One-Step Loading of Gold and Gd2O3 Nanoparticles within

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Cite This: ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

One-Step Loading of Gold and Gd2O3 Nanoparticles within PEGylated Polyethylenimine for Dual Mode Computed Tomography/Magnetic Resonance Imaging of Tumors Du Li,†,‡ Shihui Wen,‡ Wenjie Sun,§ Jiulong Zhang,∥ Dayong Jin,‡ Chen Peng,*,∥ Mingwu Shen,*,§ and Xiangyang Shi*,†,§

ACS Appl. Bio Mater. Downloaded from pubs.acs.org by UNIV OF READING on 08/12/18. For personal use only.

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State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, People’s Republic of China ‡ Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia § College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People’s Republic of China ∥ Cancer Center, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China S Supporting Information *

ABSTRACT: We report here a facile method for one-step loading of gold (Au) and gadolinium oxide (Gd2O3) nanoparticles (NPs) within polyethylenimine (PEI) premodified with polyethtylene glycol (PEG) for dual mode computed tomography (CT) and magnetic resonance (MR) imaging of tumors. PEGylated PEI was used as a template to complex Au(III) and Gd(III) salts, followed by sodium borohydride reduction and acetylation of remaining PEI surface amines to generate the hybrid PEI@Au/Gd2O3 NPs. The hybrid NPs exhibit a remarkable colloidal stability and cytocompatibility and possess a high X-ray attenuation efficacy and r1 relaxivity, enabling their uses for dual mode CT/MR imaging of tumors. KEYWORDS: polyethylenimine, gold nanoparticles, gadolinium oxide, dual-modal CT/MR imaging, tumors

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for T1-weighted positive MR imaging. Gd3+-based NPs (e.g., Gd2O3 and NaGdF4 NPs) have also been used for T1-weighted MR imaging.14,16−19 Moreover, by integrating multiple imaging components within one nanoparticulate platform, hybrid NPs may become robust CAs for dual mode imaging to enhance the diagnosis accuracy.14,16,20−22 For this purpose, various integrated structures have been created for CT/MR dual mode imaging.1,23,24 In most of the developed CT/MR dual mode imaging CAs, Au NPs and Gd3+ ions have been combined, and expensive Gd3+ chelator has to be used. With the high risk of nephrogenic system fibrosis syndrome in vivo due to the Gd3+ leakage into the blood, it is quite challenging to obtain stable chelator-free Gd3+ hybridized with Au NPs for dual mode imaging applications.1,4 In this study, we presented a facile chelator-free method to prepare hybrid Au/Gd2O3 NPs entrapped within polyethylenimine (PEI) premodified with polyethylene glycol (PEG) for

omputed tomography (CT) and magnetic resonance (MR) imaging are the most popular tools in clinical practice to provide pathological information for disease diagnosis. CT offers better spatial and density resolution as well as fast imaging, while MR possesses unlimited signal penetration level and better soft tissue contrast. Therefore, CT/MR dual mode imaging affords more accurate and detailed in vivo information for disease detection.1−3 For more accurate clinical diagnosis, contrast agents (CAs) are frequently employed to enhance the contrast effect and the sensitivity of the images.4,5 However, clinical MR and CT CAs are small organic molecules, suffering problems of relatively short half-decay time, renal toxicity, and nonspecificity. Recently, nanoparticles (NPs) have displayed tremendous potential as CAs with the advantages of long half-decay time and passive tumor targeting ability resulting from enhanced permeability and retention (EPR) effect.6−12 For example, gold NP (Au NP) is a perfect radiopaque contrast media due to its high density and atomic number, providing excellent X-ray attenuating property for CT imaging.5,13−15 Gd3+ enables efficient shortening of longitudinal relaxation time of protons © XXXX American Chemical Society

Received: June 24, 2018 Accepted: August 6, 2018 Published: August 7, 2018 A

DOI: 10.1021/acsabm.8b00265 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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ACS Applied Bio Materials

Figure 1. (A) Schematic illustration of the synthesis of PEI@Au/Gd2O3 NPs. (B) Application of PEI@Au/Gd2O3 NPs for dual modal CT/MR imaging of a tumor model via passive EPR effect. TEA and Ac2O are triethylamine and acetic anhydride, respectively.

Figure 2. TEM image (A), high resolution TEM image (inset in panel A), size distribution histogram (B), and UV−vis spectrum (C) of PEI@Au/ Gd2O3 NPs with Au/Gd molar ratio at 1:1 (Sample 3).

The created PEGylated PEI (PEI-mPEG) was then used as a template to entrap Au and Gd2O3 NPs via one-step reduction by NaBH4. After that, the available PEI surface amines were converted to acetamide according to our previous reports.13,24 X-ray diffraction (XRD) patterns were first employed to disclose the crystal structure of the hybrid NPs. As shown in Figure S2 (Supporting Information), very broad XRD patterns are observed for all the NPs with different Au/Gd molar ratios (Sample 1, 1:0; Sample 2, 3:1; Sample 3, 1:1; Sample 4, 1:3; and Sample 5, 0:1). This could be ascribed to the ultrasmall size of the particles. For Sample 1, only a typical peak located at 38.7° is found, and it could be assigned to the (111) face of Au NPs. With the addition of Gd3+ during the synthesis, a new peak at 25.2° appears, which can be assigned to the (222) face of Gd2O3.25 It should be noted that the peak of Gd2O3 NPs is broad here and has a slight shift to the low 2θ when compared with the standard (222) peak due to the small size of the particle, in consistence with the literature.26 With the increase of Gd/Au molar ratio, the ratio of Gd/Au intensity increased, indicating the formation of the desired nanocrystals with different compositions. For Sample 5 with Au/Gd molar ratio

dual mode CT/MR imaging of tumors (Figure 1). PEGylated PEI was first complexed with Au(III) and Gd(III) ions, and the complexes were reduced by sodium borohydride (NaBH4) to generate both Au and Gd2O3 NPs. After the following acetylation of the remaining PEI surface amines, the formed hybrid PEI@Au/Gd2O3 NPs were characterized to illustrate their structure, composition, morphology, stability, cytocompatibility, X-ray attenuation intensity, and MR relaxometry. Finally, we used the hybrid NPs for CT/MR dual mode imaging of a xenografted tumor model. According to our literature investigation, our study is the first example dealing with the formation of PEI@Au/Gd2O3 NPs with a chelatorfree method for dual mode CT/MR imaging of tumors. In this current study, PEI was chosen as the platform to entrap NPs due to its numerous primary, secondary, and tertiary amine units and its internal cavity.13 To render the particles with extended blood circulation time and decreased macrophage cellular uptake, prior to the formation of inorganic NPs, PEI was first reacted with mPEG-COOH, similar to our previous work.13,23,24 Through 1H NMR peak integration, the number of mPEG-COOH conjugated to each PEI was evaluated to be 12.5 (Figure S1, Supporting Information). B

DOI: 10.1021/acsabm.8b00265 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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ACS Applied Bio Materials

Figure 3. In vivo CT images (A), relative CT values (B), T1-weighted MR images (C), and the ratio of MR SNR of tumor and muscle (D) of nude mice bearing HeLa tumor at different time points (0, 1, 2, 3, and 4 h, respectively) postinjection of PEI@Au/Gd2O3 NPs.

Au NPs.1,13 Considering that the aggregation of Au NPs has a direct association with the variation of UV−vis absorption feature, we used UV−vis spectrometry and dynamic light scattering (DLS) to assess the stability of the PEI@Au/Gd2O3 NPs in aqueous solution (Figure S6, Supporting Information). The absorption features of PEI@Au/Gd2O3 NPs did not display any significant changes at different pHs (from 4.0 to 8.0, Figure S6A) and temperatures (4, 25, 37, and 50 °C, Figure S6B). The hydrodynamic size of PEI@Au/Gd2O3 NPs was measured to be 105.8 ± 1.6 nm in phosphate buffered saline (PBS) solution (Table S1, Supporting Information). It should be noted that the hydrodynamic size of the PEI@Au/ Gd2O3 NPs in PBS is much larger than that measured by TEM. This is because DLS measures particles in a hydrated state, which may form a clustered structure consisting of many single PEI@Au/Gd2O3 NPs, while TEM only measures the single inorganic Au/Gd2O3 core, in agreement with the literature.27 After 5 days’ storage in PBS and cell culture medium containing 10% serum, the particles did not show any evident changes in hydrodynamic size, which was verified by the photos taken during this period (Figures S6C and S6D). Furthermore, the acetylation of PEI surface amines was also proven by the surface potential changes. Before acetylation, the PEI-entrapped NPs always exhibit a surface potential of 25−35 mV;13 however, after acetylation, the surface potential of the particle was determined to be 3.7 ± 0.8 mV, suggesting the successful surface acetylation modification (Table S1, Supporting Information). This neutralized surface potential is important to render the NPs with improved biocompatibility for imaging applications.28 To investigate the CT imaging ability of the PEI@Au/ Gd2O3 NPs, phantom studies were performed first (Figures S7A and B, Supporting Information). The attenuation intensity of PEI@Au/Gd2O3 NPs increases with Au concentration. Quantitative analysis reveals that the slope of the CT value of PEI@Au/Gd2O3 NPs is 5031 (Figure S7B), which is dramatically larger than that of PEI@Au NPs (3726, Figure S8A, Supporting Information). This is because the existence of Gd2O3 NPs contributes significantly to the enhancement of Xray attenuation due to the relatively high K-edge energy of Gd

at 0:1, the NPs were synthesized without Au, and the peak attributed to Gd2O3 only is observed. Next, we used X-ray photoelectron spectroscopy (XPS) to check the binding energies of Gd and Au in the hybrid nanomaterials (Figures S3A and S4, Supporting Information). In Gd 3d XPS spectrum (Sample 3, Au/Gd molar ratio at 1:1), Gd 3d3/2 and Gd 3d5/2 peaks (Figure S3B) are found at 1219.18 and 1187.7 eV, and Gd 4d5/2 peak (Figure S3C) at 141.8 eV. Based on these, we ensure that the Gd XPS peaks are ascribed to the Gd(III).25 Likewise, the Au 4f5/2 and Au 4f7/2 peaks are observed at 86.88 and 83.18 eV, respectively (Figure S3D), and these peaks could be ascribed to Au(0). Similarly, the varied peak intensities of Gd and Au in other samples having different Au/Gd molar ratios (Figure S4) are in good agreement with the results of XRD. To quantify the amount of Au and Gd(III) in the hybrid NPs, inductively coupled plasma optical emission spectroscopy (ICP-OES) was used. We showed that each PEI entrapped around 480, 350, 230, and 100 Au atoms in Samples 1, 2, 3, and 4, respectively, and 124, 248, 372, and 475 Gd(III) in Samples 2, 3, 4, and 5, respectively. Transmission electron microscopy (TEM) was used to further check the morphology and size of the hybrid NPs. Figure 2A shows that the hybrid NPs (Sample 3) have a nearly round shape with a narrow size distribution. The mean diameter of Sample 3 was estimated to be 4.4 nm (Figure 2B). High resolution TEM image shown in the inset of Figure 2A reveals the highly crystalline nature of the hybrid particles, as clear lattice structure of single NPs can be observed. Apparently, the different lattice distances at different locations of one single hybrid nanocrystal are obvious. Specifically, the lattice distances of 0.31 and 0.24 nm belong to Gd2O3 and Au crystals, respectively. These results indicate the successful formation of hybrid PEI@Au/Gd2O3 NPs. The TEM images and size distributions of Samples 1, 2, 4, and 5 are also shown as a further proof of the XRD results (Figure S5, Supporting Information). The formation of the hybrid NPs was also validated by UV− vis spectroscopy (Figure 2C). PEI@Au/Gd2O3 NPs have a surface plasma resonance (SPR) peak at 520 nm attributable to C

DOI: 10.1021/acsabm.8b00265 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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ACS Applied Bio Materials (50.2 keV).14 MR phantom and relaxometry studies were performed to check the capability to use the hybrid NPs for T1-weighted MR imaging (Figures S7C and D). The intensity of MR signals of the PEI@Au/Gd2O3 NPs increases with the Gd concentration. The plot of the inverse T1 versus Gd concentration shows that the r1 relaxivity of the particles is 4.226 mM−1 s−1 (Figure S7D), more or less similar to the commercial agent of Gd(III)-DTPA complexes and PEI@ Gd2O3 NPs without Au (Figure S8B).29 Our data suggest that the coating of PEGylated PEI onto the surface of the hybrid particles does not seem to hinder the accessibility of water protons to the Gd(III). Taken together, the PEI@Au/Gd2O3 NPs may act as dual mode CT/MR imaging CAs. Before the usage of PEI@Au/Gd2O3 NPs as a dual modal imaging CA, it is important to study their cytocompatibility. MTT cell viability assay shows that HeLa cells maintain good viability after being treated with the PEI@Au/Gd2O3 NPs at the highest investigated Au concentration of 50 μM, which is comparable to the control cells treated with PBS (Figure S9, Supporting Information). This suggests that PEI@Au/Gd2O3 NPs possess an excellent cytocompatibility. Based on the encouraging in vitro CT and MR performance and cytocompatibility of the PEI@Au/Gd2O3 NPs, the particles were then used for in vivo dual mode CT/MR imaging of tumors. The mice xenografted with HeLa tumors were imaged at 1, 2, 3, and 4 h post intravenous injection (Figure 3). Enhanced CT and T1-weighted MR contrast in the tumor site are observed when compared with that in the tumor site before injection. Moreover, within the first 3 h post administration, the tumor and the margin region of tumor gradually turn out to be clearer and sharper in both CT and MR images (Figures 3A and C), suggesting the effective diffusion and distribution of the CA in the tumor area via passive EPR effect. By measuring the CT value of tumor area and the surrounding tissue, we calculated the ratio of HUtumor and HUsurrounding tissue (RHU) to quantitatively compare the contrast effect in CT imaging before and after injection at different time points. As shown in Figure 3B, the RHU reaches a maximum of 1.77 at 3 h postinjection and gradually decreases after 3 h. For MR imaging, the signal-to-noise ratio (SNR) in MR images was calculated before and at different time points postinjection. As shown in Figure 3D, the SNR of tumor and muscle increases with time, reaching a highest value of 2.57 at 3 h, which is significantly higher than the group before injection (p < 0.05). In vivo biodistribution of the hybrid particles is important to assess their biocompatibility. We studied the biodistribution of Au and Gd in different organs including liver, heart, spleen, lung, and kidney (Figure S10, Supporting Information). It can be seen that the liver and spleen have more Au and Gd uptake than other organs at all the studied time points, indicating that the particles could be cleared by these reticuloendothelial system (RES)-rich organs. With the time extension from 4 to 96 h, the content of Au at heart, kidney, and lung decreases from around 0.15 mg/g to below 0.015 mg/g, while the content of Au at liver and spleen decreases from 1.2 and 0.7 mg/g to 0.4 and 0.16 mg/g, respectively, at the same time points. These results suggest that the hybrid particles could be excreted out of these organs. Notably, the Gd content in all organs has a trend similar to that of Au, indicating the excellent in vivo stability of the formed PEI-based hybrid particles. To conclude, we presented an easy method to synthesize hybrid PEI@Au/Gd2O3 NPs for dual modal CT/MR imaging

applications. The one-pot NaBH4 reduction method allows for simultaneous robust entrapment of Au and Gd2O3 NPs within PEGylated PEI with an average core size of 4.4 nm. The PEI@ Au/Gd2O3 NPs displayed both good X-ray attenuation property and r1 relaxivity as well as nice stability and cytocompatibility, allowing for CT/MR dual mode imaging of tumors. The developed PEI@Au/Gd2O3 NPs may offer the possibility for dual mode CT/MR imaging of different biosystems.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsabm.8b00265.

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Full experimental section and additional data of XRD, DLS, ζ-potential, XPS, TEM, in vitro CT/MR phantom studies, stability assessment of PEI@Au/Gd2O3 NPs, cytotoxicity assay, and biodistribution data (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (C.P.) *E-mail: [email protected] (M.S.). *E-mail: [email protected] (X.S.). ORCID

Dayong Jin: 0000-0003-1046-2666 Mingwu Shen: 0000-0002-1065-0854 Xiangyang Shi: 0000-0001-6785-6645 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the Science and Technology Commission of Shanghai Municipality (17540712000 and 15520711400), the Fundamental Research Funds for the Central Universities (for M.S. and X.S.), and the National Natural Science Foundation of China (Grants 81761148028 and 21773026).

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DOI: 10.1021/acsabm.8b00265 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX