A hybrid PET‐MRI: An integrated molecular‐genetic imaging system with HRRT‐PET and 7.0‐T MRI

A PET‐MRI fusion system is developed for molecular‐genetic imaging. The purpose of the system is to obtain images of the in‐vivo human brain using two high‐end imaging devices, an advanced PET and an ultrahigh‐field MRI. These are the HRRT‐PET, a high‐resolution research tomograph dedicated to brain imaging on the molecular level, and the 7.0‐T MRI, an ultrahigh field version used for morphological imaging. HRRT‐PET delivers high‐resolution molecular imaging with a resolution down to 2.5 mm FWHM, which is currently the highest spatial resolution available for the observation of the human brain's molecular activities, including enzymes and receptors, which are manipulated genetically, such as reporter genes and probes. The 7.0‐T MRI began to reveal submillimeter resolution images of the cortical as well as deep brain areas, down to 250 μm, which allows us to visualize the fine details of the cortical and brainstem areas, including the line of Gennari in the visual cortex and the corticospinal tracts in the pontine area. The current PET‐MRI fusion imaging system produces the highest quality images of molecular and genetic activities of the human brain in vivo. It is starting to provide many answers to the key questions about the neurological diseases. Some of these start providing answers to many cognitive neuroscience problems with clear molecular and genetic bases. There is great potential in the PET‐MRI for early diagnosis of cancers as well as other neurological diseases, which we were previously unable to diagnose, such as microscopic molecular changes that occur in Parkinson's and Alzheimer's diseases. © 2007 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 17, 252–265, 2007     

Dendrimer‐Assisted Formation of Fe3O4/Au Nanocomposite Particles for Targeted Dual Mode CT/MR Imaging of Tumors

A unique dendrimer‐assisted approach is reported to create Fe₃O₄/Au nanocomposite particles (NCPs) for targeted dual mode computed tomography/magnetic resonance (CT/MR) imaging of tumors. In this approach, preformed Fe₃O₄ nanoparticles (NPs) are assembled with multilayers of poly(γ‐glutamic acid) (PGA)/poly(l ‐lysine)/PGA/folic acid (FA)‐modified dendrimer‐entrapped gold nanoparticles via a layer‐by‐layer self‐assembly technique. The interlayers are crosslinked via 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide chemistry, the assembled Au core NPs are then used as seed particles for subsequent seed‐mediated growth of Au shells via iterative Au salt reduction process, and subsequent acetylation of the remaining amines of dendrimers leads to the formation of Fe₃O₄/Au_n.Ac‐FA NCPs with a tunable molar ratio of Au/Fe₃O₄. It is shown that the Fe₃O₄/Au_n.Ac‐FA NCPs at an optimized Au/Fe₃O₄ molar ratio of 2.02 display a relatively high R₂ relaxivity (92.67 × 10^?3 M^?1 s^?1) and good X‐ray attenuation property, and are cytocompatible and hemocompatible in the given concentration range. Importantly, with the FA‐mediated targeting, the Fe₃O₄/Au_n.Ac‐FA NCPs are able to be specifically uptaken by cancer cells overexpressing FA receptors, and be used as an efficient nanoprobe for targeted dual mode CT/MR imaging of a xenografted tumor model. With the versatile dendrimer chemistry, the developed Fe₃O₄/Au NCPs may be differently functionalized, thereby providing a unique platform for diagnosis and therapy of different biological systems.     

磁性氧化铁高效磁共振造影剂的制备及应用

采用高温热分解法, 以乙酰丙酮铁为铁源, 生物相容性良好的聚乙二醇(PEG1000)作为溶剂、还原剂及修饰剂制备PEG修饰的氧化铁纳米粒子(PEG-SPIONs), 并研究其在小鼠体内的造影效果。X射线衍射(XRD)分析表明样品中含有Fe₃O₄晶相。透射电镜(TEM)结果显示, 合成的PEG-SPIONs形貌均一, 主要为等轴晶形, 纳米粒度及电位分析表明其表面呈负电性, 分散在水中的动力学粒径为20 nm。磁性能结果表明合成的PEG-SPIONs室温下具有超顺磁性, 并且具有较高的r₂/r₁值。细胞活性研究表明PEG-SPIONs具有较低的生物毒性, 体内的磁共振成像结果显示出PEG-SPIONs优异的对比增强效果, 说明PEG-SPIONs可以作为高效的T₂磁共振成像造影剂。     

Nanoparticles for Optical Molecular Imaging of Atherosclerosis

Molecular imaging contributes to future personalized medicine dedicated to the treatment of cardiovascular disease, the leading cause of mortality in industrialized countries. Endoscope‐compatible optical imaging techniques would offer a stand‐alone alternative and high spatial resolution validation technique to clinically accepted imaging techniques in the (intravascular) assessment of vulnerable atherosclerotic lesions, which are predisposed to initiate acute clinical events. Efficient optical visualization of molecular epitopes specific for vulnerable atherosclerotic lesions requires targeting of high‐quality optical‐contrast‐enhancing particles. In this review, we provide an overview of both current optical nanoparticles and targeting ligands for optical molecular imaging of atherosclerotic lesions and speculate on their applicability in the clinical setting.

     

Development of Novel Tumor‐Targeted Theranostic Nanoparticles Activated by Membrane‐Type Matrix Metalloproteinases for Combined Cancer Magnetic Resonance Imaging and Therapy

A major drawback with current cancer therapy is the prevalence of unrequired dose‐limiting toxicity to non‐cancerous tissues and organs, which is further compounded by a limited ability to rapidly and easily monitor drug delivery, pharmacodynamics and therapeutic response. In this report, the design and characterization of novel multifunctional “theranostic” nanoparticles (TNPs) is described for enzyme‐specific drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery. TNPs are synthesized by conjugation of FDA‐approved iron oxide nanoparticles ferumoxytol to an MMP‐activatable peptide conjugate of azademethylcolchicine (ICT), creating CLIO‐ICTs (TNPs). Significant cell death is observed in TNP‐treated MMP‐14 positive MMTV‐PyMT breast cancer cells in vitro, but not MMP‐14 negative fibroblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV‐PyMT tumor‐bearing mice and subsequent MRI demonstrates significant tumor selective accumulation of the TNP, an observation confirmed by histopathology. Treatment with CLIO‐ICTs induces a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death is observed in normal tissues following treatment with CLIO‐ICTs, ICT, or ferumoxytol. These findings demonstrate proof of concept for a new nanotemplate that integrates tumor specificity, drug delivery and in vivo imaging into a single TNP entity through attachment of enzyme‐activated prodrugs onto magnetic nanoparticles. This novel approach holds the potential to significantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens.     

Smart Magnetic Fluorescent Nanoparticle Imaging Probes to Monitor MicroRNAs

An imaging system that can be used to evaluate the expression levels of microRNAs during neuronal development can provide noninvasive information for investigating a variety of biological phenomena related to microRNAs (miRNAs, miRs). Herein, the development of a novel imaging platform to monitor intracellular miR124a during neuronal differentiation is reported using rhodamine‐coated cobalt ferrite magnetic fluorescent (MF) nanoparticles linked to a quenching molecular system containing an miR124a binding sequence (MF‐miR124a beacon). During neuronal differentiation, in vitro fluorescence signals of the MF‐miR124a beacon are significantly increased under conditions where miR124a is highly expressed, and dramatically return to the original quenched fluorescence after anti‐miR124a treatment. In vivo fluorescence images show enhanced fluorescence signals in mice with P19 cells within a poly‐L ‐lactic acid scaffold after induction of neuronal differentiation. In addition, magnetic resonance (MR) images provide in vivo tracking of cells containing the MF‐miR124a beacon. These studies represent the first step toward the use of nanotechnological imaging of mature miRNA, and this technique could be used for cellular tracking with a MR imaging system as well as for simultaneous monitoring of the miRNA expression pattern in vivo.     

Smart‐Dust‐Nanorice for Enhancement of Endogenous Raman Signal,Contrast in Photoacoustic Imaging,and T2‐Shortening in Magnetic Resonance Imaging

Raman microspectroscopy provides chemo‐selective image contrast, sub‐micrometer resolution, and multiplexing capabilities. However, it suffers from weak signals resulting in image‐acquisition times of up to several hours. Surface‐enhanced Raman scattering (SERS) can dramatically enhance signals of molecules in close vicinity of metallic surfaces and overcome this limitation. Multimodal, SERS‐active nanoparticles are usually labeled with Raman marker molecules, limiting SERS to the coating material. In order to realize multimodal imaging while acquiring the rich endogenous vibronic information of the specimen, a core–shell particle based on “Nanorice”, where a spindle‐shaped iron oxide core is encapsulated by a closed gold shell, is developed. An ultrathin layer of silica prevents agglomeration and unwanted chemical interaction with the specimen. This approach provides Raman signal enhancement due to plasmon resonance effects of the shell while the optical absorption in the near‐infrared spectral region provides contrast in photoacoustic tomography. Finally, T2‐relaxation of a magnetic resonance imaging (MRI) experiment is altered by taking advantage of the iron oxide core. The feasibility for Raman imaging is evaluated by nearfield simulations and experimental studies on the primate cell line COS1. MRI and photoacoustics are demonstrated in agarose phantoms illustrating the promising translational nature of this strategy for clinical applications in radiology.     

High‐Performance Upconversion Nanoprobes for Multimodal MR Imaging of Acute Ischemic Stroke

Multimodal magnetic resonance (MR) imaging, including MR angiography (MRA) and MR perfusion (MRP), plays a critical role in the diagnosis and surveillance of acute ischemic stroke. However, these techniques are hindered by the low T₁ relaxivity, short circulation time, and high leakage rate from vessels of clinical Magnevist. To address these problems, nontoxic polyethylene glycol (PEG)ylated upconversion nanoprobes (PEG‐UCNPs) are synthesized and first adopted for excellent MRA and MRP imaging, featuring high diagnostic sensitivity toward acute ischemic stroke in high‐resolution imaging. The investigations show that the agent possesses superior advantages over clinical Magnevist, such as much higher relaxivity, longer circulation time, and lower leakage rate, which guarantee much better imaging efficiency. Remarkably, an extremely small dosage (5 mg Gd kg^?1) of PEG‐UCNPs provides high‐resolution MRA imaging with the vascular system delineated much clearer than the Magnevist with clinical dosage as high as 108 mg Gd kg^?1. On the other hand, the long circulation time of PEG‐UCNPs enables the surveillance of the progression of ischemic stroke using MRA or MRP. Once translated, these PEG‐UCNPs are expected to be a promising candidate for substituting the clinical Magnevist in MRA and MRP, which will significantly lengthen the imaging time window and improve the overall diagnostic efficiency.     

Synthesis of Brightly PEGylated Luminescent Magnetic Upconversion Nanophosphors for Deep Tissue and Dual MRI Imaging

A method is developed to fabricate monodispersed biocompatible Yb/Er or Yb/Tm doped β‐NaGdF₄ upconversion phosphors using polyelectrolytes to prevent irreversible particle aggregation during conversion of the precursor, Gd₂O(CO₃)₂?H₂O:Yb/Er or Yb/Tm, to β‐NaGdF₄:Yb/Er or Yb/Tm. The polyelectrolyte on the outer surface of nanophosphors also provided an amine tag for PEGylation. This method is also employed to fabricate PEGylated magnetic upconversion phosphors with Fe₃O₄ as the core and β‐NaGdF₄ as a shell. These magnetic upconversion nanophosphors have relatively high saturation magnetization (7.0 emu g^?1) and magnetic susceptibility (1.7 × 10^?2 emu g^?1 Oe^?1), providing them with large magnetophoretic mobilities. The magnetic properties for separation and controlled release in flow, their optical properties for cell labeling, deep tissue imaging, and their T₁‐ and T₂‐weighted magnetic resonance imaging (MRI) relaxivities are studied. The magnetic upconversion phosphors display both strong magnetophoresis, dual MRI imaging (r₁ = 2.9 mM^?1 s^?1, r₂ = 204 mM^?1 s^?1), and bright luminescence under 1 cm chicken breast tissue.     

Intracellular Construction of Cathepsin B-Guided Gadolinium Nanoparticles for Enhanced T2-Weighted MR Tumor Imaging

Magnetic resonance imaging (MRI) is a superior and noninvasive imaging technique with unlimited tissue penetration depth and superb spatiotemporal resolution, however, using intracellular self-assembly of Gd-containing nanoparticles to enhance the T₂-weighted MR contrast of cancer cells in vivo for precise tumor MRI is rarely reported. The lysosomal cysteine protease cathepsin B (CTSB) is regarded as an attractive biomarker for the early diagnosis of cancers and metastasis. Herein, taking advantage of a biocompatible condensation reaction, a “smart” Gd-based CTSB-responsive small molecular contrast agent VC-Gd-CBT is developed, which can self-assemble into large intracellular Gd-containing nanoparticles by glutathione reduction and CTSB cleavage to enhance the T₂-weighted MR contrast of CTSB-overexpressing MDA-MB-231 cells at 9.4 T. In vivo T₂-weighted MRI studies using MDA-MB-231 murine xenografts show that the T₂-weighted MR contrast change of tumors in VC-Gd-CBT-injected mice is distinctly larger than the mice injected with the commercial agent gadopentetate dimeglumine, or co-injected with CTSB inhibitor and VC-Gd-CBT, indicating that the accumulation of self-assembled Gd-containing nanoparticles at tumor sites effectively enhances the T₂-weighted MR tumor imaging. Hence, this CTSB-targeted small molecule VC-Gd-CBT has the potential to be employed as a T₂ contrast agent for the clinical diagnosis of cancers at an early stage.     

Facile Preparation of Multifunctional WS2/WOx Nanodots for Chelator‐Free 89Zr‐Labeling and In Vivo PET Imaging

While position emission tomography (PET) is an important molecular imaging technique for both preclinical research and clinical disease diagnosis/prognosis, chelator‐free radiolabeling has emerged as a promising alternative approach to label biomolecules or nanoprobes in a facile way. Herein, starting from bottom‐up synthesized WS₂ nanoflakes, this study fabricates a unique type of WS₂/WO_x nanodots, which can function as inherent hard oxygen donor for stable radiolabeling with Zirconium‐89 isotope (⁸⁹Zr). Upon simply mixing, ⁸⁹Zr can be anchored on the surface of polyethylene glycol (PEG) modified WS₂/WO_x (WS₂/WO_x‐PEG) nanodots via a chelator‐free method with surprisingly high labeling yield and great stability. A higher degree of oxidation in the WS₂/WO_x‐PEG sample (WS₂/WO_x (0.4)) produces more electron pairs, which would be beneficial for chelator‐free labeling of ⁸⁹Zr with higher yields, suggesting the importance of surface chemistry and particle composition to the efficiency of chelator‐free radiolabeling. Such ⁸⁹Zr‐WS₂/WO_x (0.4)‐PEG nanodots are found to be an excellent PET contrast agent for in vivo imaging of tumors upon intravenous administration, or mapping of draining lymph nodes after local injection.