Ultrasmall Gold Nanoparticles Behavior in Vivo Modulated by Surface

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Ultra-Small Gold Nanoparticles Behavior in Vivo Modulated by Surface PEG Grafting Shuaidong Huo, Shizhu Chen, Ningqiang Gong, Juan Liu, Xianlei Li, Yuanyuan Zhao, and Xing-Jie Liang Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.6b00488 • Publication Date (Web): 12 Oct 2016 Downloaded from http://pubs.acs.org on October 14, 2016

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Bioconjugate Chemistry

Ultra-Small Gold Nanoparticles Behavior in Vivo Modulated by Surface PEG Grafting

Shuaidong Huo,†, ‡, * Shizhu Chen, †, ¶ Ningqiang Gong,†, ‡ Juan Liu,†, § Xianlei Li,†, ‡ Yuanyuan Zhao,† and Xing-Jie Liang †, ‡, ¶, *

†

Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences

(CAS) Center for Excellence in Nanoscience; and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, NO. 11 Beiyitiao, Zhongguancun, Beijing 100190, P. R. China ‡

University of Chinese Academy of Sciences, Beijing 100049, P. R. China

¶

College of Chemistry & Environmental Science, Chemical Biology Key Laboratory

of Hebei Province, Hebei University, Baoding, P.R. China §

Tissue Engineering Lab, Beijing Institute of Transfusion Medicine, Beijing 100850,

China

* Address correspondence to [email protected] and [email protected].

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ABSTRACT Ultra-small nanoparticles provide us essential alternatives for designing more efficient nanocarriers for drug delivery. However, the fast clearance of ultra-small nanoparticles limits their application to some extent. One of the most frequency compound used to slow the clearance of nanocarriers and nanodrugs is PEG, which also approved by FDA. Nonetheless, few reports explored the effect of the PEGylation of ultra-small nanoparticles on their behavior in vivo. Herein, we investigated the impact of different PEG grafting level of 2 nm core sized gold nanoparticles on their biological behavior in tumor-bearing mice. The results indicates that partial (~50%) surface PEGylation could prolong the blood circulation and increase the tumor accumulation of ultra-small nanoparticles to a maximum extent, which guide us to build more profitable small-sized nanocarriers for drug delivery.

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Introduction Smaller (sub 10 nm) nanoparticles provide higher payload-to-carrier ratio and superior penetrating efficiency, which have become particularly important candidates for biomedical applications.1-5 Similarly, the physicochemical properties of the small nanoparticles altogether determine their interactions and behaviors in living systems.6-10 For example, Rotello et al. demonstrated a quantitative correlation between surface hydrophobicity of 2 nm gold nanoparticles and immune system activation.11 Our previous work found that size also plays another critical role in determining the cell uptake in vitro, as well as the interaction with the cell nucleus.2 Compared with the larger sized (50-100 nm) nanoparticles, smaller particles (Sub 10 nm) can be cleared out of the body more rapidly through renal filtration, even these smaller nanoparticles can penetrate deeply into tumor tissues more effectively than their larger counterparts.3,12,13 It is thought that Poly-(ethylene glycol) (PEG) confer a stealth effect, which can extend the blood half-lives of nanodrugs and nanocarriers via reducing non-specific protein adsorption to some extent.14-20 Meanwhile, PEG are especially useful for masking lager nanoparticles from the intravascular immune system and help targeting cancer cells due to the EPR effect.21 However, few studies explored the PEGylation of ultra-small nanoparticles on the impact of blood circulation time and tissue accumulation amount, which is one of the most critical issues when we consider them for biomedical application, especially in cancer therapy.22,23 Herein, 2 nm core sized gold nanoparticle with different proportion of PEG ligand were prepared to investigate the impact of surface PEG grafting level on determining 3



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their pharmacokinetics and biodistribution in vivo. As we expected, prolonged circulation time in blood, increased accumulation in tumor and decreased retention in kidney were detected of PEGylated ultra-small nanoparticles after single tail intravenous injection on tumor-bearing mice. However, this growth/decline trend almost reached to a plateau when increased the PEG coating percentage from 50% to 100%. The results show that complete surface PEGylation could not bring increasing changes in circulation and accumulation for the ultra-small particles in vivo. This work demonstrate the importance of surface PEG grafting level on regulating the behavior of ultra-small nanoparticles within the mice, and give us reference to engineer more efficient small-sized nano-systems with predictable functions in biomedical field.

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RESULTS AND DISCUSSION

Figure 1. Characterization of as-synthesized 2 nm core sized gold nanoparticles with different surface PEG grafting level. (A) General structure of Au NPs, with different surface PEG grafting percentage (0%, 10%, 50%, and 100%). (B) TEM images, (C) Hydrodynamic diameter change curve, and (D) Zeta potential change curve of 2 nm core sized gold nanoparticles with different surface PEG grafting level.

In order to investigate the influence of surface PEG grafting level on ultra-small nanoparticles in blood circulation time and tissue distribution, a set of gold nanoparticle were designed and synthesized in this study. As described in Supporting Information, 2 nm core sized gold nanoparticles with different surface PEG grafting proportion were synthesized by reducing chloroauric acid in the presence of precisely controlled ratio of tiopronin and PEG ligand.24 Here, tiopronin is a thiol drug with 5



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good biocompatibility and usually used as a stabilizing agent for metal nanoparticles.25 Meanwhile, PEG is a FDA-approved polymer compound, which also frequently chosen to increase the biocompatibility and stability, as well as slow the clearance of nanocarriers and nanodrugs.26-29 After modified by thiol group, SH-PEG also can be used as a surface protecting ligand for gold nanoparticle synthesis.1 With the ligand molar ratio of tiopronin to SH-PEG switched from 10:0, to 9:1, to 5:5, and to 0:10 (Figure 1A), Au NPs with core size of 2 nm were obtained (Figure 1B and Figure S1). Dynamic light scattering (DLS) analysis (Figure 1C and Figure S2) confirmed the increased hydrodynamic diameter change of gold nanoparticles with increasing the surface PEG grafting level. Additionally, zeta- potential measurements also showed surface charge neutralization when improving the PEG coverage proportion. All of the characterization data verified that the PEGylation process was successful in this study. In oder to test the biocompatibility of these ultra-small nanoparticles, we first evaluated their cytoxicity against MCF-7 cells before injecting them into the mice. As shown in Figure S3, Au NPs at a high concentration of 100 nM had negligible cytotoxicity on MCF-7 cells as measured by MTT assay. Then, cell uptake study was followed to investigate the cell uptake efficiency affected by the PEGylation level on nanoparticle surface. As shown in Figure 2A, average number of ultra-small gold nanoparticles picked by per cell decreased after PEGylation of nanoparticles. Compared with the none PEGylation Au TIOP NPs, 50% PEG coverage reduced the cell uptake efficiency from 100% down to 40% after 24h incubation. However, added 6


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amount of PEG modification didn’t play a significant role in cell uptake any more, even after a longer incubation time (Figure 2B), which indicated that partial PEGylation is abundant to incease the cellular uptake of ultra-small nanoparticles.

Figure 2. Cellular uptake of as-synthesized 2 nm core sized gold nanoparticles with different surface PEG grafting level by MCF-7 cells after 3 h and 24 h treatment at a particle number concentration of 100 nM. (A) Average number of gold nanoparticles per cell and (B) Cell uptake percentage trend of the gold nanoparticles (compared to the Au-TIOP NPs) towards MCF-7 Cells after 24 h incubation. The amount of gold nanoparticles per cell was determined by ICP-MS. Mean values ± standard deviation, N = 3.

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Figure 3. Blood elimination profiles of Au content following a single intravenous injection of the as-synthesized 2 nm core sized gold nanoparticles with different surface PEG grafting level at a dose of 5 mg Au/kg in the tumor-bearing mice. Mean values ± standard deviation, N = 3.

To evaluate how the surface PEG grafting level affect the pharmacokinetics and biodistribution of ultra-small gold nanoparticles in vivo, tumor-bearing mice were developed. Firstly, the pharmacokinetics behavior of these gold nanoparticles were investigated after a single intravenous injection at a dose of 5 mg Au/kg, respectively. As shown in Figure 3, almost all the nanoparticles (~1 µg/mL) were eliminated from blood after 24 h circulation time. However, nanoparticles with higher surface PEG grafting level kept higher concentrations in blood in 3 h. Compared with the nanoparticle without PEGylation, the nanoparticle with 100% PEG coverage has almost 3-folds higher concentration after 3 h circulation. It was known that PEG can reduce protein adsorption from the surface of nanoparticle to escape the scavenging of immune system, thus to extend their circulation time in the blood. However, the result speculated that the tiopronin modified nanoparticles were opsonized easily by the proteins and quickly cleared through the kidney.

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Figure 4. Tissue biodistribution of Au content in the tissues including tumor, liver, spleen, kidney, lung, brain and heart at 24 h after single intravenous injection of as-synthesized 2 nm core sized gold nanoparticles with different surface PEG grafting level. Mean values ± standard deviation, N = 3.

In terms of the accumulation and distribution of gold nanoparticles in tumor and other tissues, all the mice were sacrificed for quantitative analysis of Au content. As shown in Figure 4, the nanoparticles did not exhibit significant difference in tissue accumulation except in tumor, heart and kidney. Obviously, the more tumor accumulation of PEGylation nanoparticle could be induced by its longer blood circulation time, as well as the slightly increased size after surface PEG grafting, which could utilize better of the EPR effect. It is noteworthy that more amount of Au (6-7 µg/g) was found in kidneys after 24 h administrations. Unlike the clearance from circulation by the mononuclear phagocyte system (MPS), the renal system extracts the nanoparticles (less than 8 nm) through the urine rather than having them accumulated in other related organs.30 In addition, columnar data indicate that PEGylation of gold

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nanoparticles lessen the Au accumulation in kidney, meanwhile, increase the cumulants in tumor and heart. It was reasonable and could be explained by the prolonged blood circulation time of nanoparticles, which caused through the so called stealth effect of PEG coating, increased the cell uptake efficiency in the related organ. For other tissues, ultra-small gold nanoparticles accumulated dominantly in liver, wherein the PEG shell of nanoparticle could be degraded by the proteolytic enzymes, which was demonstrated by Parak et al. in their recent works.31,32 Furthermore, only little amount of nanoparticles distributed in the brain (Table S1).

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Conclusion In summary, we studied the important impact of surface PEG coating of ultra-small nanoparticles on their practical behaviors in tumor-bearing mice. It was found that the PEG grafting level of 2 nm core sized gold nanoparticle could influence their blood pharmacokinetics and tissue accumulations in various degrees. Furthermore, appropriate amount of PEG modification, for example 50%, can achieve the equivalent aftereffect as 100% PEG coverage of nanoparticles, which also demonstrated that the stealth effect of PEG is relatively limited. The results provided guidelines to make PEGylation of ultra-small nanoparticles for different purposes in the field of nanomedicine.

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Conflicts of Interest: The authors declare no competing financial interests. Acknowledgments: This work was supported by the Natural Science Foundation key project (31630027 and 31430031), National Distinguished Young Scholars grant (31225009). The authors also appreciate the support by the “Strategic Priority Research Program” of the Chinese Academy of Sciences, Grant No. XDA09030301 and support by the external cooperation program of BIC, Chinese Academy of Science, Grant No. 121D11KYSB20130006, and the National Natural Science Foundation of China (31570968 and 81201194).

Supporting Information description: Nanoparticle synthesis and characterization, cell culture, cell uptake and additional experimental details and figures. This material is available free of charge via the Internet at http://pubs.acs.org.

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