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Routes to Potentially Safer T1 Magnetic Resonance Imaging Contrast in a Compact Plasmonic Nanoparticle with Enhanced Fluorescence Luke Henderson, Oara Neumann, Caterina Kaffes, Runmin Zhang, Valeria Marangoni, Murali K. Ravoori, Vikas Kundra, James Bankson, Peter Nordlander, and Naomi J. Halas ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.8b03368 • Publication Date (Web): 08 Aug 2018 Downloaded from http://pubs.acs.org on August 8, 2018
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ACS Nano
Routes to Potentially Safer T1 Magnetic Resonance Imaging Contrast in a Compact Plasmonic Nanoparticle with Enhanced Fluorescence Luke Henderson,1,4 Oara Neumann,2,4 Caterina Kaffes,5 Runmin Zhang,3,4 Valeria Marangoni,1 Murali K. Ravoori,6 Vikas Kundra,6,7 James Bankson,5 Peter Nordlander,3,4 and Naomi J. Halas1,2,3,4
1
Department of Chemistry, 2Department of Electrical and Computer Engineering, 3Department
of Physics and Astronomy, and 4Laboratory for Nanophotonics, Rice University, 6100 Main St, Houston, Texas 77005, United States 5
Department of Imaging Physics, 6Department of Cancer Systems Imaging, 7Department of
Diagnostic Radiology The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, TX 77030, United States
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Correspondence Email:
[email protected] KEYWORDS: nanomatryoshka, magnetic resonance, contrast agent, fluorescence, photostability
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ABSTRACT Engineering a compact, near-infrared plasmonic nanostructure with integrated image-enhancing agents for combined imaging and therapy is an important nanomedical challenge. Recently we showed that Au@SiO2@Au nanomatryoshkas (NM) are a highly promising nanostructure for hosting either T1 MRI or fluorescent contrast agents with a photothermal therapeutic response in a compact geometry. Here we show that a near-infrared-resonant NM can provide simultaneous contrast enhancement for both T 1 magnetic resonance imaging (MRI) and fluorescence optical imaging (FOI) by encapsulating both types of contrast agents in the internal silica layer between the Au core and shell. We also show that this method of T 1 enhancement is even more effective for Fe(III), a potentially safer contrast agent compared to Gd(III). Fe-NM based contrast agents are found to have relaxivities 2X greater than those found in the widely used Gadolinium chelate, Gd(III) DOTA, providing a practical alternative that would eliminate Gd(III) patient exposure entirely. This dual-modality nanostructure can not only enable tissue visualization with MRI, but also fluorescence-based nanoparticle tracking, for quantifying nanoparticle distributions in vivo, in addition to a near-infrared photothermal therapeutic response.
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Theranostic (therapeutic and diagnostic) near-infrared (NIR) resonant gold nanoparticles (NP) are highly desired in biomedicine due to their excellent biocompatibility, long blood circulation time, and strong photothermal properties. 1-2 NIR NPs can be conjugated to avoid various tissuerelated immune reactions and can cross cell membrane barriers, enabling advanced therapy. 3 Despite their outstanding potential as theranostic agents, the ability to determine their distribution and concentration at anatomically precise locations in the body, before, during, and after treatment is a critically important yet largely unfulfilled technical challenge. A key step towards accomplishing this goal is to design NIR NPs systems with incorporated imaging agents. Various theranostic NPs have been engineered to extend their circulation time, reduce nonspecific clearance, and enable drug molecule release to desired locations. 4-8 Additional imaging modalities have been added to these systems to visualize tumors and monitor treatment efficacy during and after therapy. Among the different imaging functionalities, MRI-active nanomaterials have several advantages, due to their non-invasive nature, high spatial and temporal resolution providing 3D topographical data, and sustained image contrast enhancement without signal reduction.9-11 MRI is a highly preferred bioimaging technique because it does not require the use of ionizing radiation or radiotracers.12-15 The two main classes of MRI contrast agents include T 1weighted (longitudinal-bright contrast) or T2-weighted (transverse-dark contrast) contrast agents. T2-weighted contrast agents are almost exclusively superparamagnetic iron oxide NPs, while T 1weighted contrast agents are mostly paramagnetic metal-chelate complexes.16 Due to the superior contrast enhancement provided by T1-weighted images, Gd(III)-chelates have been extensively used as MRI contrast agents. Gd(III) has been functionalized on the surface of Au nanostructures and, in this embodiment, can exhibit a markedly enhanced T 1 relaxivity.17-20 It is well understood that attaching molecular chelates to larger macrostructures should enhance the T1 relaxivity due to
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the reduced molecular tumbling of the contrast agent relative to water protons. 21 However, following nearly universal clinical use of Gd(III) chelates for MRI contrast enhancement worldwide, Gd deposition in tissues has been reported in patients with nephrogenic systemic fibrosis (NSF).22-23 (Nephrogenic systemic fibrosis (NSF) is a systemic disorder of patients with severe renal insufficiency who have received gadolinium (Gd)-based magnetic resonance contrast agents.) More recently, Gd deposits have been detected in the brain tissues of patients even without severe renal dysfunction following the administration of Gd(III) contrast agents. 24-25 These observations raise strong toxicity concerns, and clearly indicate that clearance of Gd-based contrast agents is an issue of utmost importance for patient safety. Indeed, these observations may ultimately result in regulating, restricting or even banning their use. For Gd(III) chelates, ligands are being developed to facilitate renal clearance, 26-27 however, for Gd(III) bound to nanoparticle surfaces, the potential for Gd(III) release in vivo becomes a serious concern. Recently, Marangoni et al. secured Gd(III) chelates within a NIR Au@SiO2 @Au nanomatryoshka (NM) to simultaneously enhance T1 relaxivity while reducing toxicity by containment of the Gd(III) chelates within the internal silica layer of the NM. 28 Sequestering Gd(III) contrast agents within a nanostructure could potentially reduce toxicity while maintaining enhanced imaging functionality. In addition to tumor imaging, theranostic NPs can be functionalized to enable particle localization, monitor biodistribution, and ensure adequate accumulation at the treatment site prior to photothermal therapy. Due to their strong fluorescence emission, chromophores have been attached to NPs to enable fluorescence imaging. 29-31 Free NIR-dye molecules typically have low quantum yield and low physiological stability and photostability. 32 Although Au NPs quench fluorescence signals when in proximity (
