Functional-Protein-Assisted Fabrication of FeâGallic Acid

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Functional Protein-Assisted Fabrication of Fe-Gallic Acid Coordination Polymer Nanonetworks for Localized Photothermal Therapy Yaqiong Wang, Jing Zhang, Chuyu Zhang, Bingjie Li, Jiaojiao Wang, Xuejun Zhang, Dong Li, and Shao-Kai Sun ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b04656 • Publication Date (Web): 22 Nov 2018 Downloaded from http://pubs.acs.org on November 25, 2018

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ACS Sustainable Chemistry & Engineering

Functional Protein-Assisted Fabrication of Fe-Gallic Acid Coordination Polymer Nanonetworks for Localized Photothermal Therapy Yaqiong Wang,† Jing Zhang,† Chuyu Zhang,† Bingjie Li,† Jiaojiao Wang,† Xuejun Zhang,† Dong Li,‡,* and Shao-Kai Sun†,* †School

of Medical Imaging, Tianjin Medical University, Tianjin 300203, China

(Corresponding author's email: [email protected]) ‡Department

of Radiology, Tianjin Medical University General Hospital, Tianjin

300052, China (Corresponding author's email: [email protected]) KEYWORDS:

polyphenols,

coordination

polymer,

biomineralization, immune activation, photothermal therapy

1

ACS Paragon Plus Environment

biocompatibility,

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ABSTRACT: Fe-polyphenols coordination polymers have emerged as a versatile theranostic nanoplatform for biological applications owing to the appealing biocompatibility of precursors from nature. Incorporating bioactive molecules with Fe-polyphenols coordination polymers is greatly significant to take full advantages of their superiorities for advanced application. Herein, we show functional protein-assisted fabrication of Fe-gallic acid (GA) nanonetworks via a mild and facile biomineralization for photothermal therapy. Mild alkaline condition is crucial to obtain protein-Fe-GA nanonetworks with intense near-infrared absorption and their unique network structure allows reducing the leakage to the surrounding normal tissues, benefiting high photothermal therapeutic efficacy and minimal side effects. The proposed bovine serum albumin-Fe-GA nanonetworks are successfully used to eradicate tumor in vivo. In addition, this universal method can be extended to synthesize

other

protein-involved

nanonetworks,

such

as

human

serum

albumin-Fe-GA and ovalbumin-Fe-GA. More importantly, the intrinsic bioactivity of protein can be retained in the nanonetworks, and the ovalbumin-Fe-GA nanonetworks enable inducing the maturation of immune cells, showing the successful fusion of immune activity of ovalbumin into the nanonetworks. The proposed biomineralization strategy shows a bright prospect in incorporating various functional proteins, such as enzymes and antibodies, to form protein-Fe-GA nanonetworks with good biocompatibility, favorable photothermal effect and specific biological function.

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INTRODUCTION Traditional cancer treatments, such as surgery excision, radiotherapy, and chemotherapy, have been widely applied for clinical cancer therapy, but suffering from the risk of side effects such as destroying the immune system and increasing the incidence of second cancers. Photothermal therapy (PTT) with the merits of high selectivity and minimal invasiveness is emerging as an alternative method for cancer therapy in recent years. PTT utilizes near-infrared (NIR) light-absorbing agents to convert the NIR light energy into heat for thermal ablation of malignant tumors, and spatially controlled light illumination and localized accumulation of photothermal agents endow PTT with high selectivity and minimal invasiveness.1-2 Besides, PTT not only owns the ability to directly “burn” tumors but also can assist the efficacy of chemotherapy, radiotherapy, and immunotherapy, inhibiting tumor relapse and metastasis effectively.3-5 Up to now, various photothermal agents, such as carbon nanostructures,6-7 noble metal nanomaterials,8-9 metal chalcogenides and oxide,10-17 semimetal

nanoparticles,18

black-phosphorus

nanomaterials,19-20

photosensitizer-containing polymers and liposome,21-26 organic nanomaterials,27-29 and dyes30-31 have been extensively explored for PTT. Despite outstanding therapeutic efficacy, the great concerns regarding the long-term safety of current photothermal agents seriously hinder their clinical applications. Coordination polymer nanostructures, also known as nanoscale metal-organic frameworks, are formed by the self-assembly between metal ions and organic polydentate bridging ligands, and show great potential as a versatile nanoplatform for 3



diverse biomedical applications due to their structural and chemical diversity and high loading capacity.32-38 Nevertheless, majority of coordination polymers inevitably suffer from tedious synthesis process and use of toxic metal elements and organic ligands.29 Rational choice of metal center and ligands with special function is the key to developing high-performance polymers for biological applications. Fe element is an essential component of hemoglobin, a substance in red blood cells that carries oxygen around the body, and also plays a crucial role in extensive biological processes.39 The definite biological function and biosafety of Fe element make it an excellent metal ion candidate for building coordination polymers. In light of organic ligands, some precursors derived from natural resources have attracted increasing attention and have been applied to fabricate coordination polymers instead of toxic ones such as imidazole and terephthalic acid. Gallic acid (GA) is a type of organic tea polyphenol with low-molecular weight derived from plant sources,40 and has been extensively used in food and medicine industries.41-42 The strong bidentate coordination interaction between Fe3+ and the two phenolic OH groups in ortho position in GA makes it possible for the fabrication of Fe-GA coordination polymer. Moreover, the Fe-GA complex possesses intense NIR absorption derived from the strong delocalization in the π-electron structure, and has been employed as an excellent PTT agent with favorable biocompatibility.43 Several hydrophilic polymers, such as poly(vinyl alcohol) (PVA),44 polyethylene glycol (PEG),45 and poly (vinylpyrrolidone) (PVP)46 have been employed as surface stabilizers of Fe-GA coordination polymers. 4


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However, previous surface modifications merely employed inactive molecules to enhance water solubility, so it is greatly significant but challenging to incorporate bioactive molecules to take full advantages of superiorities of Fe-GA coordination polymer for advanced application.47 Proteins, such as antibodies, enzymes, structural proteins, signaling proteins, and transport proteins, fulfill many functions as one type of most significant biomolecules in biology.48 Proteins are rich in functional groups such as amino, carboxyl, and thiol groups, thus exhibiting strong coordination capacities with transition-metal ions like Fe3+. Moreover, the unique spatial structure and molecular chain flexibility make protein an expansive hollow nanoreactor suitable for biomineralization.49 Up till now, plenty of bioactive proteins, such as bovine serum albumin (BSA), human serum albumin (HSA), ovalbumin (OVA), catalase, lactoferrin, transferrin, ferritin, pepsin, trypsin, papain, horseradish peroxidase (HRP), ribonuclease, lysozyme, and insulin, have been employed for the fabrication of diverse nanostructures with fascinating properties for biological applications.50-51 For instance, noble nanoclusters (Pt, Au, Cu),52-55 metal sulfide (PbS, Bi2S3, CuS, FeS, ZnS:Mn),56-58 and metal oxide (Gd2O3, Au/Gd2O3, and MnO2)59-63 have been synthesized via biomineralization for theranostics of various diseases. Therefore, bioactive proteins as excellent templates show great potential in the fusion of diverse biological functions with the unique merits of Fe-GA coordination polymer.64-68 Herein, we showed functional protein-assisted fabrication of Fe-GA nanonetworks via a mild and facile biomineralization way for localized photothermal therapy. Mild 5



alkaline condition permitted the formation of Fe-GA nanonetworks with favorable NIR absorbance and impressive photothermal performance. The BSA-Fe-GA nanonetworks exhibited a unique network structure with an appropriate size of 193.5 nm, facilitating their retention in tumor site and minimizing the leakage to surrounding normal tissues after localized administration. The BSA-Fe-GA nanonetworks with outstanding biocompatibility and excellent photothermal performance were applied in localized photothermal therapy in vitro and in vivo against tumors successfully. To testify the universality of the protein-assisted fabrication strategy of coordination polymers, other proteins like HSA and OVA were also employed to construct Fe-GA coordination polymers. Both HSA and OVA enabled the formation of protein-Fe-GA coordination polymers with similar network structure and excellent photothermal effect to those of BSA-Fe-GA nanonetworks (Scheme 1). Moreover, the proposed OVA-Fe-GA nanonetworks successfully induced the maturation of dendritic cells (DC2.4) and macrophage cells (RAW264.7). The immune activity of OVA in OVA-Fe-GA nanonetworks was retained efficiently via the mild synthesis approach, showing great potential in the development of multifunctional nanovaccine.69 The proposed biomineralization strategy shows a bright prospect in the incorporation of functional proteins, such as enzymes and antibodies, with Fe-GA coordination polymers for various biological applications.

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Scheme 1. The schematic illustration of functional protein-assisted fabrication of Fe-GA coordination polymer nanonetworks for localized photothermal therapy. RESULTS AND DISCUSSION Synthesis and Characterization of BSA-Fe-GA, OVA-Fe-GA, and HSA-Fe-GA Nanonetworks. BSA-Fe-GA nanonetworks were prepared through a facile and one-step biomineralization approach. Briefly, 60 mg of BSA and 80 mg of FeCl3·6H2O were dissolved in 15 mL water with magnetically stirring. Then 1 mL of NaOH solution (1 M) was rapidly added to the mixture liquid with pH changing from 3 to 9. GA aqueous solution (4 mL, 10 mg/mL) was then introduced into the orange complex mixture, immediately giving rise to a dark solution due to rapidly self-cross-linking of Fe3+ and GA along with the existence of protein in water. Alkaline aqueous environment induced loose and unfolded structure of protein, contributing a stable network of BSA-Fe-GA coordination polymer.70 Moreover, we 7



found a mild basic condition was crucial to obtain BSA-Fe-GA nanonetworks with maximum NIR absorption, since the slightly high pH can strengthen the bidentate coordination interaction between Fe3+ and the two phenolic OH groups in ortho position in GA (Supporting Information, Figure S1, Table S1).43 Besides, mild synthesis condition also ensured the minimal impairment to the function of protein. The resulting BSA-Fe-GA nanonetworks were purified by dialysis against deionized water for 24 h and stored at 4 ℃for further use. OVA-Fe-GA and HSA-Fe-GA nanonetworks were also synthesized under optimal synthetic conditions for BSA-Fe-GA nanonetworks. The composition, size and morphology of the as-prepared protein-Fe-GA nanonetworks were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform-infrared spectroscopy (FT-IR), and inductively coupled plasma-atomic emission spectrometry (ICP-AES). The TEM images indicated BSA-Fe-GA coordination polymer owned a network structure (Figure 1a, Supporting Information, Figure S2a), and analogous morphology were observed for OVA-Fe-GA and HSA-Fe-GA nanonetworks (Supporting Information, Figure S2b-c). The hydrodynamic sizes of BSA-Fe-GA, OVA-Fe-GA, and HSA-Fe-GA nanonetworks in water were determined to be 193.5, 233.1, and 196.5 nm, respectively (Figure 2a). Protein-Fe-GA nanonetworks were dispersed in different buffer solution (10 mM, pH=4.0, 5.0, 7.0, 7.4, and 8.0) for the zeta potential test. The zeta potential values of BSA-Fe-GA, OVA-Fe-GA and HSA-Fe-GA 8


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nanonetworks were around -20 to -30 mV in neutral and weak alkaline environment due to abundant carboxyl groups in protein and GA (Figure 2d, Supporting Information, Figure S4a). The presence of BSA and GA in the prepared protein-Fe-GA nanonetworks was verified by their characteristic bands in FT-IR spectra. -CH2- symmetrical vibrations at 2932 cm-1, amide I (mainly C=O stretching vibrations) at 1654 cm-1 and amide II (coupling of bending vibrations of N-H and stretching vibrations of C-N) bands at 1534 cm-1 were all corresponding to BSA in BSA-Fe-GA nanonetworks. The characteristic peak at 1265 cm-1 (C-O stretch) and 1026 cm-1 (O-H in-plane deformation) of GA confirmed the incorporation of GA in BSA-Fe-GA nanonetworks. Besides, the disappearance of characteristic peak at 3,283 cm-1 (O-H stretching) of GA indicated the coordination interaction between the phenolic groups and carboxylic groups in GA and Fe3+ in BSA-Fe-GA nanonetworks (Figure 1b).71 FT-IR spectra of GA, HSA, OVA, OVA-Fe-GA, and HSA-Fe-GA nanonetworks also proved the successful incorporation of HSA, OVA into Fe-GA coordination polymers (Supporting Information, Figure S3a-b). BSA-Fe-GA nanonetworks had a strong NIR absorbance resulting from the strong delocalization in the π-electron structure, benefiting the high photothermal efficacy under an 808-nm light irradiation.43 Even at a low concentration at 0.1 mg/mL, the absorbance of BSA-Fe-GA nanonetworks at 808 nm could reach around 0.3 (Figure 1c). The extinction coefficient of the proposed BSA-Fe-GA nanonetworks was 2.902 L·g-1·cm-1, which was 7.5 times larger than that of ultrasmall BSA-Fe-GA 9



nanoparticles (0.388 L·g-1·cm-1) at 808 nm wavelength (Figure 1d, Supporting Information, Figure S8).67-68, 72 The UV-Vis-NIR absorption spectra and extinction coefficient of OVA-Fe-GA and HSA-Fe-GA nanonetworks both revealed similar NIR absorbance to that of BSA-Fe-GA nanonetworks, testifying the universality of proposed method (Supporting Information, Figure S5a-b, Figure S6a). The content of Fe in the proposed BSA-Fe-GA, OVA-Fe-GA, and HSA-Fe-GA nanonetworks were determined to be 16.6%, 17.7%, and 18.8% (w/w), respectively. The high loading of Fe-GA complex ensured the intense NIR absorption of the proposed BSA-Fe-GA nanonetworks.

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Figure 1. Characterization of the BSA-Fe-GA nanonetworks. (a) TEM image of BSA-Fe-GA nanonetworks. Scale bar: 200 nm. (b) FT-IR spectra of BSA, GA and BSA-Fe-GA nanonetworks. (c) UV-vis-NIR absorption spectra of BSA-Fe-GA nanonetworks solution with different concentrations (0.1, 0.2, 0.3, and 0.4 mg/mL). (d) UV-vis-NIR absorbance at 808 nm as function of gradient concentrations of BSA-Fe-GA nanonetworks and ultrasmall BSA-Fe-GA. (e) Photothermal heating curves of pure water and different concentrations of BSA-Fe-GA nanonetworks (0.1, 11



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0.2, and 0.4 mg/mL) under an 808-nm laser irradiation (2 W/cm2) for 10 min. (f) Temperature elevation of BSA-Fe-GA nanonetworks over four LASER ON/OFF cycles with an 808 nm laser irradiation at a power density of 2 W/cm2 (LASER ON time: 10 min; LASER OFF time: 10 min). Long-term

Colloidal

Stability

of

Protein-Fe-GA

Nanonetworks.

The

as-prepared BSA-Fe-GA nanonetworks can be easily dissolved in various media including water, PBS (10 mM, pH=7.4), normal saline, 1640 culture medium, DMEM culture medium and fetal bovine serum (FBS), and no apparent precipitation was observed for 0.1 mg/mL of BSA-Fe-GA nanonetworks for 20 days. The hydrodynamic size of BSA-Fe-GA nanonetworks exhibited no obvious change during 20 days, further confirming their long-term colloidal stability (Figure 2b-c). We further evaluated the colloidal stability of protein-Fe-GA nanonetworks in buffer solution with different pH values. Owing to the protein isoelectric point at around 4.8, precipitate appeared in the protein-Fe-GA solution when pH value was 4.0 or 5.0. However, no apparent precipitation and obvious hydrodynamic diameter change were observed for BSA-Fe-GA and OVA-Fe-GA nanonetworks dispersed in phosphate buffer solution (10 mM, pH=7.0, 7.4, and 8.0) for 20 days, further indicating their long-term colloidal stability in the simulated physiological environment (Supporting Information, Figure S4b-d). HSA-Fe-GA nanonetworks showed a relatively large hydrodynamic size and poor colloidal stability, which is probably attributed to the

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small chemical structure difference between BSA and HSA (Supporting Information, Figure S4e).

Figure 2. Colloidal properties of protein-Fe-GA nanonetworks. (a) Hydrodynamic sizes of BSA-Fe-GA, OVA-Fe-GA, and HSA-Fe-GA nanonetworks dispersed in pure water. (b) Monitoring the hydrodynamic size change of BSA-Fe-GA nanonetworks during 20 days. (c) The photos of 0.1 mg/mL BSA-Fe-GA nanonetworks dispersed in different media (from left to right: water, PBS, normal saline, 1640 culture media, DMEM culture media and FBS) for 20 days. (d) Zeta potential of 0.1 mg/mL BSA-Fe-GA, OVA-Fe-GA, and HSA-Fe-GA nanonetworks dispersed in PBS (pH=7.4, 10 mM). BFG, OFG and HFG mean the abbreviation of BSA-Fe-GA, OVA-Fe-GA, and HSA-Fe-GA.

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Cytotoxicity of BSA-Fe-GA Nanonetworks. The cytotoxicity of BSA-Fe-GA nanonetworks was investigated by a standard cellular methyl thiazolyl tetrazolium (MTT) assay. 4T1, DC2.4, and RAW264.7 cells were incubated with different concentrations of BSA-Fe-GA nanonetworks ranging from 0 to 400 μg/mL. High cell viability (over 70%) was observed after the treatment of different concentrations of BSA-Fe-GA nanonetworks ranging from 0 to 400 μg/mL, demonstrating the low cytotoxicity of BSA-Fe-GA nanonetworks (Figure 4a, Supporting Information, Figure S9a). In Vitro Cellular Uptake Test. To investigate the in vitro cellular distribution of protein-Fe-GA nanonetworks, the Fe content in cells were determined after different treatments and the results revealed that in vitro DC2.4 and RAW264.7 cells can internalize OVA-Fe-GA and BSA-Fe-GA nanonetworks in a concentration and time dependent manner (Figure S9c-d). Such an effective phagocytosis of protein-Fe-GA nanonetworks in vitro ensured their potential for the immune activation. The Immune Activation of OVA-Fe-GA Nanonetworks in Vitro. OVA as model antigen has been widely applied to elicit immune response.73-75 To verify the function of OVA in the fabricated nanonetworks, we typically investigated the immune activation effect of OVA-Fe-GA nanonetworks via co-stimulatory molecules expression and cytokines secretion of DC2.4 and RAW264.7 cells.76 Before flow cytometry quantification and ELISA analysis were performed, the cytotoxicity of OVA-Fe-GA nanonetworks towards immune cells was also investigated by the 14


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standard cellular MTT assay. DC2.4 and RAW264.7 cells were incubated with different concentrations of OVA-Fe-GA nanonetworks ranging from 0 to 400 μg/mL, and the MTT results clearly showed the low cytotoxicity of OVA-Fe-GA nanonetworks

(Supporting

Information,

Figure

S9b). The capability

of

OVA-Fe-GA nanonetworks inducing DCs and macrophages maturation was evaluated by up-regulation of costimulatory molecules CD80 and CD83 on their membrane. CD80 can recognize and bind to B7 molecules on the T cells, providing the “second signal” for T cell activation. CD83 can modulate the maturity of DC and macrophage and further activate T cell and B cell. Taken together, increase expression of CD80 and CD83 molecules could be recognized as important markers for immune cells maturation.77 The percentages of mature DCs expressing CD80 increased from 1.37% to 18.4%, and CD83 increased from 1.36% to 13.1% after incubation with 200 μg/mL of OVA-Fe-GA nanonetworks, respectively (Figure 3a-b, Supporting Information, Figure S10). We further carried out the same immune activation experiments on RAW264.7 cells, and the percentages of mature RAW264.7 cells with costimulatory molecules expression were determined to be 4.91% and 11.7% for CD80 and for CD83 after incubation with 200 μg/mL of OVA-Fe-GA nanonetworks, respectively (Figure 3e-f, Supporting Information, Figure S11). The CD80 and CD83 expression levels induced by OVA-Fe-GA nanonetworks in DC2.4 and RAW264.7 cells were both superior to that resulted from pure OVA at the same concentration. ELISA quantification of IL-6 and TNF-α inflammatory cytokines secretion of DC2.4 15



and RAW264.7 cells incubated with pure OVA, OVA-Fe-GA and LPS for 24 h demonstrated that OVA-Fe-GA nanonetworks could induce higher levels of cytokines secretion compared with pure OVA (Figure 3c-d, g-h). Such evident immune responses in vitro manifested the sufficient immune activation capability of OVA-Fe-GA nanonetworks, which showed great potential in nanovaccine-based immunotherapy. In addition, BSA-Fe-GA nanonetworks also exhibited a stronger immunoactivation effect than free BSA, which serves as an exogenous antigen for DC2.4 and RAW264.7 cells (Supporting Information, Figure S10- Figure S12).78

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Figure 3. Immune stimulation effect of OVA-Fe-GA nanonetworks in vitro. The expressions of the co-stimulatory molecules of CD80 (a) and CD83 (b) in DC2.4 and CD80 (e) and CD83 (f) in RAW264.7 cells incubated with OVA, OVA-Fe-GA, and LPS for 24 h, respectively. IL-6 (c) and TNF-α (d) inflammatory cytokines secreted 17



by DC2.4, and IL-6 (g) and TNF-α (h) inflammatory cytokines secreted by RAW264.7 cells co-cultured with OVA, OVA-Fe-GA, and LPS for 24 h, respectively. Photothermal Performance of Protein-Fe-GA Nanonetworks. To evaluate the photothermal performance of the designed nanonetworks, pure water and BSA-Fe-GA nanonetworks were both irradiated by an 808-nm laser (2 W/cm2) for 10 min. The concentration dependent temperature elevation was observed, and the temperature of 0.4 mg/mL BSA-Fe-GA nanonetworks can raise by 23.6 °C, while pure water only showed a slight temperature change of 4.7 °C (Figure 1e). Besides, BSA-Fe-GA nanonetworks exhibited excellent photothermal stability, and maximum temperature increase kept over 20 ℃ during four LASER ON/OFF cycles with an 808-nm laser irradiation (Figure 1f). The excellent photothermal heating effect of HSA-Fe-GA and OVA-Fe-GA nanonetworks were also confirmed by the fact of remarkable temperature increase, and the temperature of 0.4 mg/mL of HSA-Fe-GA and OVA-Fe-GA nanonetworks can raise by 22.2 and 27.6 ℃, respectively (Supporting Information, Figure S5c-d). The infrared thermal photos further intuitively proved the outstanding photothermal effect of BSA-Fe-GA, HSA-Fe-GA, and OVA-Fe-GA nanonetworks (Supporting Information, Figure S6b). The photothermal conversion efficiency (η) was measured according to the precious work.79 The 808 nm laser heat conversion efficiencies (η) of the as-synthesized BSA-Fe-GA, OVA-Fe-GA, and HSA-Fe-GA nanonetworks are further calculated to be 20.33%, 18.76%, and 14.66%, respectively (Supporting Information, Figure S7). Therefore, the as-prepared 18


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protein-Fe-GA nanonetworks with high photothermal efficiency could serve as effective photothermal agents to ablate tumors. In Vitro Photothermal Therapy of BSA-Fe-GA Nanonetworks towards 4T1 Tumor Cells. The photothermal therapy in vitro was assessed by 4T1 cells incubated with BSA-Fe-GA nanonetworks and irradiated by an 808-nm laser for 10 min. MTT assay revealed that the cell viability with the treatment of the networks or laser irradiation alone was similar to the negative control group. However, the cell viability witnessed obvious reduction with the combined treatments of BSA-Fe-GA nanonetworks and laser irradiation. Majority of 4T1 cells were destroyed after the incubation with 400 μg/mL of BSA-Fe-GA nanonetworks under an 808-nm laser irradiation at a power density of 2 W/cm2 (Figure 4b). Ultimate temperature of 4T1 cells with different treatments after 10 min were measured by an infrared thermometer camera, indicating distinct temperature rise after PTT (Figure 4c-d). Moreover, live/dead cell dual staining was carried out to intuitively assess the photothermal therapy efficacy. The fluorescence images of cells co-stained by calcine acetoxymethyl ester (Calcine AM) and propidium iodide (PI), which differentiated the live (shown in green) and dead cells (shown in red), also proved the remarkable photothermal therapy effect of BSA-Fe-GA nanonetworks (Figure 4e).

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Figure 4. Photothermal performance of BSA-Fe-GA nanonetworks in vitro. (a) MTT assay of 4T1 cells after incubation with different concentrations (0 to 400 μg/mL) of BSA-Fe-GA nanonetworks. (b) 4T1 cell viability after incubation with 0, 200, and 400 μg/mL of BSA-Fe-GA nanonetworks under an 808-nm laser irradiation at power densities of 0, 0.5, 1, and 2 W/cm2, n=3, *p < 0.05. The infrared thermal photos (c) and terminal temperature (d) of 4T1 cells in a 96-well plate incubated with 0, 200, and 400 μg/mL of BSA-Fe-GA nanonetworks under an 808-nm laser irradiation at power densities of 0, 0.5, 1, and 2 W/cm2 for 10 min. (e) 4T1 cells were 20


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exposed to 0, 200, and 400 μg/mL of BSA-Fe-GA nanonetworks and an 808-nm laser irradiation at power densities of 0, 0.5, 1, and 2 W/cm2 for 10 min, and then live and dead cells were stained with calcein AM and PI to be green and red, respectively. In Vivo Photothermal Therapy of BSA-Fe-GA Nanonetworks. The BALB/C mice with xenografts 4T1 cells were randomly divided into 3 groups (n=3) for different treatments, and BSA-Fe-GA nanonetworks or PBS were intratumorally injected to the mice. The temperature of tumor surface could raise by 37.2 ℃ and reach to 65.8 °C after the treatment of BSA-Fe-GA nanonetworks plus laser irradiation for 10 min, which was high enough to kill tumor cells. In contrast, the tumor in mice treated with PBS (10 mM, pH=7.4) plus laser irradiation only exhibited slight temperature increasement by 8.4 °C (Figure 5a, Supporting Information, Figure S13). The digital photographs of 4T1 tumor-bearing mice at different time points (0, 3, 6, 21 and 30 d) intuitively confirmed the complete eradication of tumor by BSA-Fe-GA nanonetworks plus irradiation (Figure 5d). The average relative tumor volume (V/V0) change of different treatments during 30 days manifested the extraordinary photothermal tumor ablation effect of BSA-Fe-GA nanonetworks (Figure 5b). The largest tumors growth occurred in mice treated with BSA-Fe-GA nanonetworks alone, and the mice treated with PBS plus laser irradiation displayed insufficient thermal therapeutic effect towards tumors. Complete tumors ablation and no more tumors recurrence were observed with the treatment of BSA-Fe-GA nanonetworks plus laser irradiation. The radio change of tumors weight to body 21



weight of the mice in each group also indicated the remarkable photothermal therapeutic effect of BSA-Fe-GA nanonetworks (Figure 5c). These results proved the admirable photothermal therapy efficacy of BSA-Fe-GA nanonetworks in vivo.

Figure 5. Photothermal therapy effects of BSA-Fe-GA nanonetworks in mice. (a) Infrared thermal images of mice bearing 4T1 tumors before and after intratumorally injection of PBS (10 mM, pH=7.4) and BSA-Fe-GA nanonetworks (13.2 mg/mL) under an 808-nm laser irradiation at a power density of 0.5 W cm/2 for 10 min. (b) The average relative tumor volume (V/V0) change after diverse treatments, shown as means ± SD, *p < 0.05. (c) The ratio of tumors weight to body weight of mice in each group, shown as means ± SD, *p < 0.05. (d) The digital photographs of 4T1 22


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tumor-bearing mice at different time points (0, 3, 6, 21 and 30 d) after different treatments with PBS + L, BFG alone, and BFG + L. L means laser irradiation (808 nm, 0.5 W/cm2, 10 min). BFG: BSA-Fe-GA. TW: Tumor Weight; BW: Body Weight.

Figure 6. The toxicity of BSA-Fe-GA nanonetworks in vivo. Representative hematoxylin and eosin (H&E) stained tissue sections of major organs including heart, liver, spleen, kidney and tumor of BALB/C mice after different treatments. Scale bar: 100 μm. L: laser irradiation (808 nm, 0.5 W/cm2, 10 min); BFG: BSA-Fe-GA. The BSA-Fe-GA nanonetworks-based therapy did not cause notable body weight decline, showing their good biocompatibility in vivo (Supporting Information, Figure S14). To further study the potential toxicity of the BSA-Fe-GA nanonetworks in vivo, hematoxylin and eosin staining (H&E staining) of different organs including heart, liver, spleen and kidney, and tumor of mice were carried out after diverse treatments (Figure 6). No morphological changes, inflammation, cell apoptosis or necrosis were observed in the heart, liver, spleen, and kidney of mice in each group. No tumor tissue was found in mice treated with BSA-Fe-GA nanonetworks plus laser irradiation. On the contrary, the tumor tissue slices of mice treated with PBS plus 23



laser irradiation and BSA-Fe-GA nanonetworks alone both illustrated a large quantity of tumor cells without obvious necrosis. These data indicated that BSA-Fe-GA nanonetworks not only possessed a powerful photothermal therapeutic effect in vivo, but also exhibited good biocompatibility. CONCLUSIONS In summary, we reported functional protein-assisted fabrication of Fe-GA nanonetworks for localized photothermal therapy. The proposed BSA-Fe-GA nanonetworks not only possessed a unique network structure with appropriate size around 200 nm, minimizing the leakage to surrounding normal tissues after localized administration, but also exhibited favorable NIR absorbance and impressive photothermal performance. Moreover, the proposed BSA-Fe-GA nanonetworks showed excellent biocompatibility due to intrinsic biosafety of the precursors, and were successfully applied in localized photothermal therapy in vitro and in vivo. This universal design can be readily extended to fabricate coordination polymers using other functional proteins, such as HSA and OVA. The formed HSA-Fe-GA and OVA-Fe-GA nanonetworks also exhibited excellent photothermal effect due to their intense NIR absorption. Moreover, the immune activity of OVA in OVA-Fe-GA nanonetworks was retained efficiently due to the mild synthesis condition, and the OVA-Fe-GA nanonetworks can induce the maturation of DC2.4 and RAW264.7 cells efficiently, showing great potential in the development of multifunctional nanovaccine. We believe the proposed functional protein assisted-synthesis strategy 24


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lays down a novel and universal way for the integration of functional proteins with coordination polymers for advanced applications. EXPERIMENTAL SECTION Reagents and Materials.

The chemical materials were all at least of analysis

grade. Bovine serum albumin (BSA) and human serum albumin (HSA) were purchased from Beijing Dingguo Biotechnology Co., Ltd. (Beijing, China). Ovalbumin (OVA) was obtained from Sigma-Aldrich Corporation (Shanghai, China). FeCl3·6H2O, sodium hydroxide (NaOH), Methyl thiazolyl tetrazolium (MTT) and Gallic acid (GA) were provided by Aladdin Reagent Co., Ltd. (Shanghai, China). Ultrapure water (Hangzhou Wahaha Group Co., Ltd.) was used throughout the synthesis procedure. Dimethyl sulfoxide (DMSO) and paraformaldehyde were purchased from Concord Technology (Tianjin, China). Calcein acetoxymethyl ester (Calcein AM) and propidium iodide (PI) were obtained from dojindo laboratories

(Shanghai, China). Anti-Mouse CD80 FITC-conjugated and CD83 PE-conjugated antibodies were purchased from eBioscience. Mouse IL-6 and TNF-α ELISA kit were obtained from MultiSciences (Lianke) Biotech Co., Ltd. (Hangzhou, China). Characterization.

The

Fe

element

content

was

quantified

by

inductively coupled plasma-atomic emission spectrometry (ICP-AES, Thermo IRIS Advantage). The size and zeta potential of protein-Fe-GA nanonetworks were determined on a Malvern Zetasizer (Nano series ZS, UK). The size and morphology of the prepared nanonetworks were characterized by a Hitachi HT7700 transmission 25



electron microscopy (TEM) (Hitachi HT7700, Japan). Fourier transform-infrared (FT-IR) spectra (of 400-4000 cm-1) of the nanonetworks were recorded with pure KBr as the background via a Nicolet IR AVATAR-360 spectrometer (Nicolet, USA). The infrared thermal photos were taken by infrared thermometer camera (FLIR E50 seires, USA). The absorption spectra of protein-Fe-GA nanonetworks were determined by a UV-3600 plus spectrophotometer (Hitachi, Japan). Preparation of Protein-Fe-GA Nanonetworks. 60 mg of protein (BSA, OVA, or HSA) and 80 mg of FeCl3·6H2O were dispersed in 15 mL ultrapure water under gentle magnetic stirring for 3 min, and then 1 mL of NaOH (1 M) was added to adjust pH to 9. After stirring for 0.5 h, GA aqueous solution (4 mL, 10 mg/mL) was introduced to the mixture and reacted for another 10 h. The obtained protein-Fe-GA nanonetworks were purified by dialysis (molecular weight cut-off is 8-14 kDa). Then the purified nanonetworks were stored at 4 ℃ for following use. Long-term Colloidal Stability. 0.1 mg/mL of BSA-Fe-GA nanonetworks were dispersed in ultrapure water, PBS (10 mM, pH =7.4), normal saline, Gibco 1640 culture medium, Gibco DMEM culture medium, and fetal bovine serum (FBS), and their photos were then taken during 20 days. The hydrodynamic sizes of BSA-Fe-GA nanonetworks dissolved in water at different time points were also recorded. To further investigate the influence of pH on the colloidal stability of different protein-Fe-GA nanonetworks, 0.1 mg/mL of BSA-Fe-GA, OVA-Fe-GA, and HSA-Fe-GA nanonetworks were dispersed in different buffer solution including 26


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sodium acetate-acetic acid buffer solution (10 mM, pH=4.0 and 5.0) and phosphate buffer solution (10 mM, pH=7.0, 7.4, and 8.0), and their photos were then taken during 20 days. The hydrodynamic sizes of BSA-Fe-GA, OVA-Fe-GA, and HSA-Fe-GA nanonetworks in different buffer solution at different time points were also recorded. Measurement of the Extinction Coefficient at 808 nm of Protein-Fe-GA Nanonetworks. The NIR absorbance in protein-Fe-GA nanonetworks with different concentrations were determined by a UV-3600 plus spectrophotometer. The extinction coefficient at 808 nm was then calculated according to the Lambert-Beer law (A/L = αC, where A is the absorption intensity, L is the length of the cuvette, C is the concentration, and α is the extinction coefficient). Assessment of Photothermal Performance. Different concentrations (0.1, 0.2, 0.4 mg/mL) of BSA-Fe-GA nanonetworks and ultrapure water were irradiated with an 808-nm laser irradiation (2 W/cm2) for 10 min. HSA-Fe-GA and OVA-Fe-GA nanonetworks solution were also irradiated with the same parameters. Temperature increase of pure water and protein-Fe-GA nanonetworks (0.1, 0.2, 0.4 mg/mL) was recorded by an infrared thermometer camera during the photothermal heating process. Magnetic stirring was necessary to ensure the homogeneity of heat distribution. To calculate the photothermal conversion efficiency, protein-Fe-GA solutions (0.4 mg/mL) were irradiated with an 808 nm laser (2 W/cm2) until the solution temperature reached a steady state. Then the solution naturally cooled down to the 27



Page 28 of 46

ambient temperature after the stoppage of laser irradiation. The photothermal conversion efficiency (η) of protein-Fe-GA nanonetworks were calculated as follow equation: 𝜂=

ℎ𝑠(𝑇𝑚𝑎𝑥 ― 𝑇𝑠𝑢𝑟𝑟) ― 𝑄0 𝐼(1 ― 10 ―𝐴)

(1)

where h is the heat transfer coefficient and s is the surface area of the container. Tmax-Tsurr is the temperature change of the protein-Fe-GA solution at the maximum steady-ambient temperature. Q0 represents heat dissipated from light absorbed by the solvent and the container. I is the power density of the laser, and A is the absorbance of protein-Fe-GA at 808 nm. In Vitro Cytotoxicity Assay. The cytotoxicity of BSA-Fe-GA and OVA-Fe-GA nanonetworks were evaluated by 4T1 cells and immune cells (DC2.4 and RAW264.7 cells), respectively. 4T1 cells were cultured in Gibco DMEM with 10% FBS, and 1% streptomycin-penicillin in an atmosphere of 5% CO2 at 37 °C. DC2.4 and RAW264.7 cells were cultured in Gibco DMEM with 10% FBS, 1% streptomycin-penicillin, and 1% L-Glutamine in an atmosphere of 5% CO2 at 37 °C. The cells were seeded in a 96-well plate at density of 1 × 104 per well. After 24 h, the cells were washed by PBS (10 mM, pH=7.4) to remove dead cells, and incubated with by fresh media containing BSA-Fe-GA and OVA-Fe-GA nanonetworks with different concentrations for another 24-h incubation. After washed with PBS again, the cells were treated with fresh medium containing MTT (10 μL, 5 mg/mL), and then incubated for 4 h in an atmosphere of 5% CO2 at 37 °C. Then 120 μL of DMSO was respectively added into 28


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each well to replace the media and dissolved the purple formazan crystals. After a 10-min gentle shaking, the absorbance of each well at 490 nm was recorded by a microplate reader (Bio-tek, USA). The cell viabilities were calculated according to the following formula. 𝐶𝑒𝑙𝑙 𝑣𝑖𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = 𝑂𝐷𝑒𝑥𝑝 𝑂𝐷 × 100% 𝑐𝑜𝑛

(2)

ODexp and ODcon are the optical density (OD) for cells treated with different concentrations of nanonetworks and cells in control group, respectively. In Vitro Cellular Uptake Test. The cellular uptake of protein-Fe-GA by DC2.4 and RAW264.7 cells was investigated by ICP-AES measurement of Fe content in cells. Briefly, DC2.4 and RAW264.7 cells were seeded in 12-well plates with a density of 5 × 105 cells per well. After 24 h, the cells were washed by PBS (10 mM, pH=7.4) to remove dead cells, and incubated with by fresh media containing BSA-Fe-GA and OVA-Fe-GA nanonetworks with different concentrations (0, 100, 200, and 400 mg/L) for different incubation time (8, 12, and 24 h). After that, each group of cells was washed with PBS three times. Then, the cells in each well were processed with aqua regia for 2 days and then diluted with water to 4 mL for ICP-AES test. In Vitro Activation and Maturation of Immune Cells Induced by OVA-Fe-GA and BSA-Fe-GA Nanonetworks. Immature immune cells including DC2.4 and RAW264.7 were seeded in a 12-well plate at a density of 5 × 105 per well, and cultured for 24 h. Then cells were washed with PBS and treated with fresh culture 29



media containing OVA, BSA, OVA-Fe-GA, BSA-Fe-GA, and LPS for another 24 h, respectively. The cell culture supernatants were collected together and then purified by centrifugation for 3 min at 1000 rpm. The obtained supernatants were stored at -80 °C for following analysis. The amounts of pro-inflammatory cytokines IL-6 and TNF-α released by cells after different treatments were analyzed by ELISA according to the manufacturer's directions. Then cells were subsequently washed with PBS and stained with FITC-conjugated anti-CD80 and PE-conjugated anti-CD83 antibodies for 1 h at 4 °C. After washed 3 times by PBS and dispersed with 200 μL of PBS again, these labeled cells were then collected for flow cytometry. In Vitro Photothermal Therapy of 4T1 Cells with BSA-Fe-GA Nanonetworks. 4T1 cells were seeded in a 96-well plate at a density of 1 × 104 per well and cultured in an atmosphere of 5% CO2 at 37 °C for 24 h. Then the cells were incubated with different concentrations of BSA-Fe-GA nanonetworks (0, 200, and 400 μg/mL) for 1 h, following by an 808-nm laser irradiation at a power density of 0, 0.5, 1, and 2 W/cm2 for 10 min. The infrared thermal photos of cells with different treatments were recorded by an infrared thermometer camera. The cell viabilities were investigated by a standard MTT assay as aforementioned. Calcein acetoxymethyl ester (Calcein AM) and propidium iodide (PI) were used to stain live and dead cells after different treatments. After incubation for 15 min, each well was washed twice with PBS carefully to remove dyes completely. The fluorescence images were obtained on an inverted fluorescence microscope. 30


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Animal Model. The tumor models were established by the subcutaneous planting of 4T1 cells onto the back of the BALB/C mice (15-18 g, HFK Bioscience Co., Ltd., Beijing,

China).

When

the

tumor

size

reached

5-7

mm

in

diameter,

in vivo photothermal therapy was carried out on the mice. In

Vivo

Photothermal

Therapy

of

BSA-Fe-GA

Nanonetworks.

The

tumor-bearing mice were randomly divided into 3 groups (A, B, C) with 3 mice in each group. The mice in different groups were treated as follows: A: intratumorally injection with 50 μL of PBS (10 mM, pH=7.4) + 808-nm laser irradiation (0.5 W/cm2 for 10 min); B: intratumorally injection with 50 μL of BSA-Fe-GA nanonetworks solution (13.2 mg/mL); C: intratumorally injection with 50 μL of BSA-Fe-GA nanonetworks solution (13.2 mg/mL) + 808-nm laser irradiation (0.5 W/cm2 for 10 min). The photothermal heating effect on 4T1 tumor-bearing mice in group A and C were recorded by an infrared thermometer camera during laser irradiation. Body weight, tumor sizes and digital photos of 4T1 tumor-bearing mice after different treatments were recorded for 30 days. Heart, liver, spleen, kidney, and tumor were dissected from the sacrificial mice and then processed with 4% formaldehyde on the 30th day and disposed with a typical H&E staining procedure to study pathologic changes. Statistical Analysis. The data are presented as the means ± standard deviation (SD). The comparison between groups was analyzed with two-tailed t tests or

31



one-way ANOVA. Differences were considered statistically significant when the p values were less than 0.05 (p < 0.05). ASSOCIATED CONTENT Supporting Information The Supporting Information (Supporting Figure S1-14, Table S1) is available free of charge on the ACS Publications website at DOI: Optimization of experimental conditions, UV-vis-NIR absorbance, TEM, FT-IR, Zeta potential, Hydrodynamic size, Photothermal heating curves, Extinction coefficients fitting lines, Time constants, Infrared thermal photos, MTT assay, Flow cytometry quantification, ELISA quantification, and Average body weight. AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] (S.-K. Sun). *E-mail: [email protected] (D. Li). ORCID Shao-Kai Sun: 0000-0001-6136-9969 Notes The authors declare no competing financial interest.

32


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ACKNOWLEDGMENTS Y. Q. Wang and J. Zhang contributed equally to this work. This work was supported by the financial support from the National Natural Science Foundation of China (Grants 21435001 and 21874101) and Natural Science Foundation of Tianjin City (No. 18JCYBJC20800). REFERENCES (1) Zou, L.; Wang, H.; He, B.; Zeng, L.; Tan, T.; Cao, H.; He, X.; Zhang, Z.; Guo, S.; Li, Y., Current Approaches of Photothermal Therapy in Treating Cancer Metastasis with Nanotherapeutics. Theranostics 2016, 6 (6), 762-772, DOI 10.7150/thno.14988 (2) Cheng, L.; Wang, C.; Feng, L.; Yang, K.; Liu, Z., Functional Nanomaterials for Phototherapies of Cancer. Chem. Rev. 2014, 114 (21), 10869-10939, DOI 10.1021/cr400532z (3) Melancon, M. P.; Zhou, M.; Li, C., Cancer theranostics with near-infrared light-activatable multimodal nanoparticles. Acc. Chem. Res. 2011, 44 (10), 947-956, DOI 10.1021/ar200022e (4) Wang, C.; Xu, L.; Liang, C.; Xiang, J.; Peng, R.; Liu, Z., Immunological responses triggered by photothermal therapy with carbon nanotubes in combination with anti-CTLA-4 therapy to inhibit cancer metastasis. Adv. Mater. 2014, 26 (48), 8154-8162, DOI 10.1002/adma.201402996 (5) Liang, C.; Diao, S.; Wang, C.; Gong, H.; Liu, T.; Hong, G.; Shi, X.; Dai, H.; Liu, Z., Tumor metastasis inhibition by imaging-guided photothermal therapy with single-walled carbon nanotubes. Adv. Mater. 2014, 26 (32), 5646-5652, DOI 10.1002/adma.201401825

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For Table of Contents Use Only

Synopsis: Multifunctional coordination polymer nanonetworks are fabricated using the precursors from nature for advanced biological applications.

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Functional-Protein-Assisted Fabrication of FeâGallic Acid

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Functional-Protein-Assisted Fabrication of FeâGallic Acid