Faraday Discussions 222(2020), 362-383
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Helmholtz-Zentrum Dresden-Rossendorf (HZDR) Ultrasmall silicon nanoparticles as a promising platform for multimodal imaging Singh, G.; Ddungu, J. L. Z.; Licciardello, N.; Bergmann, R.; de Cola, L.; Stephan, H.; Originally published: October 2019 Faraday Discussions 222(2020), 362-383 DOI: https://doi.org/10.1039/C9FD00091G Perma-Link to Publication Repository of HZDR: https://www.hzdr.de/publications/Publ-29786 Release of the secondary publication based on the publisher's specified embargo time. Faraday Discussions PAPER Ultrasmall silicon nanoparticles as a promising platform for multimodal imaging Received 00th January 20xx, a b,c a# a b,c* Accepted 00th January 20xx Garima Singh , John L. Z. Ddungu , Nadia Licciardello , Ralf Bergmann , Luisa De Cola , a* DOI: 10.1039/x0xx00000x Holger Stephan Bimodal systems for nuclear and optical imaging are currently being intensively investigated due to their comparable detection sensitivity and complementary information they provide. In this perspective, we have implemented both modalities on biocompatible ultrasmall silicon nanoparticles (Si NPs). Such nanoparticles are particularly interesting since highly biocompatible, covalent surface functionalization and demonstrated a very fast body clearance. We prepared monodisperse citrate-stabilized Si NPs (2.4 ± 0.5 nm) with more than 40 accessible terminal amino groups per particle and, for the first time, simultaneously a near-infrared dye (IR800-CW) and a radiolabel (64Cu-NOTA = 1,4,7-triazacyclononane- 1,4,7-triacetic acid) have been covalently linked to the surface of such Si NPs. The obtained nanomaterials have been fully characterized them by HR-TEM, XPS, UV-Vis and FT-IR spectroscopy. These dual-labelled particles do not exhibit any cytotoxicity in vitro. In vivo studies employing both positron emission tomography (PET) and optical imaging (OI) techniques revealed a rapid renal clearance of dual-labelled Si NPs from mice. and sensitivity, making the achievement of precise and reliable Introduction information at the disease site difficult. In order to circumvent the limitations of a single imaging technique and exploit their Molecular imaging is a non-invasive method that provides advantages synergistically, multimodal molecular imaging has reliable information on anatomy, as well as physiological and recently gained importance. Of particular interest is the pathophysiological processes in living systems. Various imaging combination of nuclear and optical methods. In this respect, modalities such as computed tomography (CT), magnetic the use of PET due to its high specificity/sensitivity (fM to pM resonance imaging (MRI), optical imaging (OI), single-photon range) and the possibility of quantifying the data, and near emission computed tomography (SPECT) and positron 1-7 infrared fluorescence imaging, which enables high resolution, emission tomography (PET) are available for this purpose. relatively deep penetration (cm range) and the use of Each imaging modality has its own unique strength and fluorescence-guided surgery is a winning combination. intrinsic limitations, mainly regarding spatial/depth resolution a. Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden - Rossendorf, Bautzner Landstraße 400, Dresden, D-01328, Germany b. Laboratoire de Chimie et des Biomatériaux Supramoléculaires, Institut de Science et d’Ingénierie Supramoléculaires (ISIS), 8 allée Gaspard Monge, Strasbourg, 67000, France c. Institut für Nanotechnologie (INT), Karlsruher Institut für Technologie (KIT) Campus North, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, 76344, Germany # Current address: International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga s/n, 4715-330 Braga, Portugal Corresponding authors: *Dr. Holger Stephan, Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328 Dresden, Germany, Phone: +49 3512603091, Fax: +49 3512603232, E-Mail: [email protected] *Prof. Luisa De Cola; Laboratoire de Chimie et des Biomatériaux Supramoléculaires, Institut de Science et d’Ingénierie Supramoléculaires (ISIS), 8 allée Gaspard Monge, Strasbourg, 67000, France, Phone: +33 368855220; Fax: +33 368855242, E-Mail: [email protected] † Electronic Supplementary Information (ESI) available. See DOI: 10.1039/x0xx00000x ARTICLE Faraday Discussions Implementation of both modalities on the same system labels for in vivo imaging.21, 22 As far as biomedical applications requires multifunctional molecules or nanomaterials. Due to are concerned, to date, Si NPs have been applied in their diverse modification possibilities, nanoscale materials bioimaging23-27 and in real-time immunofluorescence have become significantly more important in recent years for imaging.28-33 For instance, to target cells in a specific way, Si imaging applications.8-16 This is due to the fact that it is NPs have been successfully coupled with single-stranded possible to anchor a large number of similar or different DNA34-36, folic acid37, sugars38, 39, peptides29 and antibodies31, modalities to a probe and thus increase the sensitivity on one 33, and several in vitro studies have been performed on their hand and to follow in vitro and in vivo processes in more detail cellular uptake 40-42 and cytotoxicity.43-45 In vitro investigations on the other. In addition, biological vector molecules can be are mostly based on the intrinsic photoluminescence of the Si introduced simultaneously for pharmaceutical targeting. For NPs. Through targeted surface modification, the luminescence medical imaging however, very small materials that reach their properties can be tailored and, in particular, the quantum yield target quickly and are renal excreted are desirable. The size significantly increased.46-50 considered optimal for such application is less than 6 nm, and In contrast to in vitro studies, there are only a few in vivo particles with such small dimension are referred to as studies with Si NPs so far using magnetic resonance and ultrasmall nanoparticles. Ultrasmall renal clearable fluorescence imaging.37, 51-55 For the first time, biodistribution nanoparticles possess enormous potential as cancer imaging and pharmacokinetic properties of radiolabelled Si NPs were agents17-20, and in this respect biocompatible silicon reported by Kauzlarich et al.56 Here, dextran-coated, nanoparticles (Si NPs) are highly attractive. Their covalent manganese-doped, Si NPs were functionalized with a 1,4,7,10- surface functionalization allows the introduction of different tetraazacyclododecane-1,4,7-triacetic acid (DO3A) derivative Scheme 1 Reaction scheme for the synthesis of amine-terminated Si NPs through the hydrothermal method [APTMS = (3-aminopropyl) trimethoxysilane]. 2 | J. Name., 2019, 00, 1-3 This journal is © The Royal Society of Chemistry 2019 Faraday Discussions ARTICLE Synthesis and characterisation of silicon-based nanoparticles Water-dispersible amine-terminated silicon-based nanoparticles (Si NPs) were synthesised in hydrothermal conditions following our previously reported method.57 A general synthetic route is depicted in Scheme 1. A broad characterisation of the Si NPs covering size, chemical composition and photoluminescence was carried out using a number of analytical techniques to show that the particles are completely comparable with our previous published work.57 Observing the Si NPs through Transmission Electron Microscopy (TEM) (Fig. 1A) revealed a system of low Fig. 2 Schematic representation of a Si-based nanoparticle surrounded by a “shell” of citric acid. polydispersity with an average size of 2.4 ± 0.5 nm. This smaller size of Si NPs compared to those achieved in our for labelling with 64Cu, enabling PET studies. Owing to their previous study57 was achieved through optimisation of the relatively large hydrodynamic diameter (HD) (15.1 ± 7.6 nm), synthetic procedure. Increasing the mixing time of the the particles have considerable liver uptake. Recently, we were reagents from a total of 30 min to 60 min before heating in the able to show that ultrasmall 64Cu-labelled Si NPs (size below 5 oven affords a much more effective dispersion of the reagents nm) are rapidly cleared from the body.57 Despite the very small during the hydrothermal process, creating more nuclei from size, multiple and different functionalities can be grafted on which Si NPs can grow. A similar hypothesis has been reported the nanoparticle surface. for other species of silicon-based nanoparticles.58 Based on our previous studies, we have selected citrate- The pristine amine-terminated Si NPs exhibit a near neutral stabilized Si NPs for further functionalization. The concurrent surface charge due to the formation of a stable citrate shell use of the bifunctional chelating agent NOTA (1,4,7- confirmed by DLS measurements (zeta potential ζ -5.3 ± 2.8 triazacyclononane-triacetic acid) and a near-infrared dye mV). More information on the surface structure of Si NPs was (IR800-CW) allows detailed in vivo studies using PET and elucidated through FT-IR spectroscopy (Fig. 1B). Notable are optical imaging in small animals. Herein, we describe the bands occurring at 1557 cm-1 and 1385 cm-1 for symmetric and synthesis of these dual-labelled particles, together with asymmetric vibrational modes of C=O bonds respectively, as absorption, emission and structural properties. Subsequent well as a band at 1224 cm-1 originating from stretching of C—O assessment of nanotoxicity, as well as radiolabelling of Si NPs bonds. These