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Biological and Medical Applications of Materials and Interfaces

A Lesson from Nature: Biomimetic Self-assembling Phthalocyanines for Highefficient Photothermal Therapy within the Biological Transparent Window Hongguang Jin, Weibang Zhong, Shulu Yin, Xingxing Zhang, Yun-Hui Zhao, Youjuan Wang, Lin Yuan, and Xiao-Bing Zhang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b21299 • Publication Date (Web): 08 Jan 2019 Downloaded from http://pubs.acs.org on January 9, 2019

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ACS Applied Materials & Interfaces

A Lesson from Nature: Biomimetic Self-assembling Phthalocyanines for High-efficient Photothermal Therapy within the Biological Transparent Window Hong-GuangJin†‡, Weibang Zhong†‡, Shulu Yin‡, Xingxing Zhang‡, Yun-Hui Zhao§, Youjuan Wang‡, Lin Yuan‡* and Xiao-Bing Zhang‡ ‡

State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and

Chemical Engineering, Hunan University, Changsha 410082, PR China. §

School of Chemistry and Chemical Engineering, Hunan University of Science and Technology,

Xiangtan, Hunan, 411201, China Keywords: biomimetics, phthalocyanine, self-assembly, photothermal therapy, biological transparent window

Abstract: Development of facile but high-efficient small organic molecule based photothermal therapy (PTT) in the in vivo transparent window (800-900 nm) has been regarded as a minimally invasive and most promising strategy for potential clinical cancer treatment. Phthalocyanine (Pc) molecules with remarkable photophysical and photochemical properties as well as high extinction coefficients in the near-infrared region are highly desirable for PTT, but as far

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satisfying single-component Pc-based PTT within the in vivotransparent window (800-900 nm) has very rarely been reported. Herein, inspired by the self-assembly algorithm of natural bacteriochlorophylls (BChl's) c, d, and e, biomimetic self-assembling tetrahexanoyl Pc Bio-ZnPc with outstanding light-harvesting capacity was demonstrated to exhibit excellent PTT efficacy evidenced by both in vitro and in vivo results, within the biological transparent window.

1. Introduction Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has been regarded as a very powerful strategy for cancer therapy recently on the basis of their distinct advantages contrasted to conventional chemotherapy and radiotherapymethods, on aspects of long-rangecontrollability, higher selectivity, and minimal invasiveness.1-4 Unlike PDT5-8 needing the patients to spend some time in the dark during and after treatmentas well as requiring oxygen for toxic singlet oxygen production to killcancer cells, recently emerged PTT,916

in which photothermal agents (PTAs) absorb and convert optical energy into thermal energy

and generate local hyperthermia to induce irreversible necrosis of cancer tissues, is particularly beneficial for treating malignant tumors with hypoxic nature of microenvironment. Furthermore, because the amount of water in a live body up to 50-80% in weight and the intrinsic light absorption of tissues and blood, in vivo biological transparent window (800-900 nm) PTT with high penetration of irradiation and minimal invasiveness are highly desirable and ideal for eradicating the target solid tumors.17-19 In contrast to kinds of inorganic nanomaterials20-22 (gold, carbon, metal-sulfide, etc.), which have been extensively explored as PTAs in the biological transparent window, small organic molecules circumventing the concern of metal-ion-induced long-term toxicity, with enhanced


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biodegradability and light absorptivity per mass, are the more ideal PTA candidates for clinical translation in the area of PTT.23-30 However, the only approved clinical organic dye indocyanine green (ICG), with high ability to convert the absorbed near-infrared (NIR) light into thermal energy upon irradiated by laser, but its poor stability seriously limits its further applicable applications.31,32 Pcs,33-35 among the most stable aromatic macrocycles with long NIR absorption wavelengths (over 650 nm), high extinction coefficients (near 105/M/cm), and controllable photophysical and photochemical properties, have been widely investigated even clinical applications as photosensitizers for PDT.26,37Nevertheless, only sporadical reports have explored the utilization of Pcs for PTT38-41 and almost all of them are combined with various other therapeutics, which leads to require complex synthetic routes and satisfying efficiency balance between different therapy modalities. Moreover, few Pc-based PTT near/within the biological transparent window (800-900 nm) have been reported,42-44 but the PTA naphthalocyanines and anthracocyanines adopted are very susceptible to oxidation as well as sensitive to air, resulted from the destabilization of their HOMO levels, in addition to the long synthetic sequences under low yields.45Thus, simple but highly effective PTT treatments in the biological transparent window based on very stable and single-component Pcs are long-sought-after for potential clinical translation. In 1969, Schmitt created the word “biomimetics” to describe the studies andimitation of natural processes, methods and mechanism.46 Many centuries ago, human began to mimic nature for inventing various new materials and devices for solving the complex problems encountered, such as Chinese made the artificial silk and Leonardo da Vinci proposed the model of flying machine.47In 2012, inspired by natural photosynthesis, the group of Nocera at MIT designed the so-called artificial leaf, which can utilize light to split H 2 O to produce O 2 and H 2 efficiently with


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easily available and inexpensive materials.48 Jacob et al. synthesized several excellent musselinspired water adhesions via incorporating the functional motifs (catechol, positive and negative charges, nonpolar moieties) of interfacial mussel foot proteins into small zwitterionic molecules, which were strong and spontaneous binding to the surfaces under wet environment.49,50 However, there is still a lot of elements and systems in the nature for our human to learn and mimic. Natural light-harvesting antenna can capture and transfer light energy to the reaction centers with a high efficiency by virtue of the very ordered self-assemblies of the functional pigments.Among them, some green photosynthetic bacteria can capture photons efficiently even at one hundred meters under water surface51,52 thanks to the well-organized self-assemblies of bacteriochlorophylls (BChl's) c, d, or e (Figure 1a). In polar solvents, the monomeric species have a strong and sharp Q y -band at ~670 nm. When self-assembly operated, this band maximum red-shifted to ~740-750 nm as well as its full-width-at-half-maximum increased by up five times mainly due to inhomogeneous broadening.53,54 This self-assembly algorithm has been successfully mimicked and extended by the group of Balaban, via incorporating different recognition and solubilizing groups onto porphyrinoids, and the obtained mimics could selfassemble utilizing the similarway as that of natural BChl’s.55-58 Of note is that, upon selfassembly, the biomimetic Pcs exhibit a broaden and red-shifted Q-band absorption up to 900 nm, which was in the biological transparent window.58


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Figure 1. (a) Natural BChls c, d, e, which self-assemble via the central Mg atom and the recognition hydroxyl and carbonyl groups. Different groups (methyl, ethyl, n-propyl or isobutyl) can be in the R8 and R12 positions, as well as diverse fatty alcohols (farnesyl, stearyl, cetyl, oleyl, etc.) can esterify the 17-propionic acid, asterisks denote stereocenters. (b) Biomimetic selfassembling tetrahexanoyl Pc (Bio-ZnPc) through extending the self-assembling algorithm of BChlsc, d, e: the peripheral carbonyl groups and the central zinc atom are as recognition motifs.58 (c) Chemical structures of two common Pcs (H 2 Pc andZnPc) represented in this work. With these considerations in mind, in the present work, inspired by nature, we developed biomimetic self-assembling tetrahexanoylZnPc (Bio-ZnPc) (Figure 1b) as a PTA for PTT. Remarkable in vitro/in vivo PTT results were demonstrated attributed to the excellent photothermal conversion efficiency of Bio-ZnPc within the biological transparent window (808 nm was selected). 2. Results and Discussion 2.1 Synthesis and Characterization Bio-ZnPc was synthesized according to our previous protocol.58 As a control, one common free-baseH 2 Pc and its metallatedZnPc (Figure 1c) were also prepared and characterized (Scheme S1, Figure S3 and S4). The biomimetic self-assembly capacity and mechanism of BioZnPchave been well documented,58 herein we further studied the self-assembly phenomenon. In chloroform-D, Bio-ZnPc exhibited obvious broad and red-shifted absorption up to 900 nm due to the biomimetic self-assembly initiated by the recognition effect of the peripheral carbonyl


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groups and the central zinc atom (Figure S5). In addition, as 1H-NMR spectra shown in Figure S6, upon addition of five drops of methanol-D 4 , which can perturb the self-assembly via competitively coordinating to the central zinc atom, into chloroform-D, the broad signals attributed to the α-protons of the peripheral carbonyl groups of Bio-ZnPc, became split and sharp, thus directly evidenced that the carbonyl groups are indeed involved in the self-assembly process. Due to the high hydrophobicity of Pcs, amphiphilic polymer (H-PEG-PPG-PEG-OH) was adopted to endow them with water-dispersity (Figure 2a). From the dynamic light scattering (DLS) measurements of the as-synthesized water soluble polymer pdots Bio-ZnPc-Pdots,H 2 PcPdots and ZnPc-Pdots, the particle sizes of these pdots were found to be about 50-60 nm (Figure 2b

Figure 2.(a) Schematic representation of synthesis of Bio-ZnPc-Pdots; (b) Size distribution, morphology (TEM image, inset left), and water dispersion (inset right) of Bio-ZnPc-Pdots; (c) Absorption spectra of water dispersions of Bio-ZnPc-Pdots, H 2 Pc-Pdots and ZnPc-Pdots; Noteworthily, Bio-ZnPc-Pdots shows obvious absorption over 808 nm when compared to H 2 Pc-Pdots and ZnPc-Pdots; (d) Absorption spectra of Bio-ZnPc, H 2 Pc and ZnPc in THF (1.5 × 10-4 M); (e) Fluorescence spectra of Bio-ZnPc, H 2 Pc and ZnPc in THF, and aqueous dispersions of Bio-ZnPc-Pdots, H 2 Pc-Pdots and ZnPc-Pdots.


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and S7), which were consistent with the results from the transmission electron microscopy (TEM) (Figure 2b inset). These pdots were highly stable in phosphate buffer solution (PBS, 25 mM, pH = 7.4), no obvious Pcs release or Pdot aggregations were observed even after several days standing. The UV-vis absorption and fluorescence emission spectra of these pdots were recorded in aqueous solution. All these pdots exhibited a broader and bathochromic absorption band (Figure 2c) when compared to their respective monomer in polar THF (Figure 2d), in which two Pctypical bands (a low-energy Q-band around 680 nm and a high-energy B-band around 340 nm) could be observed. However, in contrasted to H 2 Pc-Pdots and ZnPc-Pdots,which were assembled and aggregated via simple π-π stacking interaction and van der Waals forces, as that of common Pcs, Bio-ZnPc-Pdots displayed a distinct broad absorption edge up to 850 nm, which ascribes to the bimimetic self-assembly thanks to the recognition effect of the central zinc atom and the peripheral carbonyl groups, as the self-assembly algorithm of natural BChl’sc, d, e. Moreover, the fluorescence of all Pdots was almost completely quenching (Figure 2e), which is in agreement with typical observed for common Pcs in the state of aggregation.33-35 This aggregation behavior can suppress the PTAs to loss theabsorbed light energyviafluorescence emission and intersystem crossing energy transfer, thus are very beneficial for high photothermal conversion efficiency.59 2.2 Photothermal Performance Study To investigate the photothermal performance of these Pdots, their conversion efficiencies were measured in water (75 µg/mL) under laser irradiation (808 nm, 1.2 W/cm2, 10 min). The temperature variation of H 2 Pc-Pdots and ZnPc-Pdotsis 8.5 and 7.4 °C, respectively (Figure 3a).


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However, the temperature increment of the Bio-ZnPc-Pdots can up to 18.7 °C (Figure 3a) as well as the solution color changed from black to white (Figure 3b). Furthermore, the extent of temperature variation of Bio-ZnPc-Pdots was correlated well with the laser power and the

Figure 3.Temperature variation profile (a) and IR thermal images (b, c, d) of water dispersions of Bio-ZnPc-Pdots, H 2 Pc-Pdots and ZnPc-Pdots (75 µg/mL) when exposed to laser irradiation (808 nm, 1.2 W/cm2, 10 min); Concentration (e) and powder (f) -dependent temperature variation of water dispersion of Bio-ZnPc-Pdots; (g) Photothermal response of water dispersion of Bio-ZnPc-Pdots (75 µg/mL) under laser irradiation (808 nm, 1.2 W/cm2) for a period of time (0-10 min) before the laser was turned-off; (h) Stability study of Bio-ZnPc-Pdots (75 µg/mL) over five heating and nature cooling cycles (808 nm, 1.2 W/cm2). concentration (Figure 3e and 3f). Thus, Bio-ZnPc-Pdots can work as an effective PTA when irradiated at 808 nmbased on its fast and excellent photothermal effect. The photothermal conversion efficiency was also recorded to evaluate the heat transfer utility (η) of Bio-ZnPc-Pdots according to a reported method.60 The temperature of the water dispersion of Bio-ZnPc-Pdots can increase to a steady state under laser irradiation (808 nm,1.2 W/cm2). After that, the laser was turned off and let the temperature decrease naturally, so that the heat transfer rate from Bio-ZnPc-Pdots solution to the environment can be estimated (Figure 3g). The efficiency then was calculated to be approximately 38.17% following the eq S1, and the


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enhanced efficiency seen for Bio-ZnPc-Pdotscompared to H 2 Pc-Pdots (11.40%) and ZnPcPdots (9.64%), was consistent with its high light-harvesting ability at 808 nm (Figure S9) attributed to the biomimetic self-assembly and its negligible fluorescence emission, which are both expected to convert NIR light to heat efficiently. 2.3 Photostability and Photochemistry of Bio-ZnPc-Pdots The photostability of Bio-ZnPc-Pdots was also investigated as compared to ICG. After standing at ambient air for 24 h, the absorbance of ICG aqueous solution at 780 nm was dropped to 78%, while no obvious reduction at 808 nm was observed over this time for Bio-ZnPc-Pdots (Figure S10). Meanwhile, the absorbance of ICG (780 nm) was decreased by 33% under laser irradiation (808 nm 1.2 W/cm2) for 10 min, mainly attributed to its serious photobleaching, nevertheless the degradation of Bio-ZnPc-Pdots was negligible evidenced by the almost unchanged absorbance (Figure S11). Furthermore, Bio-ZnPc-Pdots was also subjected to repeated irradiation-cooling cycles (Figure 3h),the maximal temperature of Bio-ZnPc-Pdots during each cycle had no obvious variation. This phenomenon is different to some reported organic PTAs, which bleaches easily under laser irradiation and are unfit for PTT.61 The photochemical features of Bio-ZnPc-Pdots was also further studied. Although the coproduction of reactive oxygen species (ROS) during PTT process contributes to the increase of cytotoxicty in some extent, it also triggers underdesired side-effects.62 Thus, we measured the singlet oxygen (1O 2 ) production to evaluate ROS generating ability of the Bio-ZnPc-Pdots under laser irradiation using 9,10-anthracenediyl-bis(methylene)-dimalonic acid (ABMDMA) as 1O 2 capture agent.63 As shown in Figure S12, the absorbance of ABMDMA at 401 nm had no obvious change, which evidenced that 1O 2 production of Bio-ZnPc-Pdots over the irradiation process can be ignored, thus no signiﬁcant amount of ROS was produced when Bio-ZnPc-Pdots


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was subjected to photoactivation. These results demonstrated that Bio-ZnPc-Pdots has high stability under laser irradiation (808 nm), which would prove as an effective PTA in vitro and in vivo. 2.4 in vitro Photothermal Therapy of Bio-ZnPc-Pdots We first studied the cytotoxicity of Bio-ZnPc-Pdots via a standard MTT assay using liver hepatocellular carcinoma cells (HepG2). Different amounts of Bio-ZnPc-Pdots were added into HepG2 cells and incubated for 24 h. The cell viabilities, as shown in Figure 4, were > 90%, even the concentration of Bio-ZnPc-Pdots up to 75 µg/mL, which manifested the good biocompatibility and low cytotoxicity of Bio-ZnPc-Pdots.

Figure 4.Concentration-dependent cytotoxic effect of Bio-ZnPc-Pdotson HepG2 cells under different treatments. In the absence of laser irradiation (blue bars), in the presence of laser irradiation (808 nm, 1.2 W/cm2, 6 min) without (red bars) and with (green bars)an ice-bath to control the temperature of cells lower than 30 °C during laser irradiation. Next, the in vitro PTT effect of Bio-ZnPc-Pdots were studied through incubating cells in a culture medium containing different concentrations of Bio-ZnPc-Pdots for 24 h, which was followed by continuous laser irradiation (808 nm, 1.2 W/cm2, 6 min). The standard MTT assay demonstrated obvious cell death, the cells were basically dead whenBio-ZnPc-Pdots is 75


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µg/mL (Figure 4). To prove the speculation that the cell inhibition is a consequence of temperature increase triggered by PTT not ROS generation, we control the cell temperature less than 30 ºC through an ice-bath over the laser irradiation process. The cell viability is almost same as that obtained from without laser irradiation. These results well demonstrated that Bio-ZnPcPdots can contributes to the phototherapy for cancer cell inhibition through high photothermal conversion (PTT), not ROS generation (PDT). In order to visualize the in vitro PTT efficacy of Bio-ZnPc-Pdots, the live/dead cell stainning assay is performed with calcein-AM (live cells, green fluorescence) and propidium iodide (PI, dead cells, red fluorescence) fluorescence dyes.HepG2 cells treated only with laser irradiation (808 nm, 1.2 W/cm2, 6 min) showed only strong fluorescence of calcein-AM at green channel, indicating no obvious cytotoxicity after only laser irradiation (Figure 5c). In contrast, treatment of HepG2 cells with Bio-ZnPc-Pdots (75 µg/mL) plus laser irradiation (808 nm, 1.2 W/cm2, 6 min) only showed strong red fluorescence of PI, indicating the high PTT efficacy of Bio-ZnPc-Pdots (Figure 5a).In addition, HepG2 cells treated with Bio-ZnPc-Pdots plus laser irradiation at an ice-bath (< 30 ºC) also showed only strong green fluorescence of calcein-AM (Figure 5b), demonstrating that the death of HepG2 cells under continuous laser irradiation was attributed to the PTT not to the ROS generation. These results achieved from fluorescence cells viability assay are consistent well with those from the MTT assay (Figure 4).


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Figure 5.Inverted microscope images of calcein-AM and PI stained HepG2 cells with different treatments: Bio-ZnPc-Pdots (75 µg/mL) with laser irradiation (808 nm, 1.2 W/cm2, 6 min) while without (a) and with (b) an ice-bath to control the temperature of cells lower than 30 °C; (c) PBS (25 mM, pH = 7.4) with laser irradiation (808 nm, 1.2 W/cm2, 6 min), scar bar 100 µm. 2.5 in vivo Photothermal Therapy of Bio-ZnPc-Pdots Encouraged by the excellent in vitro PTT efficacy of Bio-ZnPc-Pdots, the in vivo PTT tests were conducted on tumor-bearing mice. We chose a malignant murine tumor cell line 4T1 as the tumor model. When the the length of tumors reached approximately to 50-70 mm, 100 µL PBS


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Figure 6. Thermographic images of mice treated with Bio-ZnPc-Pdots (75 µg/mL) (a) and PBS (25 mM, pH = 7.4) (b) exposed to continuous laser irradiation (808 nm, 1.2 W/cm2) at different times; (c) Temperature profiles of tumor sites upon laser irradiation (808 nm, 1.2 W/cm2) versus irradiation time; Tumor relative volume (d) and body weight (e) curves of the experiment and control groups of mice after treatments. (f) H&E-stained images of major organs and tumors from the experiment and control groups of mice after treatments.(Scale bars: 200μm.)


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(25 mM, pH = 7.4) dispersion of Bio-ZnPc-Pdots was intratumorally injected into the mice. First, we used an infrared thermal camera to monitor the real-time temperature change of the tumor region under laser irradiation. After being intratumorally injected for 10 min, mice of the experment groupwere irradiated with continuous laser (808 nm, 1.2 W/cm2). Under irradiation, the tumor temperature increased remarkably to 56 ºC within 3 min (Figure 6b and 6c), which is high enough to kill the cancer cells.9-16 As a comparsion, the temperature of tumor with PBS (25 mM, pH = 7.4) injection as control only increased to 41 ºC (Figure 6b and 6c). These results proved that the Bio-ZnPc-Pdots can efficiently converted the absorbed light energy to local hyperthemia for PTT. Then, we further studied the anti-cancer effects of Bio-ZnPc-Pdots to the mice of experiment group. The tumor of each mouse in the experiment group (n = 6) was laser irradiated (808 nm, 1.2 W/cm2, 6 min). The two control groupsincluded mice treated with saline (n = 6) followed by exposure to laser irradition, and mice treated with only Bio-ZnPc-Pdots (n = 6). We recorded the volume of the tumors every 2 days for two weeks. Of note is that for the experiment group treated with Bio-ZnPc-Pdots plus laser irradition, the solid tumor gradually shrinked and almost scabbedafter 2 days of treatment (Figure 6d). In contrast, boththe saline treated group followed by laser irradition andthe only Bio-ZnPc-Pdots treated group, could not inhibit tumor growth (Figure 6d). Meanwhile, we also monitored the body weight of mice over the experiment process to evaculate the potential side effects, the values of mice from all groups did not change significantly during the treatment period (Figure 6e). These results evidenced that Bio-ZnPcPdots was an excellent PTA with an high tumor inhibition and did not brought systemic toxicity. Hematoxylin and eosin (H&E) staining was adopted to further evaluate the biosafety of Bio-ZnPc-Pdots. Mice from the experiment and both two control groups were sacrificed at day


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2 after treatments, and the main organs, including livers, spleens, kidneys, and hearts, as well as the tumors were collected and used forhistological analysis. All of the organs and the tumors from the two control groups showed nodiscernible histopathological damage, however, the tumor from the experiment group exhibited obvious apoptosis of cells, which can be attributed to the PTT treatment (Figure 6f).These results demonstrated that Bio-ZnPc-Pdots is a hopeful candidate of PTAs for potential application in theranostic. 2.6 Photoacoustic Imaging of Bio-ZnPc-Pdots The excellent photothermal performance of Bio-ZnPc-Pdots motiviates us to study its promising use in photoacoustic (PA) imaging. We chose 808 nm as the absorbance wavelength to monitor thein vitro and in vivo PA signal. With the increase of the concentration of PBS (25 mM, pH = 7.4) dispersion of Bio-ZnPc-Pdots, the in vitro PA intensity was gradually enhanced (Figure 7a), and it also exhibited a good line relationship in the low concentration range (0100µg/mL) (Figure 7b). The in vivo PA imaging was also recorded on a nude mice, which was intratumorally injected with 50 μL PBS dispersion of Bio-ZnPc-Pdots (75 µg/mL). As shown in Figure 7c, the tumor region exhibited strong PA signal after injection with Bio-ZnPc-Pdots, and its average PA singal intensity increased by 5.3-fold compared to the tumor site without Pdot injection. The excellent in vitro/in vivo PA imaging capacity of Bio-ZnPc-Pdots make it a potential candidate for PA-imaging guided PTT platform for cancer treatment, which could offer high contrast images of biological tissues through circumenting the disadvantages of photon scattering in living systems.


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Figure 7. (a) PA images of aqueous solution of Bio-ZnPc-Pdots with different concentrations; (b) PA intensity versus the concentration of aqueous solution of Bio-ZnPc-Pdots(0-100 µg/mL); (c) PA images and (d) average PA intensity of the tumor before and after Bio-ZnPc-Pdots PBS (25 mM, pH = 7.4) dispersion injection. Red circles mark the tumor location.

3 Conclusion In summary, inspired by nature, we have developed a highly efficient but simple singlecomponent organic PTT system in the biological transparent window (800-900 nm) based on the robust chromophore Pc Bio-ZnPc. Bio-ZnPc, within the peripheral carbonyl groups and the central zinc atom as recognition motifs mimicking the self-assembling algorithm of natural bacteriochlorophylls (BChl's) c, d, and e, could self-assemble inside the amphiphilic pdots and the formed mimic Bio-ZnPc-Pdots exhibited remarkable red-shifted and broaden lightharvesting capacity in the biological transparent window. The excellent photothermal performance of Bio-ZnPc-Pdots was investigated in detail, and the photothermal conversion efficiency at 808 nm was 38.2%. Furthermore, in vitro and in vivo PTT tests confirmed that Bio-


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ZnPc-Pdots can effectively eradicate cancer cells under laser irradiation in the biological window without causing damage to normal tissues in living mice. In addition, excellent in vitro and in vivo PA imagings suggested that Bio-ZnPc-Pdots may serve as PA-imaging guided PTT. These data demonstrated that Bio-ZnPc-Pdots, as an satisfying organic PTA, had great potential for clinical PTT application, as some Pcs that had been clinically applied in PDT. Last but not least, this unique work presented here also showed an intelligent way to solve some scientific problem by learning from nature.

ASSOCIATED CONTENT Supporting Information is available from pubs.acs.org. AUTHOR INFORMATION Corresponding Author *[email protected] Author Contributions †

H.-G. Jin and W. Zhong contributed equally to this work.

Funding Sources This work was supported by NSFC (21877029, 21622504) and the Science and Technology Project of Hunan Province (2017RS3019),H.-G. Jin also thanks the China Postdoctoral Science Foundation Grant Project (2018M632955).


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All animal experiments were approved by the Animal Ethics Committee of College of Biology of Hunan University under the Guidelines for Care and Use of Laboratory Animals of Hunan University. Notes The authors declare no conflict of interest. REFERENCES (1) Sun, M.; Xu, L.; Ma, W.; Wu, X.; Kuang, H.; Wang, L.; Xu, C. Hierarchical Plasmonic Nanorods and Upconversion Core-Satellite Nanoassemblies for Multimodal Imaging-Guided Combination Phototherapy. Adv. Mater. 2016, 28, 898-904. (2) Chen, G.; Xu, M.; Zhao, S.; Sun, J.; Yu, Q.; Liu, J. Pompon-like RuNPs-Based Theranostic Nanocarrier System with Stable Photoacoustic Imaging Characteristic for Accurate Tumor Detection and Efficient Phototherapy Guidance. ACS Appl. Mater. Interfaces 2017, 9, 3364533659. (3) Chang, K.; Liu, Z.; Fang, X.; Chen, H.; Men, X.; Yuan, Y.; Sun, K.; Zhang, X.; Yuan, Z.; Wu, C. Enhanced Phototherapy by Nanoparticle-Enzyme via Generation and Photolysis of Hydrogen Peroxide. Nano Lett. 2017, 17, 4323-4329. (4) Rosal, B.; Jia, B.;Jaque, D. Beyond Phototherapy: Recent Advances in Multifunctional Fluorescent Nanoparticles for Light-Triggered Tumor Theranostics. Adv. Funct. Mater. 2018, 28, 1803733-1803757. (5) Ge, J.; Lan, M.; Zhou, B.; Liu, W.; Guo, L.; Wang, H.; Jia, Q.;Niu, G.; Huang, X.; Zhou, H.; Meng, X.; Wang, P.; Lee, C.; Zhang, W.; Han, X. A Graphene Quantum Dot Photodynamic Therapy Agent with High Singlet Oxygen Generation. Nat. Commun. 2014, 5, 4596-4603.


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SYNOPSIS Simple but satisfying photothermal therapy based on small organic molecules within the biological transparent window (800-900 nm) have been regarded as a minimally invasive and most promising strategy for clinical cancer treatment. Herein, inspired by nature, biomimetic self-assembling phthalocyanine Bio-ZnPc mimicking the self-assembling algorithm of natural bacteriochlorophylls (BChl's) c, d, or e, was demonstrated to exhibit excellent in vitro/in vivo PTT efficacy within the biological transparent window.

ToC figure


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Lesson from Nature: Biomimetic Self-Assembling ... - ACS Publications

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