Nanoparticles for Supersensitive Drug Release - ACS Publications

Research Article Cite This: ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Near-Infrared-Light-Induced Morphology Transition of Poly(ether amine) Nanoparticles for Supersensitive Drug Release Haozhe He,†,‡ Junli Zhou,‡,§ Yingjie Liu,‡,§ Shi Liu,‡ Zhigang Xie,*,‡ Meng Yu,† Yong Wang,† and Xintao Shuai*,† †

PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China ‡ State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China § University of Chinese Academy of Sciences, Beijing 100049, P. R. China S Supporting Information *

ABSTRACT: Near-infrared (NIR)-light-controlled drug release has aroused great interest because of its advantages in spatiotemporal control. Herein, a photothermally induced morphology transition of the nanoparticles (NPs) for supersensitive drug release has been demonstrated. Doxorubicin (DOX)- and cyanine (Cy)-coloaded thermosensitive poly(ether amine) NPs (DOX&Cy@PEA81) were developed. Because of the photothermal activity of Cy upon irradiation, increase in temperature at the tumor site results, which would be used not only for photothermal therapy but also to spur the release of DOX from the NPs for tunable chemotherapy. The NIR-laser-driven DOX release was validated by a series of intracellular and in vivo experiments on animals. Meanwhile, the chemo-photothermal combinatorial therapy results in optimal cytotoxicity and tumor inhibition. This article provides a promising approach to realizing supersensitive drug release and synergistic chemo-photothermal therapy for cancer. KEYWORDS: poly(ether amine), morphology transition, NIR-controlled release, drug delivery, chemo-photothermal therapy temperature was above its phase-transition temperature.20 If polymeric nanomaterials are thermosensitive and their architectures could be changed when the temperature rises above their phase-transition temperature, they could be used for thermally controlled drug release. Near-infrared (NIR) laser possess an excellent tissue penetration depth and is less attenuated in biological tissues for in vivo application.1,2,21−27 Recently, NIR-laser-induced photothermal therapy (PTT) has shown a great potential for solid tumor ablation using various photosensitizers, such as fluorescent dyes19,22,28 and gold nanomaterials.29−32 Cyanine (Cy) is a type of NIR photosensitizer with high extinction coefficients and narrow absorption bands,33,34 which could produce hyperthermia upon laser irradiation for PTT. However, tumor cells could not be killed completely because of the heterogeneous distribution of heat over tumors, which leads to tumor recurrence. Thus, to improve the efficacy of the treatment, it is imperative to develop a combinational treatment including PTT with other treatments, especially with chemotherapy drugs. In this work, doxorubicin (DOX) and carboxyl-containing cyanine (Cy) were loaded into thermosensitive poly(ether amine) NPs (DOX&Cy@PEA81). This nanoparticle formula-

1. INTRODUCTION Recently, smart drug delivery systems (DDSs) that respond to various stimulations (light,1−3 temperature,4,5 magnetic field,6,7 ultrasound,8,9 pH,10,11 reduction and oxidation,12,13 and enzymes14) have shown a great potential in cancer therapy. These smart DDSs make full use of the nanocarriers for achieving the controlled release of drugs on the tumor site with reduced systemic toxicity.15−17 Relatively thermosensitive polymeric nanocarriers exhibit particular advantage for releasing drugs by the change of temperature.1,11,18,19 The mechanisms of drug release from polymeric carriers can be divided into two categories. One is diffusion-controlled mechanism, in which an increase in temperature speeds up the diffusion of a drug from the nanoparticles (NPs). Recently, Wang and co-workers reported polymeric NPs possessing flowing cores and an accelerated drug release was achieved after local heating upon near-infrared (NIR) irradiation.1,11 No significant structural changes occurred in the case of diffusion-controlled drug release as the temperature increased. The other one is the degradation-controlled mechanism, that is a quick release of payloads based on the degradation or disintegration of the NPs. For instance, Zhu et al. demonstrated a controlled drug release through the melting of the NPs caused by the increased temperature.3 Yan et al. observed a quick release of doxorubicin (DOX) from DOX/IR780-loaded thermosensitive liposomes upon irradiation because the lipid bilayer of liposomes was destructed when the © XXXX American Chemical Society

Received: January 4, 2018 Accepted: February 6, 2018 Published: February 6, 2018 A

DOI: 10.1021/acsami.8b00194 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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ACS Applied Materials & Interfaces

blocks. The ideal LCST for hyperthermia cancer therapy should be around 45 °C, which is a little higher than the body temperature.35 PEA81 and PEA11 possess LCSTs of 43.2 and 60.8 °C, respectively. Temperature-dependent changes in the transmittance of PEA81 and PEA11 at pH 7.4 are shown in Figure S4. The LCST between PEA81 and PEA11 varied from 43.2 to 60.8 °C because of the different poly(ethylene oxide) (PEO) contents in PEAs. 1 H NMR spectra were used to understand the phase transitions of PEA81 and PEA11 in aqueous solution at different temperatures. The main differences in 1H NMR spectra at different temperatures were reflected at a and a′, as shown in Figures 1a and S5, for PEA81 and PEA11, respectively (i.e., the difference in the proton resonance intensity of methyl in poly(propylene oxide) (PPO) chains). When the temperature was lower than the LCST, the intensity of the peaks at a was almost invariable (for PEA81, the temperatures were 25, 37, and 45 °C, and for PEA11, the temperatures were 25, 37, 45, 50, and 60 °C). However, when the temperature was above the LCST, the intensity of the peaks was significantly increased (for PEA81, the temperatures were 50, 60, and 70 °C, and for PEA11, the temperature was 70 °C). Both PEA81 and PEA11 are amphiphilic polymers and can disperse in aqueous media. Assumably, when the temperature was above the LCST, the hydrated shell layer of PEO chains would shrink and a part of the hydrophobic PPO chains would be exposed. In an extreme case, even a collapse of the micelle structure may be induced to make the NPs dissolve in aqueous solution at a single molecular chain level. As a result, the −CH3 protons in the hydrophobic core became stronger at the temperature above its LCST. The 1H NMR results supported the proposed transition process. 2.3. Preparation and Characterization of DOX-/CyLoaded PEA Nanoparticles. Thermoresponsive PEA81 was used to encapsulate DOX and Cy to form DOX&Cy@PEA81 through the coprecipitation method. DOX@PEA81, Cy@ PEA81, and DOX&Cy@PEA11 were prepared as controls. The morphologies of the as-prepared NPs were observed by transmission electron microscopy (TEM). As depicted in Figure S6, DOX&Cy@PEA81 and DOX&Cy@PEA11 NPs possessed diameters of 50 and 60 nm, respectively. Previous reports had demonstrated that small-sized NPs are more likely to be engulfed by tumor cells and can pass through deeper tumors.36 The drugloading contents (DLCs) and drug-loading efficiencies (DLEs) are given in Table 1. The DOX content in the nanoparticles is 4 wt %. For DOX@PEA81, DOX&Cy@PEA11, and DOX&Cy@ PEA81, the DLE of DOX is more than 80%. The DLC of Cy is 8 wt % for DOX&Cy@PEA11 and DOX&Cy@PEA81. The absorption and fluorescence spectra are illustrated in Figure 1c,d. DOX- and Cy-containing NPs all possess the typical absorption peaks at 480 and 787 nm, which are similar to those for free DOX and Cy. Compared with free Cy, Cy-containing NPs show a red shift from 816 to 825 nm. These data suggested that both DOX and Cy were encapsulated into NPs. The photostability was monitored by the attenuation of fluorescence intensity (Figure 1e). The fluorescence intensity of Cycontaining NPs (Cy@PEA81, DOX&Cy@PEA11, and DOX&Cy@PEA81) remained nearly 92% of the original value after 24 h; in contrast, the value of free Cy decreased to 70%. Free Cy possessed only 20% of the original fluorescence after 5 days, and Cy-containing NPs could keep more than 75% of the fluorescence. The size stability was evaluated by dynamic light scattering in phosphate-buffered saline (PBS) (pH 7.4) containing 10% fetal bovine serum at 37 °C (Figure 1f). All of

tion combines real-time tracking, controlled drug release, and chemo-photothermal therapy (Scheme 1). Herein, DOX is for Scheme 1. Schematic Representation of the NIR-Activated Drug Release from Polymeric Nanocarriers for ChemoPhotothermal Therapy.

chemotherapy, Cy is an NIR photosensitizer that causes hyperthermia and regulates the release of DOX, and PEA81 is a thermoresponsive nanocarrier that can cause structural changes at high temperatures (the phase-inversion temperature is 43.2 °C). We demonstrated that NIR irradiation of the NPs will lead to a rapid DOX release because of the increasing temperature.

2. RESULTS AND DISCUSSION 2.1. Synthesis and Characterization. In our previous work, we reported a temperature-responsive poly(ether amine) (PEA819) for fluorescence imaging.24 Herein, we re-built PEA81 and PEA11 according to our reported procedure,24 except that the reaction time and temperature were modified. Detailed synthetic methods are provided in the Supporting Information, and the schematic illustration for the synthesis is shown in Figure S1. The molecular weights (Mn) and the molecular weight distributions (Mw/Mn) of the prepared PEAs were determined by gel permeation chromatography. Mn and Mw/Mn for PEA81 were 2.07 × 104 and 1.72, respectively, whereas the values for PEA11 were 1.68 × 104 and 1.54. Cy was prepared on the basis of previous reports.33 All of the molecular structures were confirmed via 1H NMR spectra, which are shown in Figures S2 and S3. 2.2. Thermoresponsive Behaviors. PEA contains a large number of ether bonds that form hydrogen bonds easily. With the temperature increasing to a certain point, the hydrogen bonds are destroyed, and this temperature is called the lower critical solution temperature (LCST). The water solubility of PEA is greatly affected by the ratio of hydrophilic to hydrophobic B


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Figure 1. (a) 1H NMR spectra of PEA81 in D2O at different temperatures. (b) Transmission electron microscopy (TEM) images of DOX&Cy@PEA81 after NIR laser irradiation (808 nm, 2 W/cm2, 5 min) and cooling to room temperature. (c) Absorption spectra of free DOX, free Cy, DOX@PEA81, Cy@PEA81, DOX&Cy@PEA11, and DOX&Cy@PEA81. (d) Fluorescence spectra of free Cy, Cy@PEA81, DOX&Cy@PEA11, and DOX&Cy@ PEA81. (e) Fluorescence stability of free Cy, Cy@PEA81, DOX&Cy@PEA11, and DOX&Cy@PEA81. (f) Size stability test of DOX@PEA81, Cy@ PEA81, DOX&Cy@PEA11, and DOX&Cy@PEA81.

power increased from 0.5 to 2.5 W/cm2. The solution temperatures of free Cy, Cy@PEA81, DOX&Cy@PEA11, and DOX&Cy@PEA81 maximally reached to 46.3, 46.1, 45.5, and 45.6 °C, respectively. However, PBS, the mixed solution of dimethylformamide and H2O, and DOX@PEA81 aqueous solution exhibited nearly no increase in temperature after

these NPs retained the original size for 7 days, implying good stability under physiological conditions. 2.4. Photothermal Effect and Drug Release. The photothermal efficiencies of Cy-loaded NPs were investigated according to the temperature changes upon laser irradiation. As shown in Figure S7, the temperatures increased when the laser C


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PEA81 in 4 min at pH 5.0. An NIR-laser-induced drug release was detected when the same NIR irradiation was repeated every 1 h, and increases in DOX release from 35.1 to 45.6% and from 50.4 to 59.7% were observed during the second and third cycles, respectively. The DOX release almost completely stopped when the NIR laser was switched off. In contrast, after three laser on/ off input cycles, only 13.2% of DOX was released from DOX&Cy@PEA11. This laser-controlled DOX release is different from that from the traditional stimuli-responsive nanocarriers.1,20 To evaluate the effect of irradiation on particles’ morphology and reveal the mechanism of supersensitive drug release, the TEM images of drug-loaded NPs upon irradiation and cooling to room temperature are shown in Figures 1b and S6. The size of DOX&Cy@PEA81 at room temperature was about 50 nm, and the nanoparticles almost disappeared upon irradiation and then reappeared after cooling to room temperature. The results demonstrated that the NPs were disintegrated and became smaller upon irradiation. However, for DOX&Cy@PEA11, no obvious morphology transition occurred and the release of DOX did not happen upon irradiation. Thus, the supersensitive drug release was caused not only by the diffusion of drug molecules but also by the morphological transition of the NPs. 2.5. In Vitro Cellular Uptake and Intracellular DOX Release. Human hepatocellular carcinoma (HepG2) cells were cultured with DOX@PEA81, DOX&Cy@PEA11, and DOX&Cy@PEA81 to study the internalization and photothermal effect by a confocal laser scanning microscope (CLSM). After 4 h, the cell nuclei were stained with Hoechst for observation by blue channel (λex = 405 nm), red channel for DOX-containing NPs (λex = 488 nm), and green channel for Cycontaining NPs (λex = 633 nm). As shown in Figure 3a, the red fluorescence was located mainly in cell nuclei after incubation with DOX. For DOX-/Cy-loaded NPs, both the red fluorescence and green fluorescence were observed mainly in the cytoplasm. For DOX&Cy@PEA11, no apparent difference was seen for the DOX&Cy@PEA11 group and the DOX&Cy@PEA11 and laser group. Notably, the red and green fluorescence were significantly enhanced in the cell nuclei and cytoplasm after the exposure of the DOX&Cy@PEA81 group to the NIR laser. These results could be ascribed to the laser-introduced heat, which enhanced the fluidity and permeability of the cells.18,24,37 Taking into account all of these factors, it can be stated that hyperthermia significantly improved the uptake of DOX and Cy in HepG2 cells. To avoid the overlapping of fluorescence signals between DOX and the probe of LysoTracker Red, Cy@PEA81 was used for fluorescence colocalization analyses instead of DOX&Cy@ PEA81. As shown in Figure S9, the red fluorescence (LysoTracker Red) and the green fluorescence (Cy@PEA81) overlapped to produce an orange fluorescence, indicating the receptor-mediated endocytosis of Cy@PEA81 NPs. 2.6. Cytotoxicity. The viability of HepG2 cells determined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, shown in Figure S10, validated the good cytocompatibility of PEA11 and PEA81 NPs. The cells incubated with DOX@PEA81 NPs, shown in Figure S11, showed high viability even at a concentration of 50 μg/mL of DOX, indicating that chemotherapy alone will not cause harm to the cells. In Figure 3b, Cy@PEA81 NPs exhibited a dose-dependent cytotoxicity upon irradiation by a 2 W/cm2 power NIR laser. The cells incubated with DOX&Cy@PEA11 and DOX&Cy@ PEA81 NPs also did not exhibit a significant cytotoxicity in the

Table 1. DLCs and DLEs of DOX/Cy in DOX@PEA81, Cy@ PEA81, DOX&Cy@PEA11, and DOX&Cy@PEA81a DLC DOX (%) DOX@PEA81 Cy@PEA81 DOX&Cy@ PEA11 DOX&Cy@ PEA81 a

DLE Cy (%)

4.03 ± 0.28

DOX (%)

Cy (%)

80.6 ± 4.4

4.41 ± 0.35

24.6 ± 1.12 8.82 ± 0.96

88.2 ± 4.7

61.5 ± 3.2 22.1 ± 1.1

3.88 ± 0.32

8.29 ± 0.87

77.6 ± 3.9

20.7 ± 0.9

The data are shown as mean ± standard deviation (SD, n = 3).

irradiation. The temperature of the aqueous solution of DOX&Cy@PEA81 NPs increased from 25.1 to 45.9 °C at the Cy concentration of 41.5 μg/mL, whereas the aqueous solution of PEA81 exhibited nearly no increase in temperature under the same conditions. The results showed that Cy produces a significant temperature elevation upon irradiation.20 Furthermore, for DOX&Cy@PEA81, the temperature is above its LCST (>43.2 °C) and could result in a sensitive DOX release from DOX&Cy@PEA81 (Scheme 1). To evaluate the temperature- and pH-sensitive behaviors, DOX-containing NPs were treated in a thermostatic vibrator in a buffer with pH 7.4 or 5.0. As illustrated in Figure S8, both DOX@ PEA81 and DOX&Cy@PEA81 displayed an obvious heatdependent drug release. In contrast, DOX&Cy@PEA11 did not show the temperature-dependent DOX release property either at 45 or 37 °C. For example, DOX@PEA81 and DOX&Cy@ PEA81 released up to 30.5 and 33.7% of DOX in the first 4 h at 45 °C at pH 7.4, respectively, whereas 37 °C treatment hardly caused the release of DOX. There is no significant difference for DOX&Cy@PEA11 at 45 and 37 °C. These results indicate that PEA81 is sensitive to temperature and pH. Although both PEA81 and PEA11 are temperature-sensitive and pH-sensitive nanoparticles, a suitable LCST of PEA81 ensures a thermoresponsive drug release behavior. Next, the sensitivity of irradiation-induced DOX release was further demonstrated. DOX&Cy@PEA11 and DOX&Cy@ PEA81 were exposed to laser irradiation for 4 min (laser on) and then incubated for 56 min (Figure 2). The release of DOX from DOX&Cy@PEA81 exhibited a laser-dependent manner at pH of 7.4 or 5.0. In contrast, DOX&Cy@PEA11 did not exhibit an NIR-laser-controlled release. For example, during the first laser on/off cycle, 31.8% of DOX was released from DOX&Cy@

Figure 2. DOX release profiles of DOX&Cy@PEA11 and DOX&Cy@ PEA81 with three laser on/off cycles upon exposure to an 808 nm laser at a power density of 2 W/cm2 (laser on-time: 4 min). D


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Figure 3. (a) CLSM images of HepG2 cells incubated with free DOX, DOX@PEA81, DOX&Cy@PEA11, and DOX&Cy@PEA81 with or without NIR laser irradiation (808 nm, 2 W/cm2, 5 min) (scale bar, 20 μm). (b) Cell viability of HepG2 cells incubated with Cy@PEA81, DOX&Cy@PEA11, and DOX&Cy@PEA81 with or without NIR laser irradiation (808 nm, 2 W/cm2, 5 min). The data are shown as mean ± SD (n = 3). (c) Fluorescence microscopic images of live/dead staining in HepG2 cells after different treatments. The live cells were stained green with calcein-acetoxymethyl (AM), and the dead cells were stained red with propidium iodide (PI).

produce hyperthermia for PTT and release more DOX than that from DOX&Cy@PEA11. To demonstrate the efficiency of the combination therapy, we stained the cells with calcein-AM and propidium iodide (PI) after irradiation for 5 min. As shown in Figure 3c, chemotherapy alone caused limited cell deaths for the DOX@PEA81 group. Moreover, in the DOX&Cy@PEA11 and laser group, the number of dead cells was not much more than that in the onlyPTT group. This was due to the fact that although the release of

absence of laser irradiation. The cells incubated with DOX&Cy@PEA11 and irradiated by a laser showed a stronger cytotoxicity than that of those incubated with Cy@PEA81 NPs because DOX&Cy@PEA11 NPs upon laser irradiation would not only produce hyperthermia for PTT but also partly release DOX for chemotherapy. Notably, cells incubated with DOX&Cy@PEA81 and irradiated by laser induced the strongest cytotoxicity. DOX&Cy@PEA81 upon laser irradiation could also E


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Figure 4. In vivo NIR imaging and biodistribution analysis of mice bearing hepatocellular carcinoma (H22) tumors after tail intravenous injection of Cy@PEA81, DOX&Cy@PEA11, or DOX&Cy@PEA81. (a) Time-lapse NIR fluorescence images in mice. (b) NIR fluorescence intensities of the tumors were quantified at indicated time points. (c) Fluorescence images of the major organs and tumors after tail intravenous injection at 48 h. (d) Semiquantitative biodistribution of ex vivo histology determined by the averaged fluorescence intensity of the organs and tumors. The data are shown as mean ± SD (n = 3).

damage.22,42−44 The PBS-treated tumor showed a negligible increase in temperature. Subsequently, to compare the therapeutic efficacies, the tumor volumes and body weights of the mice were measured every 2 days. Figure 5b shows that the tumors treated with PBS grew rapidly. The tumor volume was still relatively large, revealing that almost no tumor growth was inhibited for free DOX. The tumor growth was slightly delayed when DOX@PEA81 was injected into the mice. Tumors in animals treated with Cy@PEA81 and laser irradiation showed a partial suppression because of PTT. It is not surprising to observe the best tumor inhibition for the DOX&Cy@PEA81 and laser irradiation group. The images of tumors further confirmed the efficacy of DOX&Cy@PEA81 upon irradiation (Figure S12). The weight of tumor is consistent with the tumor volume (Figure S13). In our study, the body weights of all of the mice increased to a certain extent and no significant differences were observed among the six groups (Figure S14). Finally, to study the damage in acute and chronic stages, the histological analyses were done by hematoxylin and eosin (H&E) staining of the main organs after the treatment with various formulations. As illustrated in Figures 5d and S15, no tissue necrosis was observed in the main organs (heart, liver, spleen, lung, and kidney) for the six groups, demonstrating that the formulations mentioned above have no obvious biological toxicity. However, the large area of the tumor tissue necrosis for the DOX&Cy@PEA81 and laser irradiation group confirmed that DOX&Cy@PEA81 could efficiently inhibit the proliferation of H22 in mice with the aid of laser irradiation. These results

DOX also occurred in this group the effect of chemotherapy was limited as hyperthermia could not result in a rapid release of DOX. However, for the DOX&Cy@PEA81 and laser group, most of the cells were dead because of hyperthermia and release of DOX. 2.7. In Vivo Imaging and Biodistribution. Nanoparticle formulations accumulated in the tumor tissue because of the enhanced permeability and retention effect.38−41 The biodistribution of DOX&Cy@PEA81 NPs was studied by an imaging system after tail intravenous injection. Figure 4a,b shows the fluorescence around the tumor. The fluorescence intensity in mice was relatively weak, except for the peritumor. Cy-containing NPs retained significantly strong fluorescence around the tumor even after 48 h. The strongest signals were obtained at 12 h postinjection, which was chosen as the time point to exert an NIR laser for PTT. The comparison of the biodistribution of the three NPs in the major organs and tumors at 48 h postinjection is shown in Figure 4c,d. Compared to the fluorescence signals in tumors and livers, those in other organs were relatively weak. 2.8. In Vivo Antitumor Efficiency. The antitumor efficiency was investigated in female Kunming mice bearing hepatocellular carcinoma (H22) tumors. First, we examined the NIR-laserinduced temperature changes at tumor sites in vivo upon 808 nm laser irradiation (1.0 W/cm2) at 12 h after tail intravenous injection with different formulations, and the temperature changes are shown in Figure 5a,c. The temperatures of the tumors injected with Cy@PEA81, DOX&Cy@PEA11, and DOX&Cy@PEA81 rapidly rose to 44.9, 44.3, and 44.6 °C, respectively, which resulted in an irreversible tumor tissue F


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Figure 5. (a) Temperature change curves of the irradiated area of nude mice bearing tumors injected with PBS, Cy@PEA81, DOX&Cy@PEA11, and DOX&Cy@PEA81 upon irradiation with an 808 nm laser at a power density of 1 W/cm2. (b) Tumor volume of mice as a function of time. (c) Infrared thermographic maps of mice after tail intravenous injection of PBS, Cy@PEA81, DOX&Cy@PEA11, or DOX&Cy@PEA81 upon irradiation with an 808 nm laser at a power density of 1 W/cm2. (d) Histological assessments of hematoxylin and eosin (H&E) staining in the main organs of mice after treatment with DOX&Cy@PEA81 and laser. Statistical significance: *p < 0.05 and ***p < 0.001.

d6 (Figure S3); temperature-dependent change in transmittance of PEA81 and PEA11 (Figure S4); 1H NMR spectra of PEA11 in D2O (Figure S5); TEM images of DOX&Cy@PEA81 and DOX&Cy@PEA11 (Figure S6); temperature changes of DOX&Cy@PEA81 NPs (Figure S7); in vitro release profiles of DOX (Figure S8); colocalization images of Cy@PEA81 and LysoTracker (Figure S9); cell viability of HepG2 cells incubated with PEA11 and PEA81 NPs (Figure S10); cell viability of HepG2 cells incubated with DOX@PEA81 NPs (Figure S11); photos of the excised tumors on day 20 (Figure S12); quantitative analysis of tumor weight on day 20 (Figure S13); body weight of the H22 cancer bearing mice (Figure S14); histologic assessments of H&E staining (Figure S15) (PDF)

proved that the DOX&Cy@PEA81 and laser irradiation group possessed a great therapeutic effect and no significant systemic toxicity.

3. CONCLUSIONS In this study, we synthesized DOX- and Cy-coloaded thermosensitive poly(ether amine) NPs. This strategy combines real-time tracking, controlled drug release, and chemo-photothermal therapy. An increase in the temperature at the tumor site could be induced upon irradiation because of the photothermal conversion of Cy. The partial hyperthermia produces tumor coagulative necrosis and also destroys the structure of polymeric carriers, which induce DOX release for an enhanced chemotherapy. This smart nanoparticle formulation enables NIR-lasercontrolled drug delivery at the desired location and greatly enhances the tumor inhibition. This work provides a promising approach to realizing the supersensitive drug release and synergistic chemo-photothermal combination therapy for tumor treatment.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel: +86-431-85262775. Fax: +86-43185262775 (Z.X.). *E-mail: [email protected]. Tel: +86-20-84110365. Fax: +86-20-84112245 (X.S.).

ASSOCIATED CONTENT

* Supporting Information S

ORCID

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.8b00194. Schematic illustration for the synthesis of PEA81 and PEA11 (Figure S1); 1H NMR of PEA81 and PEA11 in CDCl3 (Figure S2); 1H NMR of Cy in dimethyl sulfoxide-

Zhigang Xie: 0000-0003-2974-1825 Yong Wang: 0000-0002-8349-7555 Notes

The authors declare no competing financial interest. G


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ACKNOWLEDGMENTS This work was supported by the Natural Science Foundation of China (51522307 and U1401242).

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Nanoparticles for Supersensitive Drug Release - ACS Publications

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