Polyacrylic Acid Functionalized Co0.85Se Nanoparticles: An

Article Cite This: ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

Polyacrylic Acid Functionalized Co0.85Se Nanoparticles: An Ultrasmall pH-Responsive Nanocarrier for Synergistic Photothermal-Chemo Treatment of Cancer Yan Ma,† Xianwen Wang,† Huajian Chen, Zhaohua Miao,* Gang He, Junhong Zhou, and Zhengbao Zha* School of Biological and Medical Engineering, Hefei University of Technology, No. 193 Tunxi road, Hefei, Anhui 230009, P. R. China S Supporting Information *

ABSTRACT: To surmount the challenges of limited drug penetration and therapeutic resistance in solid tumors, stimuliresponsive nanocarrier-based drug delivery systems (DDSs) with relatively small sizes are inherently favorable for combined treatment of cancerous cells. In this work, poly(acrylic acid) (PAA) functionalized Co0.85Se nanoparticles (PAA-Co0.85Se NPs) were synthesized through an ambient aqueous precipitating approach for synergistic photothermal-chemo treatment of cancer. The obtained PAACo0.85Se NPs possess ultrasmall size (8.2 ± 2.6 nm), considerable near-infrared (NIR) light absorption, high photothermal transforming efficiency (45.2%) and low cytotoxicity, all of which are beneficial for localized photothermal ablation of cancer cells. Doxorubicin hydrochloride (DOX·HCl) was then successfully loaded on PAACo0.85Se NPs with a loading capacity up to 8.3% to form PAA-Co0.85Se-DOX composites, which exhibited an exciting acidic pHresponsive drug release property due to the protonation of amino groups in DOX and carboxyl groups in PAA molecules. As expected, when HeLa cells were treated with PAA-Co0.85Se-DOX NPs as well as NIR laser irradiation, a significant synergistic cell-killing effect was observed, greatly improving the treatment efficiency. Thus, this work presents novel insight into the design of ultrasmall stimuli-responsive nanocarrier-based DDSs for synergistic photothermal-chemo treatment of cancer cells. KEYWORDS: cobalt selenide, cancer cells, photothermal-chemo, pH-responsive

1. INTRODUCTION Suffering from the low therapeutic efficacies and serious sideeffects of traditional cancer treatment approaches in clinic, malignant tumors (cancer) still have poor prognosis and high mortalities in the world.1−3 For instance, chemotherapy, a widely utilized cancer therapeutic option, always encounters significant challenges including limited drug penetration in solid tumors, severe side-effects, and drug resistance.4−6 To surmount this dilemma, researchers have developed numerous stimuli-responsive nanocarrier based drug delivery systems (DDSs), which are sensitive to either internal (acidic pH, hypoxia, etc.) or external (light, heat, magnetic field, ultrasound, etc.) stimuli, to increase intratumoral drug accumulation and reduce toxic systemic side-effects.7−11 However, because of the disorganized vasculature and increased interstitial fluid pressure in solid tumors, nanocarrier-based DDSs usually infiltrated into no more than one or two cell layers away from the blood vessels and failed to penetrate the tumor parenchyma throughout.12 This limited interstitial transport of drugs accompanied by unsatisfactory curative efficacy may result in tumor regeneration or metastasis. Fortunately, previous studies have revealed that small-sized nanoparticles (NPs) owned more superior tumor penetration capability, such as poorly permeable pancreatic tumor allowed only 30 nm polymer NPs to © XXXX American Chemical Society

penetrate rather than other larger size NPs (50, 70, and 100 nm).13,14 Thus, nanocarrier based DDSs with relatively small sizes are inherently favorable for tumor penetration to effectively treat cancerous cells. Another big challenge for further applications of nanocarrierbased DDSs is that most deep-seated tumor cells usually overexpressed specific proteins to adapt to their extremely harsh conditions (hypoxia, angiogenesis, nutrient scarcity, and acidic pH) and gain strong therapeutic resistance.12,15,16 Thus, completely erasing solid tumors is unlikely solvable via monochemotherapy. On the other hand, as an emerging noninvasive tumor treatment modality, photothermal therapy (PTT) has caught considerable attentions owing to the ability of directly transforming photon energy to local heating for cancerous cells ablation. Inspired by the fact that elevated temperature in tumor site could enhance cellular uptake of chemotherapeutic drugs, the combination of PTT and chemotherapy has been proven to be an effective approach in maximizing the efficiency of cancer treatment.17 Up to now, lots of photothermal conversion agents (PTCAs), such as goldReceived: November 14, 2017 Accepted: December 23, 2017 Published: December 24, 2017 A

DOI: 10.1021/acsbiomaterials.7b00878 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

Article

ACS Biomaterials Science & Engineering

Scheme 1. Schematic illustration of developing PAA-Co0.85Se NPs and PAA-Co0.85Se-DOX NPs for synergistic photothermalchemo cancer treatment

based nanostructures,18,19 copper chalcogenides,2,20−24 prussian blue nanomaterials,25 organic polymers,26−28 and carbon-based nanomaterials29−31 have been explored as nanocarrier-based DDSs for synergistic PTT-chemo cancer treatment. However, PTCAs with relatively small size as stimuli-responsive nanocarrier based DDSs for synergistic photothermal-chemo treatment of cancer cells is still a great challenge. In recent years, inspired by their fascinating physicochemical properties, lots of efforts have been devoted to investigate the potential applications of cobalt chalcogenides in lithium-ion batteries, catalysis, solar cells, and so on.32−36 Among these cobalt chalcogenides, cobalt selenide has attracted plenty of attention because of their acid-stable property and tunable activity.35 Very recently, polyacrylic-acid-functionalized Co9Se8 (PAA-Co9Se8) nanoplates have been developed for photoacoustic/magnetic resonance dual model imaging guided combined PTT-chemo cancer treatment.37 However, a relatively large size (around 100 nm), complicated preparation method and surface modification of PAA-Co9Se8 nanoplates restrict their further applications in biomedical fields. To the best of our knowledge, sub-10 nm cobalt selenide nanomaterials with considerable absorption in near-infrared (NIR) region and high photothermal transforming efficacy as novel nanocarrier based DDSs for combined PTT-chemo treatment of cancer cells have not yet been reported. Motivated by the above requirements, novel ultrasmall PAACo0.85Se NPs with a homogeneous morphology had been successfully developed via a facile aqueous route (Scheme 1). The obtained PAA-Co0.85Se NPs possess a considerable absorbance in NIR region and high photothermal transforming efficiency upon exposure to NIR laser (808 nm), which are promising for localized ablation of cancerous cells by PTT. After loading chemotherapeutic drug (doxorubicin hydrochloride, DOX·HCl) on PAA-Co0.85Se NPs mainly through the electrostatic interaction of DOX and PAA molecules, the finally obtained PAA-Co0.85Se-DOX NPs exhibited an acidic pH promoted drug release property, suggesting the potential of PAA-Co0.85Se NPs as nanocarrier based DDSs to realize combined PTT-chemo treatment of cancer cells. In addition to a significant cell-killing ability which depended on not only the

dose of PAA-Co0.85Se-DOX NPs but also the radiant quantities of NIR laser irradiation, a synergistic cell-killing effect was also observed from the cell culture assay. Therefore, PAA-Co0.85Se NPs developed here could be used as new smart nanocarrier based DDSs for maximizing the cell-killing efficacy through combined PTT and chemotherapy of cancer cells.

2. EXPERIMENTAL SECTION 2.1. Materials. Polyacrylic acid (PAA, MW = 3000−5000, 99%) was purchased from Tianjin Kemiou Chemical Reagent Co., Ltd. Cobalt chloride hexahydrate (CoCl2·6H2O, 98%), selenium power (∼200 mesh, ≥ 99.9%) and sodium borohydride (NaBH4, 99%) were obtained from Aladdin. Doxorubicin hydrochloride (DOX•HCl) was received from Beijing Huafeng United Technology Co., Ltd. Deionized water (DI water) with a resistivity of 18.2 MΩ cm was used for all experiments. All reagents were used directly without any further purification. 2.2. Synthesis of PAA-Co0.85Se NPs. PAA-Co0.85Se NPs were synthesized through a facile rapid aqueous precipitating method. Briefly, selenium precursor (NaHSe) was first obtained by thoroughly mixing Se powder (0.1 mmol) and NaBH4 (0.3 mmol) in DI water (9.0 mL) under N2 atmosphere at room temperature. After adding CoCl2·6H2O (0.1 M, 1.0 mL) and 100 μL PAA in DI water (90 mL), the prepared NaHSe solution was dropwise added into the mixture. A black solution was immediately generated, suggesting the successful formation of PAA-Co0.85Se NPs. Followed by a purification with dialysis membrane (molecular weight cutoff of 50 kDa), the purified PAA-Co0.85Se NPs were finally obtained and stored at 4 °C for further use. 2.3. Characterization of PAA-Co0.85Se NPs. A NanoBrook-90 Plus instrument was used to determine the hydrodynamic diameter of PAA-Co0.85Se NPs. The morphology and composition of PAACo0.85Se NPs were acquired using a transmission electron microscope (JEM-2100F). The phase purity and crystallographic structure of PAACo0.85Se NPs were analyzed by powder X-ray diffraction (XRD) patterns (PANalytical B. V., Holland). An X-ray photoelectron spectrometer (ESCALab 250Xi, Thermo Scientific, USA) was used to characterize the X-ray photoelectron spectroscopy (XPS) of asprepared PAA-Co0.85Se NPs. A spectrophotometer (U-5100, Hitachi) was used to characterize the UV−visible−NIR absorption spectra of PAA-Co0.85Se NPs. 2.4. Photothermal Transforming Ability of PAA-Co0.85Se NPs under NIR Laser Irradiation. Inspired by the considerable NIR light B


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Figure 1. Characterization of as-prepared PAA-Co0.85Se NPs. (a) TEM image (insets: diameter distribution and HRTEM image); (b) energydispersive X-ray (EDX) elemental mapping images and (c) spectra of the PAA-Co0.85Se NPs; (d) XRD pattern collected on PAA-Co0.85Se NPs, which exhibits a good match with hexagonal phase Co0.85Se (JCPDS No.52−1008); XPS spectra of the as-prepared PAA-Co0.85Se NPs: (e) Co 2p core level spectrum; (f) Co 3p and Se 3d core level spectrum. Human Umbilical Vein Endothelial Cells (HUVECs) according to a standard MTT assay.40 Localized photothermal cell-killing ability of PAA-Co0.85Se NPs upon NIR laser irradiation was qualitatively investigated by incubating with HeLa cells. Typically, HeLa cells (1 × 105 cells/well) were seeded and cultivated in 24-well plate for 1 day. After refreshing with PAACo0.85Se NPs solution with various concentrations (400 μL), the HeLa cells were illuminated by 808 nm NIR laser (2.0 W) for 0, 3, and 5 min, respectively. Following a standard Live/Dead assay for cell staining, the fluorescent images of HeLa cells were acquired by an inverted fluorescent microscope (MF 52, MshOt, China). Synergistic cell-killing effect was further analyzed using MTT assay. Briefly, after cultivating HeLa cells (1 × 104 cells per well) in a 96-well plate for 24 h, gradient concentrations of free DOX, PAA-Co0.85Se NPs and PAA-Co0.85Se-DOX NPs solutions were utilized to refresh HeLa cells. Upon NIR laser irradiation and further cultivation for 24 h, a MTT assay was performed to test the cell viabilities. 2.7. Enhanced DOX Cellular Uptake. Fluorescence micrographs of HeLa cells were took to directly observe the heat-enhanced cellular DOX uptake through illumination by NIR laser. Typically, exponentially growing HeLa cancer cells was treated with free DOX or PAA-Ni0.85Se-DOX NPs solutions (0.25 or 0.5 mM), and then irradiated for 0, 3, or 5 min. After that, fluorescence micrographs of HeLa cells were took, and the fluorescence intensity of each photo was measured by ImageJ software. Fluorescence activated cell sorting (FACS) technology was used here to quantitatively evaluate the effect of enhanced DOX uptake upon laser irradiation. Typically, exponentially growing HeLa cancer cells (1 × 105 cells per well) were cultivated in 24-well plates for 24 h. Followed refreshing with free DOX or PAA-Ni0.85Se-DOX NPs solutions, the cells were irradiated immediately with a 808 nm NIR laser (1.0 W) for 0, 3, or 5 min, respectively. After that, FACS analysis was performed to determine the amount of intracellular DOX according to previously reported method.41

absorption, the photothermal transforming ability of PAA-Co0.85Se NPs was investigated by illuminating the solution of NPs (3.0 mL) with an 808 nm NIR laser (2.0 W) for 10 min. A digital thermometer was used here to monitor and record solution temperature every 10 s. In addition, five LASER ON/OFF cycles of NIR laser irradiation were used to assess the photothermal stability of PAA-Co0.85Se NPs. Meanwhile, the photothermal transforming efficiency of PAA-Co0.85Se NPs was also calculated according to the reported method.38,39 2.5. In Vitro DOX Loading and Release Properties. To demonstrate the potential of PAA-Co0.85Se NPs as nanocarrier based DDSs, DOX·HCl was loaded onto the surface of PAA-Co0.85Se NPs to generate PAA-Co0.85Se-DOX NPs mainly through electrostatic interaction of PAA and DOX molecules. Typically, aqueous solutions of DOX with various concentrations were stirred with PAA-Co0.85Se NPs (1 mg mL−1, 3.0 mL) overnight. The formed PAA-Co0.85Se-DOX NPs were then purified by ultrafiltration (9000 rpm, 5.0 min) and resuspended in phosphate buffer solution (PBS, pH 7.4) for further use. The DOX loading capacity (LC) and loading efficiency (LE) were calculated as following equations: LC =

weight of initial DOX − weight of DOX in discarded solutions 100% weight of PAA‐Co0.85Se‐DOX NPs

(1) LE =

weight of initial DOX − weight of DOX in discarded solutions 100% weight of initial DOX

(2) To investigate the acidic pH promoted DOX release property, a dialysis bag (Mw = 3500 Da) containing 1.0 mL of aqueous solution of PAA-Co0.85Se-DOX NPs (1 mg mL−1) was submerged in 30 mL PBS (pH 7.4 or 5.0) with a constant temperature of 37 °C. Followed by collecting 3.0 mL of the release medium at predetermined time interval, the amount of released DOX was calculated from its fluorescence. The influence of NIR laser irradiation on DOX release was also carried out. 2.6. Cell Cytotoxic Study. The biocompatibility of as-prepared PAA-Co0.85Se NPs was evaluated by determining the viability of C


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Figure 2. Characterization of PAA-Co0.85Se NPs: UV−vis−NIR spectra of PAA-Co0.85Se NPs dispersed in (a) DI water and (b) DMEM culture medium (inset: photographs of PAA-Ni0.85Se NP solution with different concentrations); (c) hydrodynamic size of PAA-Co0.85Se NPs in various mediums; (d) photographs of PAA-Co0.85Se NP dispersions.

3. RESULTS AND DISCUSSION Without complicated and high-temperature involved procedures, ultrasmall PAA-Co0.85Se NPs were obtained through a facile aqueous precipitation approach and standard purification process at room temperature. The as-prepared NPs showed a monodisperse, dot-like morphology with an average diameter of 8.2 ± 2.6 nm (Figure 1a and Figure S1). Well-defined crystalline lattice in the typical HRTEM image with a lattice spacing of 0.27 nm matches well with that of (101) planes of Co0.85Se, which can be further confirmed by the XRD analysis. As shown in Figure 1b, characteristic diffraction peaks at 33.3°, 44.8, 50.6, 60.4, and 61.8° that can be clearly assigned to the (101), (102), (110), (103), and (112) planes of hexagonal phase Co0.85Se (JCPDS No. 52−1008). Energy-dispersive X-ray (EDX) elemental mapping images of the as-prepared PAACo0.85Se NPs have been shown in Figure 1c, d, exhibiting a uniform distribution of Co and Se elements with a Co/Se stoichiometry of 0.80:1, which was close to the stoichiometric proportion of Co0.85Se crystals. Therefore, the above analysis suggests that the PAA-Co0.85Se NPs have been prepared successfully through this facile ambient aqueous solution approach. Moreover, XPS characterization was also used here to examine the chemical bonding states of each element on their subsurface of cobalt selenide NPs (Figure 1e, 1f and Figure S2). A Co/Se stoichiometry of around 0.82:1 indicated the successful formation of quasi-stoichiometric Co0.85Se crystals. As shown in Figure 1d, characteristic binding energies of 780.8, 779.0, 797.2, and 793.4 eV can be clearly assigned to Co2+ 2p3/2, Co3+ 2p3/2, Co2+ 2p1/2, and Co3+ 2p3/2, respectively, suggesting the coexistence of two types of cobalt oxidation state (Co2+ and Co3+). In the Co 3p and Se 3d spectra, the distinctive peaks at 59.6 and 54.5 eV are assigned to Co 3p and

Se 3d, respectively (Figure 1f). Meanwhile, PAA molecules on the surface of Co0.85Se NPs guaranteed the stability of asprepared Co0.85Se NPs and generation of C 1s and O 1s peaks during XPS measurements (Figure S2). Thus, based on the results of XPS characterization, the as-prepared NPs had a composition of Co2+, Co3+, and Se2−, which was in good agreement with the Co0.85Se phase confirmed by the XRD and EDX results. Considerable absorption in the NIR region and good stability are two basal preconditions for the use of PAA-Co0.85Se NPs in photothermal treatment of cancerous cells. As shown in Figure 2a, b and Figure S3, the as-prepared PAA-Co0.85Se NPs possess considerable NIR light absorption, and the absorbance decreased with the increase in wavelength number without no featured absorption peak. The obtained PAA-Co0.85Se NPs show good dispersity both in DI water and DMEM cell culture medium, which is further confirmed by the linearly increased relation between absorbance at 808 nm and NPs concentrations (Figure. S4). In addition, the mass extinction coefficient of Co0.85Se was determined to be 13.65 L g−1 cm−1 based on the Lambert−Beer law, which is comparable to that of Bi2Se3 nanosheets (11.5 L g−1 cm−1)42 and black phosphorus quantum dots (14.8 L g−1 cm−1)43 (Table S1). The long-term stabilities of PAA-Co0.85Se NPs in various solutions including DI water, PBS, saline, DMEM containing 10% fetal bovine serum and pure serum were also investigated. No significant change in hydrodynamic diameter and macroscopic aggregates was observed after 8 days (Figure 2c, d), indicating excellent long-term stability due to the PAA hydrophilic stabilizers on the surface of PAA-Co0.85Se NPs. Moreover, the experiment of going through filter membranes of nanoparticles suggested that PAA-Co0.85Se NPs might have good peneD


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Figure 3. Temperature elevation of PAA-Co0.85Se NPs (3.0 mL) dispersions with (a) different concentrations irradiated by a 808 nm NIR laser (2.0 W) and b) different NIR power density (solution concentration: 300 μM); (c) temperature increase of 3 mL of PAA-Co0.85Se NPs (300 μM) and (d) UV−vis−NIR spectra over five LASER ON/OFF cycles of NIR laser irradiation; (e) photothermal profile of PAA-Co0.85Se NPs aqueous solution (3.0 mL, 300 μM) irradiated by NIR laser for 1500 s, followed by natural cooling to room temperature; (f) time constant is determined to be τs = 704.7 s.

method,44 the photothermal transforming efficiency of PAACo0.85Se NPs was quantitatively calculated to be 45.2% (Figure 3e, f), which is higher than the majority of common photothermal agents (Table S2). Thus, the obtained data suggested that PAA-Co0.85Se NPs developed here could act as a novel efficient and stable photothermal transforming agent for potential cancer therapy. To tackle the therapeutic limitation of monotherapy for cancer treatment, the possibility of PAA-Co0.85Se NPs to be nanocarrier based DDSs was also evaluated by using DOX·HCl as model chemotherapeutic drug. Because of the electrostatic attraction between DOX and PAA molecules, PAA-Co0.85SeDOX NPs could be successfully obtained by thoroughly mixing DOX·HCl and PAA-Co0.85Se NPs overnight followed a purification process. As shown in Figure 4a, PAA-Co0.85SeDOX NPs possess characteristic absorption of both PAACo0.85Se NPs and free DOX without showing any macroscopic aggregates, implying the successful loading of DOX which was further confirmed by the significant fluorescent quenching of

trability because of the ultrasmall size, which may be favorable for tumor treatment (Figure S5). To test the photothermal transforming ability of as-prepared PAA-Co0.85Se NPs, we exposed 3.0 mL of aqueous solution of PAA-Co0.85Se NPs with various concentrations to a NIR laser (808 nm) for 10 min. As shown in Figure 3a, b, the magnitude of solution temperature elevation exhibited both solution concentration and laser intensity dependent manners (Figure S6). Specifically, the temperature of an aqueous solution PAACo0.85Se NPs (300 μM, 3.0 mL) would elevated from 20.1 to 50.3 °C with 10 min NIR laser irradiation (808 nm, 2.0 W), whereas the temperatureof DI water increased by only 2.2 °C. Moreover, five LASER ON/OFF cycles were used to assess the photothermal stability of PAA-Co0.85Se NPs (Figure 3c, d). Neither significant decrease in the elevated magnitude of solution temperature nor observable change of UV−vis-NIR spectra was found before and after five irradiation cycles, indicating the good photothermal stability of as-prepared PAACo0.85Se NPs. In addition, according to previously reported E


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Figure 4. (a) UV−vis−NIR spectra of free DOX, PAA-Co0.85Se NPs and PAA-Co0.85Se-DOX NPs (inset: photographs of solutions); (b) fluorescent spectra of free DOX and PAA-Co0.85Se-DOX NPs solution; (c) Hydrodynamic size of PAA-Co0.85Se NPs and PAA-Co0.85Se-DOX NPs, (d) in vitro DOX release profiles.

hydronamic size was observed for DOX-loaded PAA-Co0.85SeDOX NPs, confirming the good potential of PAA-Co0.85SeDOX NPs as DDSs without inducing any blocking in blood vessels. A typical in vitro drug release experiment was conducted to test the potential stimuli-responsive drug release profile of asprepared PAA-Co0.85Se-DOX NPs. The influence of solution pH and NIR laser irradiation was both investigated by submerging the PAA-Co0.85Se-DOX NPs solution in PBS (pH 7.4 or 5.0) with/without 10 min NIR laser irradiation (808 nm, 2.0 W). Comparing with the release profile of free DOX (released 100% over 10 h), the cumulative released amount of DOX from PAA-Ni0.85Se-DOX NPs over 10 h was 19.0% or 38.8% at pH 7.4 or 5.0, respectively, indicating the good delaying drug release effect of PAA-Ni0.85Se-DOX NPs (Figure 4d). The acidic pH promoted DOX release property may be caused by protonation of amino groups in DOX and carboxyl groups in PAA molecules under an acidic environment, which would weaken the electrostatic attraction between DOX and PAA-Co0.85Se NPs because that the pKa of DOX and PAA were 8.6 and 4.8, respectively.45 This acidic pH promoted DOX release property was similar to that of other reported PAAmodified nanocarriers for DOX delivery,46−50 which was favorable for tumor-site preferred drug delivery due to the acidic microenvironment.51−53 However, either release speed or cumulative releasedamount of DOX was slightly changed with NIR laser irradiation at both pH 7.4 and 5.0 release medium, ascribed to no photo/thermo responsive components in asprepared PAA-Co0.85Se-DOX NPs. Therefore, any potential synergistic cell-killing effect of combined photothermal-chemo treatment is maybe resulted from heat-promoted DOX cellular uptake rather than heat-enhanced DOX release.

DOX molecules (Figure 4b). To eliminate the influence of the particle scattering effect, the absorbance of PAA-Co0.85Se-DOX NPs using PAA-Co0.85Se as the background was shown in Figure S7a, which was similar to the absorbance of free DOX. To investigate the mechanism of fluorescence quenching, the fluorescent spectra of free DOX, PAA-Co0.85Se NPs mixed with DOX (freshly prepared), PAA-Co0.85Se-DOX NPs and PAACo0.85Se NPs solutions were measured (equivalent DOX concentration for these three solutions). As shown in Figure S7b, the fluorescence of PAA-Co0.85Se NPs mixed with DOX was significantly lower than that of free DOX. Because the PAA-Co0.85Se NPs mixed with DOX was freshly prepared, there should be lots of free DOX in the solution of PAA-Co0.85Se NPs mixed with DOX. Hence, the fluorescence quenching should be mainly attributed to the strong absorbance of PAACo0.85Se NPs. In addition, it was found that the fluorescence intensity of PAA-Co0.85Se NPs mixed with DOX (freshly prepared) was a little higher than that of PAA-Co0.85Se-DOX NPs (equivalent DOX concentration), and this should be attributed to the effect of high local concentration. Hence, both strong absorbance of PAA-Co0.85Se NPs and high local concentration of DOX should be responsible for fluorescence quenching for DOX loading on PAA-Co0.85Se NPs. In addition, the loading capacity and efficiency of DOX in PAA-Co0.85SeDOX NPs exhibited a DOX concentration dependent manner (Table S3). Particularly, around 91.0% of DOX was successfully loaded with a DOX loading capacity of 8.3% when the feeding ratio of free DOX vs PAA-Co0.85Se NPs to be 1:10. To balance the increased loading capacity and decreased loading efficiency with incremental feeding DOX, we selected PAA-Co0.85SeDOX NPs with a feeding weight ratio of 1:10 for DOX to PAANi0.85Se NPs for further investigations. In comparison to ultrasmall PAA-Co0.85Se NPs, no distinctive increase in F


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Figure 5. (a) Localized photothermal killing of HeLa cells: (b) cell viability of HUVECs exposed to various concentrations of PAA-Co0.85Se NPs for 24 h. Cell viability of HeLa cells after treatment with PAA-Co0.85Se-DOX NPs and laser irradiation for various periods: (c) 0, (d) 3, and (e) 5 min. PAA-Co0.85Se NPs and free DOX were used as controls.

treatment of NIR laser irradiation, PAA-Co0.85Se NPs or free DOX, depicting no apparent cell death. In sharp comparison, red fluorescence emerged when cells were simultaneously treated with both PAA-Co0.85Se NPs and NIR laser irradiation, indicating severe cell death due to the strong photothermal effect of PAA-Co0.85Se NPs upon NIR laser irradiation. In addition, it was found that the region of dead cells expanded with the increase of irradiation time and concentration of PAACo0.85Se NPs, which should be ascribed to the heat diffusion from illumination region to surrounding region. Hence, it is feasible to adjust the NPs concentration and irradiation time to obtain the most appropriate cancer treatment. Next, a MTT assay was further conducted to confirm the synergistic cancer cell-killing effect. As shown in Figure 5c, without laser irradiation or DOX, the cell viability of HeLa cells was around 85% even after incubation with PAA-Co0.85Se NPs

Nanomaterials for biomedical applications should possess good biocompatibility. To assess the cytotoxicity of PAACo0.85Se NPs, we conducted a standard MTT assay using HUVECs as model cells. As shown in Figure 5b, the cell viability of HUVECs was still higher than 80% after 24 h incubation with PAA-Co0.85Se NPs at gradient concentrations ranging from 0 to 2.5 mM, suggesting the minimal cytotoxicity of as-prepared PAA-Co0.85Se NPs. Encouraged by the low cytotoxicity, localized tumor photohyperthermic effect of PAACo0.85Se NPs was further evaluated. HeLa cancer cells as model cells were incubated with PAA-Co0.85Se NPs or free DOX, followed by NIR laser irradiation (808 nm, 2.0 W) for 0, 3, or 5 min, respectively. After various treatments, calcein-AM and propidium iodide (PI) were applied to visualize live and dead HeLa cells, respectively. As illustrated in Figure 5a, vivid green fluorescence was observed when HeLa cells suffered from single G


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Figure 6. (a) Fluorescence images of HeLa cells treated with DOX and PAA-Co0.85Se-DOX NPs (0.5 mM) under laser irradiation; (b) the corresponding quantitative fluorescence intenstiy estimated through ImageJ software.

Figure 7. FACS analysis of DOX uptake by HeLa cells treated with (a) free DOX, (b) 0.25 mM and (c) 0.5 mM PAA-Co0.85Se-DOX NPs under laser irradiation (808 nm, 1.0 W); (d) quantitative assessment of intracellular DOX after various treatments.

at a concentration as high as 330 μM, further confirming the good biocompatibility of PAA-Co0.85Se NPs. In contrast, obvious cell death happened after laser irradiation or DOX treatment and the cell viability decreased significantly with the increase of irradiation time and DOX dose (Figure 5d, e). Besides, a synergistic effect of combined PTT and chemotherapy for killing HeLa cells was observed. Particularly, as shown in Figure 6e, the cell viabilities of HeLa cells incubated with PAA-Co0.85Se NPs and free DOX (0.2 μg mL−1) for 24 h plus laser irradiation for 5 min were 92.8 and 82.7%, respectively. However, the cell viability was only 43.4% when

PAA-Co0.85Se-DOX NPs (equivalent DOX concentration of 0.2 μg mL−1) rather than PAA-Co0.85Se NPs were used for cell incubation. In other words, the cell mortality of HeLa cells for PAA-Co0.85Se-DOX was as high as 56.6%, which was obviously higher than the sum of 7.2% for PAA-Co0.85Se and 17.3% for free DOX, strongly proving the synergistic effect of combined PTT-chemo treatment of cancer cells in PAA-Co0.85Se-DOX NPs under NIR laser irradiation. Confirmed by the results of in vitro DOX release profiles, laser irradiation would not promote the release speed and amount of DOX, suggesting the possible mechanism of H



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synergistic cell killing effect may be ascribed to the heatpromoted cellular uptake of DOX. To demonstrate this hypothesis, HeLa cells were incubated with free DOX, 0.25 mM NPs and 0.5 mM NPs (equivalent DOX concentration), and then irradiated for 0, 3, and 5 min. As shown in Figure 6 and Figure S8, fluorescence micrographs of HeLa cells were taken to directly observe the heat-enhanced cellular uptake. Cell nuclei can be visualized by DAPI staining and DOX can be accumulated in the nuclear region because of its ability of intercalating DNA. It was found that fluorescence intensity increased with the increase in irradiation time and NPs concentration. Particularly, fluorescence intensity of HeLa cells treated with 0.5 mM NPs for 5 min is significantly higher than that of HeLa cells treated with free DOX, which should be attributed to that heat produced by the photothermal effect of NPs under laser irradiation can enhance the cellular uptake of DOX, further resulting in the improvement of fluorescence intensity. Hence, these fluorescence images can directly prove the existence of heat-enhanced cellular uptake of DOX. To further confirm the mechanism of heat-promoted cellular uptake of DOX, we further carried out FACS analysis to assess cellular uptake behavior of DOX molecules after different treatments. As illustrated in Figure 7, almost no difference of DOX accumulation was observed for HeLa cells incubated with either free DOX (equivalent concentration of 0.25 mM PAACo0.85Se-DOX NPs) or PAA-Co0.85Se-DOX NPs (0.25 mM and 0.5 mM) for only 10 min without NIR laser irradiation. In contrast, after HeLa cells were treated with both PAA-Co0.85SeDOX NPs and NIR laser irradiation (808 nm, 1.0 W), the amount of accumulated DOX in HeLa cells from PAACo0.85Se-DOX NPs was found to be significantly enhanced and increased with incremental concentration of NPs and radiation dose of NIR laser illumination. Specifically, the amount of intracellular DOX from HeLa cells treated with 0.5 mM PAACo0.85Se-DOX NPs and 5 min of NIR laser illumination was about 2.7 times higher than that of HeLa cells treated with free DOX. Therefore, these data verified the hypothesis that heat induced by the photothermal effect of PAA-Co0.85Se-DOX NPs upon NIR laser irradiation would promote the cellular uptake of DOX because of increased cellular metabolism and cell membrane permeability, resulting in a remarkable synergistic cell-killing effect.

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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/acsbiomaterials.7b00878. Stability of as-prepared PAA-Co0.85Se NPs; XPS spectra of the as-prepared PAA-Co0.85Se NPs; UV−vis−NIR (200−1250 nm) spectra of PAA-Co0.85Se NPs; absorbance of PAA-Co0.85Se NPs at 808 nm vs concentration of NPs; plot of temperature change (ΔT) and DOX loading capacity (LC) and loading efficiency (LE); experiment of going through filter membranes; the absorbance spectrum of PAA-Co0.85Se-DOX NPs using PAA-Co0.85Se as the background; fluorescent spectra of free DOX, PAA-Co0.85Se NPs mixed with DOX, PAACo0.85Se-DOX NPs, and PAA-Co0.85Se NPs solutions; fluorescence images of HeLa cells treated with DOX and PAA-Co0.85Se-DOX NPs; and the comparison of mass extinction coefficient and photothermal transforming efficiency of photothermal agents (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel: +86 551 62901285. *E-mail: [email protected]. ORCID

Zhengbao Zha: 0000-0003-3646-4969 Author Contributions †

Y.M. and X.W. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (31500808, 81501590), the Anhui Provincial Natural Science Foundation (1608085MH188).

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REFERENCES

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4. CONCLUSIONS In summary, PAA-Co0.85Se NPs with a relatively small size were successfully developed as a novel nanocarrier base DDSs for combined photothermal-chemo cancer treatment through a facile aqueous solution approach at room temperature. The obtained PAA-Co0.85Se NPs occupied not only considerable absorption in the NIR region, but also remarkable photothermal transforming efficiency as high as 45.2%, implying high potential for localized tumor ablation. Moreover, after loading chemotherapeutic drug, DOX·HCl, onto the surface of PAACo0.85Se NPs through electrostatic attraction between DOX and PAA molecules, the formed PAA-Co0.85Se-DOX NPs exhibited an acidic pH promoted drug release profile due to the protonation of amino groups in DOX and carboxyl groups in PAA molecules. Upon NIR laser irradiation, heat-enhanced cellular uptake of DOX molecules would result in a obvious synergistic cell-killing effect for PAA-Co0.85Se-DOX NPs, highlighting the great potential of as-prepared PAA-Co0.85Se NPs to serve as a novel nanocarrier-based DDSs for efficient cancer treatment. I


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Polyacrylic Acid Functionalized Co0.85Se Nanoparticles: An

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