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A Magneto-Optical Nanoplatform for Multimodality Imaging of Tumors in Mice Guosheng Song,†,‡ Xianchuang Zheng,‡ Youjuan Wang,† Xin Xia,† Steven Chu,§ and Jianghong Rao*,‡
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State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China ‡ Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, 1201 Welch Road, Stanford, California 94305-5484, United States § Departments of Physics and Molecular & Cellular Physiology, Stanford University, Stanford, California 94305, United States S Supporting Information *
ABSTRACT: Multimodality imaging involves the use of more imaging modes to image the same living subjects and is now generally preferred in clinics for cancer imaging. Here we present multimodalityMagnetic Particle Imaging (MPI), Magnetic Resonance Imaging (MRI), Photoacoustic, Fluorescentnanoparticles (termed MMPF NPs) for imaging tumor xenografts in living mice. MMPF NPs provide long-term (more than 2 months), dynamic, and accurate quantification, in vivo, of NPs and in real time by MPI. Moreover, MMPF NPs offer ultrasensitive MPI imaging of tumors (the tumor ROI increased by 30.6 times over that of preinjection). Moreover, the nanoparticle possessed a long-term blood circulation time (half-life at 49 h) and high tumor uptake (18% ID/g). MMPF NPs have been demonstrated for imaging breast and brain tumor xenografts in both subcutaneous and orthotopic models in mice via simultaneous MPI, MRI, fluorescence, and photoacoustic imaging with excellent tumor contrast to normal tissues. KEYWORDS: magnetic particle imaging, iron oxide nanoparticles, multimodality imaging, tumor imaging, long blood circulation, semiconducting polymers
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developing multimodal imaging probes that integrate multiple imaging modalities into a single agent to provide complementary imaging information for cancer diagnosis.2,11−14 Magnetic Particle Imaging (MPI) was first introduced by Gleich in 2005.15,16 By employing the nonlinear remagnetization behavior of superparamagnetic nanoparticles, MPI directly detects spatial distribution and local concentration of particles,16 and has the advantages of positive contrast, linear quantification, no background, and high sensitivity (nanograms of Fe) in comparison to MRI.13,17 In addition, MPI does not use ionizing radiation unlike CT, PET, and SPECT,9,14,18 but provides whole-body tomographic imaging.10,19 Furthermore, iron oxide nanoparticles were approved for clinic application.20,21 With the MPI scanner commercially available, MPI has gained increasing use for a variety of applications. We have
ancer remains one of the primary causes of human death. Early accurate detection of malignancy tumors is key to the fight of lowering the death rate of cancer.1,2 Biomedical imaging is indispensable for early detection and diagnosis of cancer.1−7 Many imaging modalities have been explored, such as magnetic resonance imaging (MRI), X-ray computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and optical imagingfluorescence and photoacoustic imaging. However, no single modality offers a perfect solution to the detection challenge, and each has its own shortcomings. For instance, MRI or CT suffers from low sensitivity for molecular imaging. Moreover, the high doses of contrast agents (such as gadolinium chelates or iopamidol) have to be administrated to enhance the signal intensity, which may be harmful to patients.1,8 SPECT and PET have high sensitivity but use ionizing radiation, in addition to low spatial resolution.9 Optical imaging is restricted by autofluorescence and depth limit of tissue penetration (even in the near-infrared II wavelength).9,10 Recently, numerous studies have focused on © XXXX American Chemical Society
Received: February 20, 2019 Accepted: June 11, 2019
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DOI: 10.1021/acsnano.9b01436 ACS Nano XXXX, XXX, XXX−XXX
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Figure 1. Synthesis and characterization of MMPF NPs. (a) Schematic preparation of MMPF NPs. (b) TEM image of Fe3O4 nanoparticles. (c) TEM image of MMPF NPs. (d) HAADF-STEM image of element distribution of Fe, C, S, and O in MMPF NPs. (e) UV−vis absorption spectra of MMPF NPs with various concentrations of Fe from 0 to 25 μg/mL. (f) Fluorescence spectra of MMPF NPs solutions with various concentrations of Fe from 0 to 12.5 μg/mL (excitation at 680 nm). (g−j) Fluorescence, T2-MRI, and MPI performance of MMPF NPs. (g) Plot of fluorescent signals versus the concentrations from 0 to 100 μg/mL of Fe (inset is the fluorescent images of tubes containing MMPF NPs from 0 to 100 μg/mL of Fe). (h) Plot of fluorescent signals versus the concentrations of MMPF NPs from 0 to 12.5 μg/mL of Fe. (i) Plot of MPI signals of MMPF NPs versus the concentrations from 0 to 100 μg/mL of Fe. (j) T2 relaxation rate (r2) of Feraheme and MMPF NPs solutions measured as the function of Fe concentration.
demonstrated that MPI is capable of noninvasively tracking cancer cells with 250-cells sensitivity in vivo.22 Iron oxide labeled macrophages and stem cells have been dynamically tracked by MPI in mice or rats.23 Tailored MPI tracers have been developed for imaging vascular, acute stroke, brain injury, gut bleeding, and lung perfusion in animal models, and even for inducing magnetic hyperthermia therapy.11,24−35 Based on its imaging principle,9,10 MPI is highly dependent on magnetic nanoparticles as tracer and iron oxide nanoparticles developed for MRI are not optimal for MPI. To date, only a few MPI tracers were developed for cancer imaging. Conolly et al. presented the first attempt to use PEGylated iron oxide for imaging cancer via systemic administration.27 Krishnan et al. further enhanced the tumor-targeting efficiency of iron oxide by lactoferrin conjugation and magnetic targeting.35 These reported MPI tracers have a relatively short blood circulation time (half-life
