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Biocompatibility of Magnetic Resonance Imaging Nanoprobes Improved by Transformable Gadolinium Oxide Nanocoil Dan Luo, Shengjie Cui, Yan Liu, Chunyan Shi, Qian Song, Xiaoyun Qin, Ting Zhang, Zhenjie Xue, and Tie Wang J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08118 • Publication Date (Web): 02 Oct 2018 Downloaded from http://pubs.acs.org on October 3, 2018
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Journal of the American Chemical Society
Biocompatibility of Magnetic Resonance Imaging Nanoprobes Improved by Transformable Gadolinium Oxide Nanocoil Dan Luo†,‡, Shengjie Cui∏,‡, Yan Liu∏,*,Chunyan Shi⊥, Qian Song§, Xiaoyun Qin§, Ting Zhang∏, Zhenjie Xue§ and Tie Wang§,* †
State Key Laboratory of Heavy Oil Processing, Institute of New Energy, Beijing Key Laboratory of Biogas Upgrading Utilization, China University of Petroleum (Beijing), Beijing 102249, China;
§
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, The Chinese Academy of Sciences, Beijing 100190, China; ∏
Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China. ⊥
Department of Radiology, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, China. Supporting Information Placeholder KEYWORDS: Ultrathin nanocoil, transformable morphology, steric hindrance, biocompatibility, MR bioimaging ABSTRACT: To design functional nanomaterials for biomedical applications, the challenge for scientists is to gain further understanding of their unique toxicological properties. Non‐specific adhesion of proteins and endocytosis are considered to be the major biotoxic sources of imaging nanoprobes. Here we fabricated ultrathin gadolinium oxide (Gd2O3) nanocoils with a low Young's modulus, which endows transformable properties in solution. The spatial configurational freedom of ultrathin nanocoils induces the steric repulsion to the non‐specific adsorption of proteins that in turn, suppresses cellular uptake and thus improves their biocompatibility. The larger number of exposed surface gadolinium atoms of the ultrathin nanocoils provided enhanced T1 magnetic resonance (MR) imaging contrast with high signal activation. Such nano‐ contrast agents were applied in in vivo MR bioimaging to achieve prolonged circulation lifetime. The improved biocompatibility by transformable Gd2O3 nanocoils could open up a new perspective towards the design and construction of various nano‐biomedicines in the future.
INTRODUCTION Magnetic resonance (MR) imaging, as a noninvasive technique, is being increasingly used in clinical diagnostics to obtain information on the anatomy, function and metabolism of tissues in vivo.1 To improve imaging sensitivity, contrast agents have been employed to accelerate the relaxation rate of water molecules and thus increase the required contrast between specific tissues or organs of interest.2,3 Compared with clinically‐ approved conventional gadolinium chelates, gadolinium oxide (Gd2O3) nanoparticles exhibit higher enhancement efficiency for T1‐weighted MR images, as highly exposed gadolinium surface atoms synergistically shorten the longitudinal relaxation (T1) time of nearby water protons.4, 5 However, their biosafety risk representing great commercial value has been considered as a necessary issue of widespread concern.6, 7 The interaction of nanoparticles with proteins fundamentally affect the in
vivo biocompatibility and toxicity of imaging nanoprobes, where the biological interface created by adsorption of serum proteins induces their entry into cells by receptor‐ mediated endocytosis. Non‐specific adsorption of proteins by nanomaterials leads to the clearance from the reticular‐endothelial system, promoting endocytosis via interaction with the cell membrane, thereby leading to cytotoxity.8‐10 Additionally, non‐specific interactions in some cases have resulted in the binding of nanoparticles to cell membranes, the extracellular matrix and cell nuclei, resulting in inefficient tagging, inaccurate detection, and genotoxicity.9‐11 Nanoparticle size, shape, surface charge, and solubility contribute significantly to the interaction with proteins, which have been well explored as factors contributing to toxicity. The common characteristic of these existing imaging nanoprobes is that they possess a fixed morphology. Polymer coating as a surface modification strategy, has been adopted primarily to reduce cytotoxity and prolong
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the circulation time of nanomaterials, due to the spatial configurational freedom of the polymer chains; 12 this approach inhibits protein absorption via steric repulsion driven by the loss of conformational entropy.13, 14 Inspired by the mechanism that the flexibility of polymer ligands resists protein adsorption, here we fabricated ultrathin Gd2O3 nanocoils with low Young's modulus that exhibit transformable feature in solution. Compared with other kinds of fixed‐morphology Gd2O3 nanomaterials, including ultrasmall nanoparticles and tripod‐, triangle‐, and disk‐shaped nanoplates, the transformable ultrathin nanocoils significantly suppressed non‐specific adsorption of proteins to hinder cellular uptake. The highest T1 contrast enhancement among various Gd2O3 nanomaterials by the nanocoils is attributable to surface spin disorder, in turn due to the enhanced exposure of surface gadolinium atoms in the ultrathin nanocoils. Via tail vein injection, the ultrathin nanocoils exhibited a shedding nature to avoid rapid clearance and prolong circulation time in in vivo experiments, which provided a new perspective to fabricate next‐generation contrast agents for patients requiring long circulation times for multiple MR scans, such as MR angiography or brain tumor surgery.
RESULTS AND DISCUSSIONS Synthesis and characterizations of transformable ultrathin nanocoils. The transformable ultrathin Gd2O3 nanocoils were synthesized via thermal decomposition of gadolinium acetate precursors in a mixture solvent of oleic acid (OA), oleylamine (OM) and octadecene. Transmission electron microscopy (TEM) showed that nanocoils with high aspect ratio (1.2 ± 0.2 nm thickness) were obtained at an OA/OM ratio of 0.22, and heated at 290 °C for 60 min (Figure 1a). High‐resolution TEM (HRTEM) showed that the ultrathin nanocoils were amorphous and lacked structural rigidity (Figure S1); their unique geometry and non‐crystalline structure allowed for a softer configuration, in which the ultrathin nanocoils could twist in solution, like a flag swings in the wind, as verified by liquid cell TEM (Figure 1b). A few microliters of nanocoil solution were fully sealed in electron transparent membranes to observe the movement of the “transformers” over time in situ.15 The electron beam could provide thermal energy to induce the mobility of solution in the sealed membranes. A single ultrathin nanocoil clearly exhibited transformable characteristics within a few seconds. The formation of ultrathin nanocoils was followed by an “oriented attachment” mechanism occurring via anisotropic assembling of active ultrasmall nanoparticles (Figure 1c), 16, 17 as monitored by in‐situ HRTEM operated at 200 kV.18 Electron charging and transfer momentum created by the electron beam initiated the approachment between neighboring ultrasmall nanoparticles.19 The ultrasmall nanoparticles undergone the fusing, and formed arc‐ shaped nanoribbons after 15 min (Figure 1c).
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Figure 1. (a) TEM image of ultrathin nanocoils. (b) Liquid TEM images showed the transformable property of nanocoils (marked with arrow): nanocoils gradually opened from scarf shape (1s, 4s) to wormlike shape (19 s). (c) Schematic representation of formation process of nanocoils via “oriented attachment” mechanism (upper). Anisotropic assembling of active ultrasmall Gd2O3 nanoparticles under the irradiation of the electron beam. The HRTEM images of ultrasmall Gd2O3 nanoparticles after irradiation with 0 min, 5 min and 15 min (lower). (d) TEM image of four fixed‐morphology nanomaterials, followed by ultrasmall nanoparticle, tripod‐shaped, triangle‐shaped and disk‐shaped nanoplates. (e) The average Young’s modulus of five different Gd2O3 nanomaterials. #: α
