NPs, 1 mg of the corresponding nanoparticles in the dialysis bag was immersed into the cuvette containing 3 mL of aqueous solution at 50 °C with pH 5.0 and the real-time release of 5-Fu was recorded by UV−vis absorption spectra. Photothermal Evaluation of PUWPFa NPs. To verify the effect of material concentration on photothermal performance, PUWPFa NPs suspensions with different concentrations (0, 50, 100, and 200 μg/mL) were irradiated with 808 nm NIR laser (2 W/cm2). Similarly, 200 μg/mL of PUWPFa NPs suspensions was irradiated with 808 nm NIR laser at power densities of 1, 2, and 3 W/cm2 for 10 min to demonstrate the important role of power density in photothermal performance. A digital thermometer with a thermocouple was used to record the change of temperature every 30 s. Photothermal Conversion Efficiency Calculation. To obtain the photothermal conversion efficiency (η), the temperature curves of 1 mL PUWPFa dispersion (200 μg/mL) were recorded as a function of time under 808 nm irradiation at 2 W/cm2 for 10 min. After that, NIR laser was turned off and the temperature was reduced to initial temperature. Subsequently, the photothermal conversion efficiency (η) was calculated according to the following equations (τs was obtained via plot and linear fit of time versus negative natural logarithm of the temperature increment for the cooling rate of PUWPFa dispersions; mi and Cp,i are the mass and heat capacity of water, respectively; Tmax is the maximum temperature induced by nanoparticles; Tmax,water is the maximum temperature induced by water; I is the laser power; A808 is the absorption of PUWPFa NPs dispersion at 808 nm)

new nanoplatform would provide an efficient combination of chemophotothermal therapy for targeting anticancer. In Vivo Performance. Inspired by the above results, in vivo experiments were performed to verify the practical anticancer application of PUWPFa nanoplatform. Xenograft female mice models bearing HeLa tumor were divided into seven groups: phosphate-buffered saline (PBS) control, NIR laser, PUWPFa NPs, 5-Fu, PUWPFa NPs + NIR laser, 5-Fu + NIR laser, and 5-Fu-loaded PUWPFa NPs + NIR laser (equivalent to 10 mg 5-Fu kg−1 mouse, NIR laser conditions: 808 nm laser irradiation at 2 W/cm2 for 10 min). As in Figure 5A, no apparent weight changes were observed throughout the treatment, indicating that the as-prepared nanohybrids possessed considerable safety and well matched the results of in vitro experiments. Furthermore, the tumor sizes in different mice groups were investigated. As expected, the treatment efficiency of synergistic chemophotothermal therapy was obviously better than that of monotherapy. It is worth noting that tumor (initial tumor volume: ∼40 mm3) growth in PUWPFa NPs + 5-Fu + NIR group was significantly inhibited, while the tumor sizes continued to grow in other comparison groups (Figures 5B and S4). Significantly, histopathological examination with hematoxylin and eosin (H&E) staining verified that no apparent heart, liver, spleen, lung, and kidney damage and inflammatory lesion were noted in the synergetic treated mice (Figure 5C), strongly demonstrating that PUWPFa nanohybrids are a promising cancer therapeutic nanoplatform.

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CONCLUSIONS In conclusion, we have successfully fabricated a proof-ofconcept dual targeted effective chemophotothermal nanoplatform by integrating surface engineering of hybrid materials with supramolecular chemistry and flexible layer-by-layer postmodification strategy. The inner substrate PPy NPs offered auxiliary photothermal performance of 5-Fu-loaded PUWPFa NPs under NIR laser irradiation, and pillar[6]arene-based supramolecular nanovalves ensured pH/temperature-responsive drug release in tumor microenvironment and was complementary to PEI−Fa targeted recognition and photothermal therapy. Both in vitro and in vivo experiments indicated that such nanohybrids showed significant anticancer effects compared to single chemotherapy or photothermal therapy, and furthermore, supramolecular nanovalves/folic acid-mediated dual identification of lesion environment promoted the anticancer efficiency. Therefore, we envision that our new strategy will pave a new way in effective cancer therapy and expand the types of multifunctional medical nanomaterials.

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EXPERIMENTAL SECTION

Preparation of PPy NPs. Polypyrrole nanoparticles (PPy NPs) were first synthesized via a well-established method.76 Poly(vinyl alcohol) (1.5 g, 34 mmol) was dissolved in 20 mL of water, followed by adding FeCl3·6H2O (1.25 g, 0.23 mol) and equilibrating for 2 h. Then, pyrrole monomer (150 μL, 0.1 mol/L) was added into the above solution at 0 °C and stirred for another 5 h. The resulted PPy NPs were obtained by centrifuging and washed with water several times and then the as-synthesized PPy NPs were redispersed in 20 mL of dimethylformamide (DMF) for subsequent modification. Preparation of 1-(6-Bromohexyl)Pyridinium Bromide (Py). To prepare the stalk of the WP6 nanovalves, pyridine (0.5 mL) was added to the solution of 1,6-dibromohexane (5 mL) in CH2Cl2 (40 mL), and the obtained solution was refluxed at 70 °C for 3 days. 34660


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ACS Applied Materials & Interfaces η=

hs =

Cultivation Program, and the Fundamental Research Funds for the Central Universities for financial support.

hs(Tmax − Tmax,water) −A808

I(1 − 10

)

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(1)

∑i miC p, i τs

τs = − ln((T (t ) − Tsur)/(Tmax − Tsur))

(1) Small, W.; Bacon, M. A.; Bajaj, A.; Chuang, L. T.; Fisher, B. J.; Harkenrider, M. M.; Jhingran, A.; Kitchener, H. C.; Mileshkin, L. R.; Viswanathan, A. N.; Gaffney, D. K. Cervical Cancer: A Global Health Crisis. Cancer 2017, 123, 2404−2412. (2) Li, J.; Dirisala, A.; Ge, Z.; Wang, Y.; Yin, W.; Ke, W.; Toh, K.; Xie, J.; Matsumoto, Y.; Anraku, Y.; Osada, K.; Kataoka, K. Therapeutic Vesicular Nanoreactors with Tumor-Specific Activation and Self-Destruction for Synergistic Tumor Ablation. Angew. Chem., Int. Ed. 2017, 56, 14025−14030. (3) Zeng, J. Y.; Zhang, M. K.; Peng, M. Y.; Gong, D.; Zhang, X. Z. Porphyrinic Metal-Organic Frameworks Coated Gold Nanorods as a Versatile Nanoplatform for Combined Photodynamic/Photothermal/ Chemotherapy of Tumor. Adv. Funct. Mater. 2018, 28, No. 1705451. (4) Goel, S.; Ferreira, C. A.; Chen, F.; Ellison, P. A.; Siamof, C. M.; Barnhart, T. E.; Cai, W. B. Activatable Hybrid Nanotheranostics for Tetramodal Imaging and Synergistic Photothermal/Photodynamic Therapy. Adv. Mater. 2018, 30, No. 1704367. (5) Yang, T.; Liu, L.; Deng, Y.; Guo, Z.; Zhang, G.; Ge, Z.; Ke, H.; Chen, H. B. Ultrastable Near-Infrared Conjugated-Polymer Nanoparticles for Dually Photoactive Tumor Inhibition. Adv. Mater. 2017, 29, No. 1700487. (6) Fan, W.; Yung, B.; Huang, P.; Chen, X. Nanotechnology for Multimodal Synergistic Cancer Therapy. Chem. Rev. 2017, 117, 13566−13638. (7) Conde, J.; Oliva, N.; Zhang, Y.; Artzi, N. Local TripleCombination Therapy Results in Tumour Regression and Prevents Recurrence in A Colon Cancer Model. Nat. Mater. 2016, 15, 1128− 1139. (8) Zhai, Y.; Ran, W.; Su, J.; Lang, T.; Meng, J.; Wang, G.; Zhang, P.; Li, Y. Traceable Bioinspired Nanoparticle for the Treatment of Metastatic Breast Cancer via NIR-Trigged Intracellular Delivery of Methylene Blue and Cisplatin. Adv. Mater. 2018, No. e1802378. (9) Shan, W.; Chen, R.; Zhang, Q.; Zhao, J.; Chen, B.; Zhou, X.; Ye, S.; Bi, S.; Nie, L.; Ren, L. Improved Stable Indocyanine Green (ICG)Mediated Cancer Optotheranostics with Naturalized Hepatitis B Core Particles. Adv. Mater. 2018, No. e1707567. (10) Li, F.; Du, Y.; Liu, J.; Sun, H.; Wang, J.; Li, R.; Kim, D.; Hyeon, T.; Ling, D. Responsive Assembly of Upconversion Nanoparticles for pH-Activated and Near-Infrared-Triggered Photodynamic Therapy of Deep Tumors. Adv. Mater. 2018, No. e1802808. (11) Qin, S. Y.; Cheng, Y. J.; Lei, Q.; Zhang, A. Q.; Zhang, X. Z. Combinational Strategy for High-Performance Cancer Chemotherapy. Biomaterials 2018, 171, 178−197. (12) Gao, C.; Liang, X.; Mo, S.; Zhang, N.; Sun, D.; Dai, Z. NearInfrared Cyanine-Loaded Liposome-like Nanocapsules of Camptothecin-Floxuridine Conjugate for Enhanced Chemophotothermal Combination Cancer Therapy. ACS Appl. Mater. Interfaces 2018, 10, 3219−3228. (13) Zhang, M. J.; Zhang, L. Y.; Chen, Y. D.; Li, L.; Su, Z. M.; Wang, C. G. Precise Synthesis of Unique Polydopamine/Mesoporous Calcium Phosphate Hollow Janus Nanoparticles for Imaging-Guided Chemophotothermal Synergistic Therapy. Chem. Sci. 2017, 8, 8067− 8077. (14) Zhang, L.; Chen, Y.; Li, Z.; Li, L.; Saint-Cricq, P.; Li, C.; Lin, J.; Wang, C.; Su, Z.; Zink, J. I. Tailored Synthesis of Octopus-type Janus Nanoparticles for Synergistic Actively-Targeted and Chemo-Photothermal Therapy. Angew. Chem., Int. Ed. 2016, 55, 2118−2121. (15) Li, L.; Zhang, L.; Wang, T.; Wu, X.; Ren, H.; Wang, C.; Su, Z. Facile and Scalable Synthesis of Novel Spherical Au Nanocluster Assemblies@Polyacrylic Acid/Calcium Phosphate Nanoparticles for Dual-Modal Imaging-Guided Cancer Chemotherapy. Small 2015, 11, 3162−3173. (16) Gao, M.; Yu, F. B.; Lv, C. J.; Choo, J. B.; Chen, L. X. Fluorescent Chemical Probes for Accurate Tumor Diagnosis and Targeting Therapy. Chem. Soc. Rev. 2017, 46, 2237−2271.

(2) (3)

Cytotoxicity Evaluation of PUWPFa NPs, 5-Fu, and 5-FuLoaded PUWPFa NPs with or without NIR Irradiation. HeLa or L02 cells with a density of 1 × 104 per well were cultured overnight in a 96-well plate at 37 °C and 5% CO2, and after removing 100 μL of culture medium, 100 μL of culture medium containing PUWPFa NPs with various concentrations was rejoined in every well and incubated at 37 °C and 5% CO2 for another 24 h. Cell viabilities were recorded by MTT assays. For comparisons, HeLa cells with a density of 1 × 104 per well were cultured overnight in a 96-well plate at 37 °C and 5% CO2. Then, they were treated with different concentrations of 5-Fu, 5Fu-loaded PUWP NPs, and 5-Fu-loaded PUWPFa NPs at the same 5Fu concentrations. After that, cell viabilities were recorded by MTT assays. To evaluate the in vitro chemophotothermal therapy of 5-Fuloaded PUWPFa NPs toward HeLa cells, the Hela cells were incubated with PUWPFa NPs (200 μg/mL), 5-Fu (15.9 μg/mL), and 5-Fu-loaded PUWPFa nanoplatforms at the same concentration of 5Fu (15.9 μg/mL, equivalent to 200 μg/mL of PUWPFa NPs) for 6 h. Then, the cells were exposed to 808 nm NIR laser with a power density of 2 W/cm2 for 10 min. After that, the cells were incubated for another 18 h. Then, cell viabilities were evaluated by MTT results. In Vivo Experiments. Female nude mice (17−22 g) were used for building the xenograft mice models. Then, xenograft female mice models bearing HeLa tumor were divided into seven groups: PBS control, NIR laser, PUWPFa NPs, 5-Fu, PUWPFa NPs + NIR laser, 5-Fu + NIR laser, 5-Fu-loaded PUWPFa NPs + NIR laser (equivalent to 10 mg 5-Fu kg−1 mouse, NIR laser conditions: 808 nm laser irradiation at 2 W/cm2 for 10 min, four times) to evaluate the in vivo anticancer efficiency with three parallel experiments. Tumor size and body weight of mice were measured and recorded every 3 days. After 12 day treatment, the mice were sacrificed, and their major tissues, including heart, liver, spleen, lung, and kidney, were selected to do histological assay. All of the in vivo experimental procedures of animals were in accordance with protocols approved by the Committee for Animal Research of Jilin University, China.

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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/acsami.8b13758. Materials and methods; TEM characterization; encapsulation efficiency; in vivo anticancer efficiency (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yan Cheng: 0000-0002-2471-2219 Hai-Yuan Zhang: 0000-0003-4076-1771 Ying-Wei Yang: 0000-0001-8839-8161 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors acknowledge the National Natural Science Foundation of China (51673084, 51473061), Jilin ProvinceUniversity Cooperative Construction Project-Special Funds for New Materials (SXGJSF2017-3), Jilin University Talents 34661


Research Article


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Multifunctional Supramolecular Materials Constructed from

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