light‐responsive biodegradable nanorattles for cancer...

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Light-Responsive Biodegradable Nanorattles for Cancer Theranostics

Chunxiao Li, Yifan Zhang, Zhiming Li,* Enci Mei, Jing Lin, Fan Li, Cunguo Chen, Xialing Qing, Liyue Hou, Lingling Xiong, Hui Hao, Yun Yang,* and Peng Huang*

C. Li, Prof. Z. Li, E. Mei, C. Chen, L. Hou, L. XiongDepartment of Dermatology and VenereologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, Zhejiang 325000, P. R. ChinaE-mail: [email protected]. Li, Dr. Y. Zhang, Prof. J. Lin, Dr. F. Li, X. Qing, Prof. P. HuangGuangdong Key Laboratory for Biomedical Measurements and Ultrasound ImagingLaboratory of Evolutionary TheranosticsSchool of Biomedical EngineeringHealth Science CenterShenzhen UniversityShenzhen 518060, P. R. ChinaE-mail: [email protected]. Hao, Prof. Y. YangNanomaterials and Chemistry Key LaboratoryWenzhou UniversityWenzhou, Zhejiang 325027, P. R. ChinaE-mail: [email protected]

The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adma.201706150.

DOI: 10.1002/adma.201706150

Multifunctional nanoplatforms integrating both diagnostics and accurate therapeu-tics have shown great potential in nano-biotechnology applications of cancer nanotheranostics.[1] Among different bio-medical imaging techniques, ultrasound (US) imaging is a clinically ubiquitous diagnostic technique with the advantages of real-time, noninvasive, low cost, and easy public accessibility.[2] Various thera-peutic agents-loaded microbubbles were extensively utilized as US contrast agents (UCAs) due to their high image quality to achieve more precise US imaging and therapy simultaneously.[3] Usually con-sisting of inert perfluorocarbon gas inside as contrast agents and polymers or pro-teins outside as stabilizing shells, these microbubbles can enhance the ultrasonic signal through resonance of gas in the sound field, benefiting from their deform-ability and compressibility.[4] Neverthe-less, these microbubbles will expand at body temperature and the gas will diffuse out from the incompact shell of micro-bubbles, resulting in a very short half-life

(<20 min).[5] Additionally, microbubble contrast agents usually have a diameter of 1–8 µm, and the large size hinders their penetration into the surrounding nonmicrovascular tissue from microvascular after intravenous injection.[6] Therefore, the improvement of stability and tumor penetration of UCAs remains a big challenge.

To overcome these issues above, nanoscale gas-generating platforms have received increasing attention.[7] Solid gas-gen-erating nanoparticles can circulate stably along with the blood-stream so that it can overcome the limitations as mentioned and may effectively accumulate in the tumor through enhanced permeation and retention (EPR) effect.[8] Furthermore, these nanoplatforms encapsulate stable gas precursors, such as NH4HCO3, CaCO3, liquid perfluoropentane (PFP), l-arginine and anethole dithiolethione (ADT), that could generate nano-bubbles, such as CO2, CO, PFP, NO, and H2S in vivo,[9] and the nanobubbles could coalesce into microbubbles, thus allowing for the persistence of the enhanced echogenic. Most intrigu-ingly, the nanobubbles were continuously generated as a result of responding to intratumoral environments or external stimuli, for example, tumoral acidic pH,[10] heating,[9b,11] enzyme,[12] light,[13] and ultrasound radiations.[14] For instance, Gu and

Cancer nanotheranostics, integrating both diagnostic and therapeutic func-tions into nanoscale agents, are advanced solutions for cancer management. Herein, a light-responsive biodegradable nanorattle-based perfluoropentane-(PFP)-filled mesoporous-silica-film-coated gold nanorod (GNR@SiO2-PFP) is strategically designed and prepared for enhanced ultrasound (US)/ photoacoustic (PA) dual-modality imaging guided photothermal therapy of melanoma. The as-prepared nanorattles are composed of a thin mesoporous silica film as the shell, which endows the nanoplatform with flexible mor-phology and excellent biodegradability, as well as large cavity for PFP filling. Upon 808 nm laser irradiation, the loaded PFP will undergo a liquid–gas phase transition due to the heat generation from GNRs, thus generating nanobubbles followed by the coalescence into microbubbles. The conversion of nanobubbles to microbubbles can improve the intratumoral permeation and retention in nonmicrovascular tissue, as well as enhance the tumor-targeted US imaging signals. This nanotheranostic platform exhibits excellent biocompatibility and biodegradability, distinct gas bubbling phenomenon, good US/PA imaging contrast, and remarkable photothermal efficiency. The results demonstrate that the GNR@SiO2-PFP nanorattles hold great potential for cancer nanotheranostics.

Theranostics

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co-workers designed ADT loaded magnetic nanoliposomes that could be triggered by enzyme and intratumorally convert to H2S microbubbles, playing magnetic resonance, US imaging, and synergetic antitumor effect.[9d] However, these bubble generators often own a size over 200 nm and are usually non-biodegradable that limits their further biomedical applications.

Herein, we constructed a PFP-loaded nanorattle with a thin mesoporous silica shell and a gold nanorod (GNR) core (GNR@SiO2-PFP) (Scheme 1). Compared to traditional micro-bubbles, the as-prepared nanorattles could stably exist in the bloodstream with long blood circulation half-life and effec-tively accumulate in tumor tissues via the EPR effect. Then, the encapsulated liquid PFP could transform into microbubbles when the tumor region was heated through the photothermal effect of GNR under near-infrared (NIR) irradiation to realize the enhanced US imaging of tumor tissues. Furthermore, the GNRs with tunable localized surface plasmon resonance (SPR) at ≈800 nm could be used for photoacoustic (PA) imaging and photothermal therapy (PTT). Most intriguingly, compared to traditional silica nanoparticles, the thin mesoporous silica shell endowed our nanorattles with large cavity, flexible morphology, and excellent biodegradability. The large cavity of GNR@SiO2 nanorattles significantly enhanced the PFP loading capacity. The as-prepared GNR@SiO2-PFP nanorattles could perform the enhanced US/PA dual-modality imaging guided PTT of mela-noma, which held great potential for cancer nanotheranostics.

To prepare GNR@SiO2, GNRs with an uniform size of about 52.24 ± 17.21 nm in longitudinal length and 16.81 ± 3.97 nm in transverse length were synthesized using the seed-mediated protocol.[15] The cetyltrimethylammonium bromide-capped GNRs were coated with ZnO and then with mesoporous silica, which eliminated their cytotoxicity and improved the biocom-patibility.[16] After ZnO layer was etched by HCl, the mono-disperse GNR@SiO2 nanorattles were obtained. As shown in transmission electron microscopy (TEM) images of Figure 1a,b, spherical GNR@ZnO and GNR@SiO2 were averagely 125.06 ± 15.94 and 142.28 ± 15.25 nm in diameter, respectively.

Moreover, the silica shell of GNR@SiO2 had an average thick-ness of 18.63 ± 5.97 nm. The morphology of samples was also investigated with scanning electron microscopy (SEM) imaging (Figure 1c, see Figure S1a,b, Supporting Informa-tion for more images) and clearly GNR@SiO2 nanorattles had high yield. Additionally, we found that the silica film of GNR@SiO2 nanorattles was flexible, evidenced by some nanorattles with irregular shapes (white arrows in Figure 1c), which promised that GNR@SiO2 could have fluid shear defor-mation to penetrate interstitium of tissues or vessels. The diameter was also analyzed in Figure S1c (Supporting Informa-tion). Because the optical absorption of GNR was very sensi-tive to surrounding media, GNR, GNR@ZnO, and GNR@SiO2 had different optical color and UV–Vis–NIR spectrum (Figure 1d,e). As we could see in Figure 1e, the UV–vis-NIR absorption spectrum of GNRs had two absorption bands which were attributed to the longitudinal SPR and transverse SPR. Moreover, the longitudinal absorption at 794 nm was much stronger than the transverse SPR at 520 nm, indicating that the GNRs were prepared at high yield. For the GNR@SiO2 nanorattles, their UV–Vis–NIR absorption of longitu-dinal SPR shifted to 799 nm which was in the NIR range and this was important to photothermal-conversion-based appli-cation. In addition, zeta potential analysis is a crucial param-eter as the negative value prevents nanoparticles from aggre-gating and ensures long-term stability, that is, it affects the in vivo fate of the particles.[17] Zeta potentials of GNR and GNR@SiO2 were recorded at pH 7.4. As shown in Figure 1f, although the zeta potential of GNR was +13.5 ± 2.95 mV, the zeta potential of GNR@SiO2 nanorattles turned to be −14.7 ± 2.46 mV due to the numerous OH groups on the surface of silica.

The individual structure of GNR@SiO2 nanorattles was crea-tively discovered to encapsulate vaporable PFP, which gener-ated nanobubbles and fused into microbubbles after triggering by heating, thus realizing the enhanced US imaging of tumors. The GNR core acted as the photothermal conversion agent. Figure 2a showed the temperature increments of GNR@SiO2

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Scheme 1. Schematic illustration of light-responsive biodegradable nanorattle-based PFP filled mesoporous silica film coated gold nanorod (GNR@SiO2-PFP) for US/PA dual-modality imaging guided PTT of melanoma.



aqueous solutions at different concentrations when exposed to a NIR laser (808 nm, 1 W cm−2) for 5 min. The temperature of GNR@SiO2 increased by 14–43 °C from the basic 29 °C when the concentrations of Au increased from 5 to 80 ppm. These results suggested that GNR@SiO2 nanorattles possessed the photothermal effects of GNRs and could be utilized as the intermediary of light-responsive gas generation.

PFP, as one kind of perfluocarbon, is well biocompatible and has been approved by European Medicines Agency for clinical use. So far, it was widely exploited to be used as UCAs.[18] The original boiling point of PFP is 29 °C, however, it will rise to 40–50 °C due to the blood pressure after intravenous

injection.[19] Therefore, it will cause a phase change from liquid to gas when the temperature is increased both in vitro and in vivo, which promises the feasibility of UCAs.[20] To verify the loading of PFP inside GNR@SiO2 nanorattles, the loaded PFP in the nanorattles was confirmed by gas chromatography-mass spectrometry (Figure 2b and Figure S1d, Supporting Infor-mation) and the fragment ions (m z−1) detected by the mass spectrometry were matched well with the standard substance (PFP, see the chemical structure in Figure S1e, Supporting Infor-mation). The PFP encapsulated inside GNR@SiO2 converted into numerous microbubbles within 2 min when treated with water bath at a temperature of 42 °C (Figure 2c) and was visualized using

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Figure 1. Characterization of the as-prepared nanorattles. a) TEM image of GNR@ZnO. b) TEM and c) SEM images of GNR@SiO2. White arrows indicate some nanorattles with irregular shapes. d) Photograph of as-prepared GNR, GNR@ZnO, and GNR@SiO2 aqueous solutions. e) UV–Vis–NIR absorbance spectra of GNR and GNR@SiO2. f) Zeta potentials of GNRs and GNR@SiO2 at pH 7.4.

Figure 2. a) Temperature elevation curves of phosphate-buffered saline (PBS) and GNR@SiO2 solutions of different concentrations (5, 10, 20, 40, and 80 ppm of Au) under 808 nm laser irradiation at the power density of 1 W cm−2 for 5 min. b) GC-MS chromatogram of PFP. c) In vitro bubble-generating after heating under the temperature of 42 °C for 2 min. d,e) Photographs of bubbles generation of GNR@SiO2-PFP solution before and after laser irradiation (808 nm, 1 W cm−2 for 5 min). f,g) Intracellular bubbles generation in A375 cells after incubated with GNR@SiO2-PFP before and after laser irradiation (808 nm, 1 W cm−2 for 5 min).



an optical microscopy (Figure S2a,b, Supporting Information). More microbubbles were generated when heated up to 42 °C than that of 30 °C. Optical microscopy was also employed to capture images of GNR@SiO2-PFP solutions on glass slides before and after laser irradiation by an 808 nm laser at a power intensity of 1 W cm−2 for 5 min (Figure 2d,e). After laser irradiation, abun-dant microbubbles were observed in Figure 2e. These micro-bubbles could be utilized as echogenic UCAs for US imaging.

Afterward, the generation of PFP microbubbles from GNR@SiO2-PFP at the cell level was investigated on A375 cells. The cells were coincubated with GNR@SiO2-PFP for 3 h followed by NIR laser irradiation for 5 min. The intracellularly gener-ated PFP microbubbles were clearly visual-ized and captured by an optical microscopy. As shown in Figure 2f and Figure S3a (Sup-porting Information), no bubbles within cells were found before laser irradiation. Con-versely, upon laser irradiation, GNR@SiO2-PFP could generate microbubbles in A375 cells (Figure 2g and Figure S3b, Supporting Information).

The biodegradability of GNR@SiO2-PFP was investigated by TEM. As shown in Figure 3, the GNR@SiO2-PFP with high elec-tron density was clearly observed, indicating their effective incorporation into A375 cells after incubation for 2, 5, and 24 h at 10 ppm Au of concentration. No GNR@SiO2-PFP was observed in the control group of normal A375 cells (Figure S4, Supporting Informa-tion). The silica shells of GNR@SiO2-PFP were unbroken at the incubation time of 2 h (Figure 3a,b), partly biodegraded at the time of 5 h (Figure 3c,d), while totally degraded at 24 h (Figure 3e,f). The morphological change of the phagocytized nanorattles tes-tified an obviously time-dependent biodeg-radation of GNR@SiO2-PFP. These results suggested that the GNR@SiO2-PFP could be gradually biodegraded into GNR in a time-dependent manner. Meanwhile, the loaded PFP may accumulate in the cells and gradu-ally excreted. Therefore, the biodegradability property of these nanorattles promises the further in vivo bioapplications.

Next, the cytotoxicity of GNR@SiO2 and GNR@SiO2-PFP on A375 cells was evaluated by using a Cell Counting Kit-8 assay. As shown in Figure 4a, GNR@SiO2 and GNR@ SiO2-PFP exhibited negligible toxicity on the cells. The viability was over 95% at all tested concentrations (0–100 ppm). The PTT effi-cacy of GNR@SiO2 on A375 cells upon 808 nm laser irradiation was further assessed. Figure 4b showed that the photocytotoxicity of GNR@SiO2 was in an irradiation time-dependent manner. With the increase of irra-diation time, the cells demonstrated a marked reducing of cell viability after treatment with

25 ppm GNR@SiO2 plus NIR laser irradiation at a laser power of 1 W cm−2. Less than 20% of A375 cells remained alive after irradiation for 5 min, while cells in the control group remained over 95% alive under the same dosage of illumination. As could be seen in Figure 4c, calcein-AM/PI double staining was car-ried out to assess PTT killing effects of A375 cells induced with GNR@SiO2. The green (calcein-AM) and red (PI) fluo-rescence severally represented live and dead or later apop-tosis cells. An intense red fluorescence signal was observed in A375 cells cultured with the as-prepared nanotheranostic agents for 24 h followed by laser irradiation for 5 min, indi-cating that most cells were killed. On the contrary, a weak

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Figure 3. Representative bio-TEM images of A375 cells incubated with GNR@SiO2-PFP (10 ppm Au content) for a,b) 2, b,d) 5, and c,f) 24 h. Scale bars, 1 µm a,c,e) and 200 nm b,d,f), respectively.



red fluorescence signal was observed from cells treated with PBS plus laser or not and GNR@SiO2 without laser. These results also demonstrated that GNR@SiO2 possessed great biocompatibility and excellent PTT effects on A375 cells, which was in agreement with the results of CCK-8 assay. Therefore, GNR@SiO2 nanorattles show great potential for PTT of cancer.

As shown in Figure S5 (Supporting Information), the PTT efficacy of GNR@SiO2 and GNR@SiO2-PFP were compared on A375 cells. We found that the similar anticancer efficacy of nanorattles with or without PFP loading, which determined the bubble generation, had little influence on the antitumor effect of nanorattles, and the PFP phase-change process had moderate cytotoxicity on cells. Meanwhile, the PFP loading did not impair the PTT effect of GNR@SiO2. The dominant ther-apeutic effect of nanorattles could be contributed to the PTT effect of gold nanorods. Our results indicated that GNR@SiO2-PFP also had great anticancer efficacy.

To implement US/PA dual-modality imaging, the image-able properties of GNR@SiO2-PFP were carefully investigated from in vitro to in vivo using the Vevo 2100 LAZR system. The echo properties of PFP microbubbles generated from GNR@SiO2-PFP were monitored. As shown in Figure 5a, the phase change of PFP from liquid to gas was induced by either heating or NIR laser irradiation. Bubbles were generated when the sam-ples were heated to 30 °C, which was higher than the boiling point of PFP that filled in the GNR@SiO2, whereas few bub-bles were found in PFP-loaded GNR@SiO2 dispersion at room temperature. Moreover, bubbles were numerously generated when the temperature was around 42 °C, or when the GNR@SiO2-PFP aqueous solution was irradiated by the 808 nm laser through photothermal response of GNRs. From B-mode images (Figure 5a), the echo signals of bubbles were almost fourfold higher than that before laser irradiation (Figure 5b). There-fore, the laser-responsive microbubbles generation confirmed

that GNR@SiO2-PFP could be used as a promising UCA. PA imaging property of GNR@SiO2-PFP nanorattles was also eval-uated using the same equipment. A concentration-dependent rise of PA signal was demonstrated in Figure 5c. There was a linear correlation (R2 = 0.997) between optical density (OD) value of samples and the corresponding PA value (Figure S6, Supporting Information). These results suggested that the GNR@SiO2-PFP showed great potential to be utilized for both enhanced US and PA imaging.

Encouraged by in vitro US/PA dual-modality imaging properties of GNR@SiO2-PFP nanorattles, the in vivo dual-modality imaging was carried out on A375 melanoma xeno-graft model. The PFP filled inside the GNR@SiO2 nanorattles was stable in the circulation, because the phase-change tem-perature of PFP was elevated due to the blood pressure and PFP was released to the deep tumor tissues when the nano-rattles were biodegraded progressively. After accumulating in the tumor, the PFP was temporarily stable due to intratumor pressure. When treated with laser, the regional temperature of tumor was persistently overheated to about 45 °C, thus generating PFP nanobubbles, and then followed by the coa-lescence into microbubbles. Therefore, the echo signal was distinctly higher (Figure 5d) and further reflected in the semi-quantification of US signal (Figure 5e). There was an obvious increasement of PA signal intensity from 0.302 ± 0.048 to 0.963 ± 0.117 a.u. around the tumor regions within 24 h after intravenous injection of GNR@SiO2-PFP (Figure 5f,g, Figure S7, Supporting Information), indicating the accumula-tion of the GNR@SiO2-PFP in the tumor tissues. The US and PA imaging were additionally acquired right after the nanorat-tles were intratumorally injected and demonstrated the rapidly gas-generating of extravascular PFP (Figure S8, Supporting Information). Overall, GNR@ SiO2-PFP could perform a high tumor accumulation, acted as an intelligent echogenic contrast

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Figure 4. In vitro cell experiments. a) Cell cytotoxicity of GNR@SiO2 and GNR@SiO2-PFP to A375 cells incubated with 0–100 ppm Au for 24 h. b) Cell viability of A375 cells incubated with GNR@SiO2 for 24 h and irradiated with laser (808 nm, 1 W cm−2) for 1, 3, and 5 min. **P < 0.01, ***P < 0.001. c) Fluorescence images of A375 cells costained with calcein AM (live cells, green fluorescence) and PI (dead cells, red fluorescence) after incubated with or without GNR@SiO2 (25 ppm Au) and laser irradiation (808 nm, 1 W cm−2, 5 min).



agents by displaying strengthened reflection at tumor tissues via a stimulation from the external 808 nm NIR irradiation, and simultaneously served as a PA signal intensifier.

With the guidance of US/PA dual-modality imaging, the therapeutic efficacy of GNR@SiO2-PFP induced PTT for cancer treatment was then investigated in vivo. PTT was car-ried out on melanoma bearing mice at 24 h after injection of GNR@SiO2-PFP (3 mg kg−1 of Au). Treatment was imple-mented when the tumors reached an unanimous volume of about 80 mm3. The mice were divided into four groups in our experiment: control group without any treatment, treat-ment groups contained PBS group, GNR@SiO2 plus laser irradiation group, and GNR@SiO2-PFP plus laser irradiation group. Based on the in vivo US and PA imaging, the 24 h time point with the maximum accumulation of the nanorat-tles was selected as the best time point for the implementa-tion of PTT. All of these groups were treated with 808 nm NIR laser (1 W cm−2) for 5 min, since the low laser power density with a short time of exposure was more appropriate in invasive tumor therapy with little damage to the surrounding normal tissues. Meanwhile, the temperature change of tumor tissues under laser irradiation was monitored by an infrared thermal camera (Figure 6a,b). There was an obvious temperature increase of tumor tissues that reached about 46.2 °C in the GNR@SiO2-PFP plus laser group. While negligible tempera-ture change was observed in mice treated with PBS plus laser group. The in vivo treatment efficacy of GNR@SiO2-PFP was evaluated by measuring the tumor volume every 3 d and the weight of tumor dissections 18 d after treatment of each group. As shown in Figure 6c, tumors in PBS and PBS plus laser groups kept growing at a similar speed and were euthanized

on day 18 due to the extensive burden of large tumor. On the contrary, the treatment groups of GNR@SiO2 and GNR@SiO2-PFP both with laser exposure showed inhibited tumor growth compared to the control group and PBS plus laser group, bene-fiting from the photothermal effect of GNRs. The tumor could be totally eliminated on day 18 posttreatment in GNR@SiO2 plus laser and GNR@SiO2-PFP plus laser groups. As shown in Figure 6d, the tumor weight difference also confirmed the cor-responding therapeutic effects. Moreover, it could be visually observed in the representative photographs of mice in different groups at various time points after treatment (Figure 6e). The therapeutic effects of the GNR@SiO2 plus laser and GNR@SiO2-PFP plus laser groups were much higher than that of control groups. Tumor sections were further prepared 24 h after laser irradiation for hematoxylin and eosin staining. As shown in Figure 6f, hematoxylin and eosin (H&E) staining images of tumors injected with GNR@SiO2 or GNR@SiO2-PFP plus laser irradiation showed hiatus in the cytoplasm and tissue space along with karyopyknosis and plasmatorrhexis, indicating serious necrocytosis and apoptosis. However, H&E staining images of PBS and PBS plus laser groups showed representative melanoma cells without obvious damage.

For the biocompatibility and biosafety assessment of as-prepared GNR@SiO2-PFP nanorattles, the hemolysis test was carried out. The results showed that the hemolysis rates of different concentrations (15–960 ppm) of GNR@SiO2-PFP were almost lower than 0.5% (Figure S9a, Supporting Infor-mation). Body weight of mice both in control group and treat-ment group was also collected and there was negligible differ-ence between the groups (Figure S9b, Supporting Informa-tion). H&E staining images of heart, kidney, liver, lung, and

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Figure 5. US and PA imaging. a) In vitro US images and b) the corresponding gray values of GNR@SiO2-PFP solutions (10 ppm of Au) before heating, after heating (30 and 42 °C), and after laser irradiation (1 W cm−2, 5 min). ***P < 0.001. c) In vitro PA images of GNR@SiO2-PFP solutions at various concentrations with different OD values (0.25–1.5). d) In vivo US images and e) the corresponding gray values of tumor tissues before injection, 24 h postinjection of GNR@SiO2-PFP, and after laser irradiation (1 W cm−2, 5 min). *P < 0.05, **P < 0.01. f) In vivo PA images and g) the corresponding PA values of tumor tissues in mice at different time before and after injection of GNR@SiO2-PFP.



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spleen were harvested from A375 tumor-bearing mice with various treatments on day 18 (Figure S10, Supporting Infor-mation). There was no observable damage or inflammation of the organs between control group and GNR@SiO2-PFP plus laser group, indicating that the nanorattles possessed excellent biosafety. Therefore, the as-prepared GNR@SiO2-PFP nanorat-tles could be a suitable candidate to act as a cancer nanothera-nostic agent.

In summary, we have successfully developed an intelli-gent biodegradable nanotheranostic agent for US/PA dual-modality imaging guided PTT of melanoma. The as-prepared GNR@SiO2-PFP was responsive specifically to the NIR light irradiation. It could generate PFP nanobubbles, permeate into the nonmicrovascular tissue, and finally coalesce into

microbubbles, thus realizing the enhanced US imaging of tumors. Moreover, with the help of laser irradiation, the nano-rattles could realize the simultaneous PA imaging and PTT of tumors in vivo. Our nanorattles also own excellent water dispersibility, flexible morphology, good biocompatibility, and biodegradability, thus facilitating its applications in cancer nan-otheranostics, particularly for enhanced dual-modality US/PA imaging guided PTT of cancer.

Supporting InformationSupporting Information is available from the Wiley Online Library or from the author.

Figure 6. In vivo therapeutic efficacy of GNR@SiO2-PFP nanorattles in A375 tumor-bearing mice. a) Representative thermographic images and b) temperature changes of A375 tumors upon laser irradiation at 24 h postinjection. *P < 0.05. c) Tumor growth curves of different groups after PTT treatment. Tumor volumes have been normalized to the initial sizes. (mean ± SD, n = 4, ***P < 0.001). d) Tumor weight of mice on day 18 after dif-ferent treatments (mean ± SD, n = 4, ***P < 0.001). e) Photographs of A375 tumor-bearing mice with various treatments. f) H&E staining images of tumor sections after different treatments.



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AcknowledgementsC.L. and Y.Z. contributed equally to this work. This work was supported by the startup fund from the Shenzhen University and the National Science Foundation of China (81401465, 51573096, 21471117, 81272987, 51703132, and 31771036), the Basic Research Program of Shenzhen (JCYJ20170412111100742 and JCYJ20160422091238319). All animal operations were in compliance with the approved protocols of institutional animal use and care regulations.

Conflict of InterestThe authors declare no conflict of interest.

Keywordscancer theranostics, light-responsive nanorattles, ultrasound imaging, photoacoustic imaging, photothermal therapy

Received: October 23, 2017Revised: November 15, 2017

Published online:

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