Application of Triarylboron Substituted with Cyclic ArginineâGlycine

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Application of triarylboron substituted with cyclic RGD motifs as a multivalent two-photon fluorescent probe for tumor imaging in vivo Jun Liu, Kai Cheng, Chenwu Yang, Jiang Zhu, Chengyi Shen, Xiaoming Zhang, Xuan Liu, and Guoqiang Yang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b01324 • Publication Date (Web): 12 Apr 2019 Downloaded from http://pubs.acs.org on April 12, 2019

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Analytical Chemistry

Application of triarylboron substituted with cyclic RGD motifs as a multivalent two-photon fluorescent probe for tumor imaging in vivo Jun Liu, a Kai Cheng, a Chenwu Yang, a Jiang Zhu, a Chengyi Shen, a Xiaoming Zhang,*a, d Xuan Liu *b and Guoqiang Yang*c a

Sichuan Key Laboratory of Medical Imaging, Affiliated Hospital of North Sichuan Medical College & Department of Chemistry, School of Preclinical Medicine, North Sichuan Medical College, Nanchong, 637000 China. E-mail: [email protected] (X. Z.); Fax: (+86) 081-7335-2031. b

School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201 China. Email: [email protected] (X. L.); Fax: (+86) 0731-5829-0045. Key laboratory of Photochemistry, Institute of Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100190, China. E-mail: [email protected] (G. Y.); Fax: (+86) 010-8261-7315. c

d Department

of radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000 China.

ABSTRACT: Detection of cancer in its early stages is difficult, and this is a major issue that impairs the timely diagnosis and treatment of tumors. Integrin αVβ3 is expressed on tumoral endothelial cells, as well as other tumor cells. By functionalizing the triarylboron (TAB) compound with multiple cyclic RGD (cRGD) motifs, which specifically bind to integrin αVβ3, a multivalent two-photon fluorescent probe TAB-3-cRGD was designed and chemically synthesized. Through cell imaging experiments, we showed that TAB-3-cRGD can selectively bind to integrin αVβ3 on the cell surface and can effectively distinguish normal cells from tumor cells overexpressing integrin αVβ3. Using a mouse model, we also showed that TAB-3-cRGD could target the tumor site in vivo, offering a promising tool for cancer detection.

INTRODUCTION Cancer is a deadly disease that threatens human health worldwide. At present, over 7 million cancer-related deaths are estimated to occur every year and this number is predicted to increase to 11 million by 2030. 1 One of the most important factors markedly influencing cancer mortality is the difficulty of detecting cancer at an early stage, when tumors are treatable and prior to the onset of metastasis and cancer cell diffusion. 2 The cytopathological and histopathological examination of biopsies is usually reliable when the disease has progressed to its middle or late stages. 3-5 Another challenge of cancer treatment is the persistence of cancerous cells and recurrence of cancer, particularly when tumors cannot be removed completely by surgery. The specificity and sensitivity of conventional imaging techniques, such as endoscopic ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), are insufficient to detect tumors less than 2 cm in diameter and it is difficult to distinguish between benign and malignant tumors. 6 Therefore, there are considerable efforts in the research community to develop new methods for the early and/or accurate diagnosis of cancer. Fluorescence imaging technology using small molecular fluorescence probes has many advantages, including high sensitivity, good selectivity, high resolution, non-invasive real-time monitoring capability, naked eye visibility and nonradioactivity, and, therefore, it is which provides a promising strategy for the selective visualization of malignant tumors. 7

Several fluorescent probes targeting tumors have been developed using fluorophores, such as boron-dipyrromethene and aggregation-induced emission. 8-10 To design cancer targeting small molecular probes, enzymes or proteins that are overexpressed in cancer cells are commonly chosen as targets and molecules capable of selectively interacting with the targets serve as targeting groups. Targeted fluorescent probes can be constructed by modifying fluorescent molecules with targeting groups. 11, 12 For example, integrin αVβ3 is an essential cell adhesion receptor that is overexpressed in tumor cells of different origins. 13 This protein mediates adhesive events during various stages of cancer, such as malignant transformation, tumor growth and progression, and cancer invasion, and metastasis. 14, 15 Therefore, αVβ3 can be used as a model target protein for early detection and treatment of rapidly growing solid tumors. Because αVβ3 can act as a unique receptor for the arginine−glycine−aspartic acid (RGD) motif, anticancer strategies based on RGD have been developed, including RGD-conjugated imaging probes and drug delivery systems. 16-18 Multivalent interactions are essential components for the mediation of biological processes and in the construction of complex (super)structures for material applications in supramolecular chemistry.19, 20 These interactions refer to the simultaneous binding of multiple ligands on one entity to multiple receptors on another and tend to be much stronger than the corresponding monovalent ligand receptor interactions, a phenomenon that is often necessary to regulate

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physiological processes. In recent years, the concept of the multivalent effect has also been applied to the construction of certain bioprobes, which can greatly improve the selectivity and sensitivity of probes. 21, 22 Π-Conjugated triarylboron (TAB) compounds are a new type of fluorophore, with three aromatic groups centered around a boron atom. 23, 24 The vacant pz orbital of the central boron can effectively conjugate with aromatic rings. When there is a strong electron donor group in the conjugated system, an intramolecular charge transfer (ICT) can be present, which usually demonstrates strong fluorescence. 25, 26 In recent years, we have developed TAB-based biological fluorescence probes for the detection of intracellular temperature, ATP, H2S, and organelles. 27-30 These studies demonstrate that TAB compounds have excellent photophysical properties, including a large two-photon cross section, high quantum yields, and extreme sensitivity to changes in their surroundings. These characteristics qualify the TAB compounds as an excellent signaling group. Furthermore, the three aromatic groups in their structure can be functionalized simultaneously to achieve the design of fluorescent probes demonstrating the multivalent effects. In this work, considering the high affinity and specificity of cyclic RGD (cRGD) to integrin αVβ3, we used the structural characteristics of TAB to integrate three cRGD units into a single molecule. As such, a novel cancer targeted fluorescence probe, TAB-3-cRGD, was designed and chemically synthesized (Figure 1). The multiple cRGD, as a whole, can combine with multiple integrin αVβ3 on the surface of cancer cells, resulting in multivalent interactions, which can endow the probe with good sensitivity and selectivity. Presence of the central TAB fluorophore ensures that the probe has good luminescent properties of the probe. Finally, the TAB-3-cRGD was applied for imaging cancer cells and tumor sites in a mouse tumor model.

Figure 1. Chemical structure of TAB-3-cRGD.

EXPERIMENTAL SECTION General information All chemical reagents were purchased from Beijing InnoChem Science & Technology Co

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(Beijing, China) and used without further purification. Absorption spectra were recorded on Hitachi UV-3010 (Hitachi, Tokyo, Japan). The fluorescence spectra were obtained on Hitachi F-7000 (Hitachi, Tokyo, Japan). Cells were analyzed using a confocal microscope (OLYMPUS FV 1000-IX81 for single-photon excited fluorescence, Olympus Corporation, Tokyo, Japan). 1H NMR spectra were obtained on BrukerAvance III 400 H (400 MHz) spectrometers (Bruker, Karlsruhe, Germany). In vivo small animal imaging system (In-Vivo MS FX PRO, Bruker, Germany). Prepararion of TAB-3-cRGD The synthetic route of TAB3-Cl is shown in Scheme S1 and the detail synthesis and characterization of all related compounds are also shown in Supplementary Information. TAB-3-Cl (4.05mg,0.005mmol) and cyclo[Arg-Gly-Asp-(D-Phe)-Cys] (cRGD) (8.67mg, 0.015mmol) was dissolved in CH3CN: H2O=1:1 (5mL) in the presence of potassium carbonate (2.1mg, 0.015mmol) with constant stirring at room temperature and for overnight. The mixture was further purified by dialyzing in water to afford TAB-3-cRGD 11.75mg (98%). Cell Culture and Viability Assay Human umbilical vein endothelial cells (HUVEC-1) were cultured in Bronchial Epithelial Cell Growth Medium supplemented with 10% fetal bovine serum (FBS). Malignant glioma cells (U87MG) and mouse fibroblast cells (NIH/3T3) were cultured in Dulbecco’s Modified Eagle Medium (DMEM) with glucose (4.5 g/L), Lglutamine, sodium pyruvate, and 10% fetal bovine serum (FBS). The cells were plated on glass bottomed dishes and incubated at 37 °C under a 5% CO2 atmosphere before imaging. Cells imaging were performed and the images were analyzed with the FV10-ASW software. Cells, pre-washed twice, were incubated with 10μM of TAB-3-cRGD in a cultured medium without FBS at 37°C under a 5% CO2 atmosphere for 15min. The cells were then washed six times with PBS to remove unbounded probes for six times before in situ imaging. NIH/3T3, HUVEC-1, U87MG cells were cultured on a 96well plate at a density of 10000 cells in each well, respectively. These cells were fistly incubated for 24 h. Then the medium was replaced with 200 μL of fresh medium containing varied concentrations of TAB-3-cRGD (from 0uM to 5uM) and these cells were cultured for another 24 h. washed with PBS for three times and replaced the medium with fresh medium (200 μL) containing MTT (0.5 mg/mL) and incubated for 4 h. The supernatant was removed, and 100 μL of DMSO was added to each well to dissolve the formed formazan and the absorbance of the solution was measured to assess the relative viability of the cells. The absorbance values (A) were recorded at a wavelength of 490 nm. Cell viability was calculated as A/A0 × 100% (A, A0 represent the absorbance of the experimental group and the control group, respectivley). Tumor model and In vivo imaging Nude mice 6-7 weeks old were provided by the Laboratory Animal Center of North Sichuan Medical College, Nanchong, China. All procedures involving animals were performed according to a protocol approved by the Institutional Animal Care and Treatment Committee of North Sichuan Medical College. These nude mice were subcutaneously injected with 1×106 U87MG cells in the right rear thigh under aseptic conditions. Then they were individually housed under specific pathogen-free conditions with free access to food and water until the formed tumor


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Analytical Chemistry grow to approximately 0.5cm in diameter by measuring caliper; tumor growth to this size took about a month. These tumor-bearing mice were fasting for 24h and then were anesthetized by intraperitoneal injection of 0.05mL 3% aqueous solution of pentobarbital. The mice were then placed into the small animal imager and injected intraperitoneally with a certain amount of probe solution for imaging.

RESULTS AND DISCUSSION The TAB-3-cRGD was synthesized according to the scheme S1 provided in the supporting information. We first synthesized TAB-3-Piperazine-Boc using the Suzuki coupling reaction. Subsequently, TAB-3-Piperazine-Boc was deprotected to generate TAB-3-Piperazine. The three active secondary amine groups of TAB-3-Piperazine were reacted with chloroacetyl chloride to produce TAB-3-Cl, which bears three active chlorines as reaction sites for the following step. Because the chloro groups in carbonyl ortho sites readily react with mercapto groups, we synthesized a sulfhydryl cRGD with a sequence of cyclo [ Arg-Gly-Asp-(D-Phe)-Cys] by using a polypeptide synthesizer and introduced it into the molecular structure of TAB-3-Cl to form TAB-3-cRGD. The nitrogen atoms conjugated with aromatic rings can function as strong electron donors to ensure the effective luminescence of ICT compounds. Because TAB-3-cRGD does not dissolve in low polarity solvents, its ICT properties were confirmed by analyzing the fluorescence spectra of its precursor TAB-3-Cl in various solvents with different polarities. Figure 2a-b shows the fluorescence spectra of TAB-3-Cl, which demonstrates a red shift with increasing polarity of solvents, a typical characteristic of ICT compounds. The solid powder of TAB-3cRGD does not dissolve in PBS, possibly because of the hydrogen bonds between the amide bonds of the cRGD groups, and a small amount of DMSO (0.1%) is needed to break the hydrogen bond and increase solubility. The similar UV absorption spectra of TAB-3-cRGD in PBS (containing 0.1%DMSO) and DMSO implies that TAB-3-cRGD was successfully dissolved and did not exist as nanoparticles, which would have an absorption spectrum with a tail. The fluorescence spectra of TAB-3-cRGD showed maximum emission at 490 nm in PBS and at 550 nm in DMSO (Figure 2c). The blueshift in PBS can be attributed to the RGD surrounding and isolating the central triarylboron fluorophore from the highly polar water environment, which offers a low polar microenvironment and ensures strong fluorescence from TAB-3-cRGD in PBS. This strong fluorescence of TAB-3cRGD makes it a good ‘always-on’ probe, which is advantageous for in vivo imaging. Compared to ‘turn on’ or ‘turn off’ probes, ‘always-on’ probes can be used conveniently to monitor the distribution of probes in various parts of the body. There was a good linear relationship between fluorescence intensity around 10 μ M of TAB-3-cRGD, excluding the possibility of reabsorption. (Figure S4a) Its ’ good photostability can also be confirmed by Figure S4b. Figure 2d show that TAB-3-cRGD demonstrate a large twophoton crosssection with 100GM at 770nm, which indicate it still maintains the excellent property of triarylboron compounds and make it a two-photon probe for bioimaging.

Figure 2. (a) UV absorption and (b) fluorescence spectra of TAB3-Cl in various solvents (10 μ M, λ exc = 405nm). (c) UV absorption and fluorescence spectra of TAB-3-cRGD in PBS （ 0.1%DMSO ） and DMSO (10 μ M, λ exc = 405nm). (d)Twophoton action spectra of TAB-3-cRGD in 10mM PBS (0.1%DMSO).

As bioimaging is often conducted in complex biological systems containing various substances, it is important to study the effect of common biological substances on the emission behavior of the probe. Metal ions such as K+, Ca2+ and Mg2+ cannot trigger any changes in fluorescence. TAB-3-cRGD demonstrates a small response to common amino acids, such as Cys and Hcy, and glutathione (GSH) (Figure S5). The specificially binding properties of TAB-3-cRGD with αVβ3 can also be verified by conducting further in vivo experiments. Since HUVECs are known to express αVβ3, the HUVEC-1 cell line was chosen to investigate whether TAB-3-cRGD can bind to these cells by bining to αVβ3. [31] For this, HUVEC-1 cells were incubated with TAB-3-cRGD for a definite period of time and fluorescence confocal live cell imaging was conducted. The results demonstrated that incubation of HUVEC-1 cells with 1 µM TAB-3-cRGD for 15 min resulted in fluorescence around the cell surface (Figure 3a-c). In contrast, under identical experimental conditions, the fluorescence signal from HUVEC-1 cells treated with free cRGD peptide is much lower (Figure 3d-f). These results suggest that the fluorescence originates from the specific binding between TAB-3-cRGD and integrin αVβ3. The low concentration of TAB-3-cRGD and short time required for cell imaging can be attributed to its multivalent effect, which can greatly improve specificity and sensitivity.



Figure 3. Fluorescence confocal images (a, d) collected at 500−550nm (λex = 405 nm) and the corresponding bright field view (b, e) of HUVEC-1 cells. (a-c) HUVEC-1 cells incubated with TAB-3-cRGD (1 μM) for 15 min; (c) Overlay image of panels (a) and (b); (d-f) HUVEC cells pretreated with cRGD (1 mM) for 30 min, followed by incubation with TAB-3-cRGD (1 μM) for 15 min; (f) Overlay image of panels (d) and (e).

Considering that TAB-3-cRGD can specifically bind to integrin αVβ3, in theory, TAB-3-cRGD can be used for imaging cancer cells overexpressing integrin αVβ3 and distinguishing them from normal cells. As seen in Figure 4a-c, NIH/3T3 cells incubated with TAB-3-cRGD for 15 min display no fluorescence, which could indicate that the level of integrin αVβ3 in these cells was low. [32] In contrast, U87MG cells display cell surface fluorescence after incubation with TBA-3-cRGD at the same experimental conditions (Figure 4df). To investigate whether the probe is distributed on the cell membrane, we performed a colocalization experiment using a commercial cell membrane tracker (DiD; red color). In this experiment, U87MG cells were first incubated with 5 µM DiD for 20min and then with 1 µM TAB-3-cRGD for 15 min. By merging the images, the green TAB-3-cRGD signal on the periphery of the cell was found to be consistent with the red DiD signal, providing evidence that TAB-3-cRGD is primarily distributed on the cell membrane, most likely through binding with integrin αVβ3 on the cell surface (Figure 4f). [33] The above three kinds of cells without treatment with any dyes present no fluorescence, which can eliminate the interference of the cells themselves. (Figure S6a-f) And all of them present bright fluorescence after treatment with TAB-3-piperazine, who is not functionalized by cRGD, demonstrating no specificity for U87MG. (Figure S6g-i) Since biocompatibility is one of the foremost property for a probe to be practically applied in living cells, we further conducted a standard 3-(4, 5dimethyl-2-thiazolyl)-2, 5-diphenyltetrazo- lium bromide (MTT) experiment to evaluate the cytotoxicity of TAB-3cRGD on NIH/3T3, HUVEC-1 and U87MG cells. The application of TAB-3-cRGD shows no obvious effects on the viability of the three cell lines, even at a concentration of 5μ M (Figure S 7), demonstrating its’good biocompatibility.

Figure 4. Confocal fluorescence images collected at 500−550nm (a) and at 575-625nm (b) (λex = 405 nm) of NIH/3T3 cells incubated with TAB-3-cRGD (1 μM) for 15 min. (c) Corresponding bright field image. (d) confocal fluorescence images collected at 500−550nm (λex = 405 nm) of U87MG cells incubated with TAB-3-cRGD (1 μM) for 15 min and costained with the the commercial membrane tracker DiD. (e) DiD excited at 635 nm and collected from 650-700nm. (f) Overlay image of panels (d) and (e).

The tumor targeting property of TAB-3-cRGD was investigated in vivo to further explore its applications. Six to seven-week-old nude mice were used to generate the subcutaneous tumor model. U87MG cells were injected into the right rear thigh of these mice and when the tumor grew to approximately 0.5 cm in diameter, each mouse was intraperitoneally injected with TAB-3-cRGD (4 mM, 200 μL). The fluorescence emitted was monitored every 15 min for 90 min using a small animal imaging apparatus. The emission from TAB-3-cRGD over time in vivo is depicted in Figure 5. The emission signal from tumor sites gradually increased with time, and the tumor can be easily observed after 60min, indicating that TAB-3-cRGD could successfully accumulate in the tumor site by binding to integrin αVβ3 on the tumor cell surface with good biocompatibility. Strong fluorescence can be maintained for over 0.5 h and can be attributed to the strong affinity between TAB-3-cRGD and integrin αVβ3, which facilitates the long retention of TAB-3-cRGD at the tumor site. The blank and control experiments results were also recorded as Figure S8, demonstrating consistent results with cell imaging. These result shows that TAB-3-cRGD can be used as a probe for targeted tumor imaging in vivo.

Figure 5. Time courses of TAB-3-cRGD (4mM, 200μL) for imaging the U87MG tumor in living mice, the fluorescence emmited was monitored at 0, 15, 30, 45, 60, 75 and 90 min.

CONCLUSIONS We developed a TAB-based cancer-targeting fluorescence probe TAB-3-cRGD, by attaching three cRGD groups around the central TAB fluorophore. By functionalizing the TAB with


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Analytical Chemistry three cRGD groups that specifically bind to integrin αVβ3, which is overexpressed by cancer cells, the multivalent effect was achieved in the specifically targeting and imaging of cancer cells. The central triarylboron unit could endow TAB3-cRGD with excellent photo-physical properties, such as intense fluorescence and a large two-photon cross-section. The binding ability of TAB-3-cRGD to integrin αVβ3 on the cell surface was verified with imaging experiments in HUVEC-1 cells, which express high levels of integrin αVβ3. TAB-3cRGD was also successfully applied for in the in vivo imaging of the U87MG tumor in a mouse model.

ACKNOWLEDGMENT We are grateful for the funding from the National Natural Science Foundation of China (Grant No. 81801768, 21703062, 81871440), the Sichuan Science and Technology Department (Grant No. 2019YJ0385), the Scientific Research Project of Sichuan Provincial Department of Education (Grant No. 18ZA0200), the Bureau of Science & Technology and Intellectual Property Nanchong City (Grant No. 16YFZJ0121, 18SXHZ0491) and the North Sichuan Medical College (Grant No. CBY16QD01).

ASSOCIATED CONTENT Supporting Information This information is available free of charge via the Internet at http ://pubs.acs.org/. Synthesis of TAB-3-Piperazine and TAB-3-Cl, NMR data, HR Mass spectra, selectivity data of TAB-3-cRGD, cytotoxicity of TAB-3-cRGD, photostability, cell imaging of TAB-3-Piperazine.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] (X. Z.); [email protected] (X. L.); [email protected] (G.

Y.).

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