Engineering of inorganic nanoparticles as magnetic resonance imaging contrast agents.

Magnetic resonance imaging (MRI) is a highly valuable non-invasive imaging tool owing to its exquisite soft tissue contrast, high spatial resolution, lack of ionizing radiation, and wide clinical applicability. Contrast agents (CAs) can be used to further enhance the sensitivity of MRI to obtain information-rich images. Recently, extensive research efforts have been focused on the design and synthesis of high-performance inorganic nanoparticle-based CAs to improve the quality and specificity of MRI. Herein, the basic rules, including the choice of metal ions, effect of electron motion on water relaxation, and involved mechanisms, of CAs for MRI have been elucidated in detail. In particular, various design principles, including size control, surface modification (e.g. organic ligand, silica shell, and inorganic nanolayers), and shape regulation, to impact relaxation of water molecules have been discussed in detail. Comprehensive understanding of how these factors work can guide the engineering of future inorganic nanoparticles with high relaxivity. Finally, we have summarized the currently available strategies and their mechanism for obtaining high-performance CAs and discussed the challenges and future developments of nanoparticulate CAs for clinical translation in MRI.

[1]  Zhi-Jun Liu,et al.  Development of PEGylated KMnF3 nanoparticles as a T1-weighted contrast agent: chemical synthesis, in vivo brain MR imaging, and accounting for high relaxivity. , 2013, Nanoscale.

[2]  In Su Lee,et al.  Hollow manganese oxide nanoparticles as multifunctional agents for magnetic resonance imaging and drug delivery. , 2009, Angewandte Chemie.

[3]  V. Pierre,et al.  Next generation, high relaxivity gadolinium MRI agents. , 2005, Bioconjugate chemistry.

[4]  Taeghwan Hyeon,et al.  Inorganic Nanoparticles for MRI Contrast Agents , 2009 .

[5]  E. Haacke,et al.  Theory of NMR signal behavior in magnetically inhomogeneous tissues: The static dephasing regime , 1994, Magnetic resonance in medicine.

[6]  F. Fang,et al.  Anchoring Group Effects of Surface Ligands on Magnetic Properties of Fe3O4 Nanoparticles: Towards High Performance MRI Contrast Agents , 2014, Advanced materials.

[7]  H. Daldrup-Link,et al.  Macrophage phagocytosis alters the MRI signal of ferumoxytol-labeled mesenchymal stromal cells in cartilage defects , 2016, Scientific Reports.

[8]  Jianlin Shi,et al.  In Vivo Bio‐Safety Evaluations and Diagnostic/Therapeutic Applications of Chemically Designed Mesoporous Silica Nanoparticles , 2013, Advanced materials.

[9]  Shuo Shi,et al.  Gd-Dots with Strong Ligand-Water Interaction for Ultrasensitive Magnetic Resonance Renography. , 2017, ACS nano.

[10]  Xin Yu,et al.  Engineering Gd-loaded nanoparticles to enhance MRI sensitivity via T1 shortening , 2013, Nanotechnology.

[11]  Zhuxian Zhou,et al.  Gadolinium-based contrast agents for magnetic resonance cancer imaging. , 2013, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[12]  Xiaoyuan Chen,et al.  Tumor Microenvironment‐Triggered Supramolecular System as an In Situ Nanotheranostic Generator for Cancer Phototherapy , 2017, Advanced materials.

[13]  Bongsoo Kim,et al.  Size-dependent magnetic properties of colloidal Mn(3)O(4) and MnO nanoparticles. , 2004, Angewandte Chemie.

[14]  Andrew Y. Wang,et al.  Preparation and control of the formation of single core and clustered nanoparticles for biomedical applications using a versatile amphiphilic diblock copolymer , 2010 .

[15]  Shreya Mukherjee,et al.  Redox-activated manganese-based MR contrast agent. , 2013, Journal of the American Chemical Society.

[16]  Jinwoo Cheon,et al.  Recent advances in magnetic nanoparticle-based multi-modal imaging. , 2015, Chemical Society reviews.

[17]  Liangping Zhou,et al.  Gd3+‐Ion‐Doped Upconversion Nanoprobes: Relaxivity Mechanism Probing and Sensitivity Optimization , 2013 .

[18]  A Paul Alivisatos,et al.  Localized surface plasmon resonances arising from free carriers in doped quantum dots. , 2011, Nature materials.

[19]  W. Tremel,et al.  Au@MnO nanoflowers: hybrid nanocomposites for selective dual functionalization and imaging. , 2010, Angewandte Chemie.

[20]  Q. Song,et al.  Shape control and associated magnetic properties of spinel cobalt ferrite nanocrystals. , 2004, Journal of the American Chemical Society.

[21]  Xiwen He,et al.  Facile synthesis of functional gadolinium-doped CdTe quantum dots for tumor-targeted fluorescence and magnetic resonance dual-modality imaging. , 2014, Journal of materials chemistry. B.

[22]  L. Prodi,et al.  Imaging agents based on lanthanide doped nanoparticles. , 2015, Chemical Society reviews.

[23]  Tymish Y. Ohulchanskyy,et al.  Combined Optical and MR Bioimaging Using Rare Earth Ion Doped NaYF4 Nanocrystals , 2009 .

[24]  E. Terreno,et al.  Improved paramagnetic liposomes for MRI visualization of pH triggered release. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[25]  G. Angelovski Heading toward Macromolecular and Nanosized Bioresponsive MRI Probes for Successful Functional Imaging. , 2017, Accounts of chemical research.

[26]  Thomas Meade,et al.  Effects of shape and size of cobalt ferrite nanostructures on their MRI contrast and thermal activation. , 2009, The journal of physical chemistry. C, Nanomaterials and interfaces.

[27]  Samuel A Wickline,et al.  Manganese-based MRI contrast agents: past, present and future. , 2011, Tetrahedron.

[28]  Yiwei Chen,et al.  Gadolinium-doped carbon dots with high quantum yield as an effective fluorescence and magnetic resonance bimodal imaging probe , 2016 .

[29]  Yongmin Chang,et al.  A facile synthesis, in vitro and in vivo MR studies of d-glucuronic acid-coated ultrasmall Ln₂O₃ (Ln = Eu, Gd, Dy, Ho, and Er) nanoparticles as a new potential MRI contrast agent. , 2011, ACS applied materials & interfaces.

[30]  B. Rutt,et al.  Application of the static dephasing regime theory to superparamagnetic iron‐oxide loaded cells , 2002, Magnetic resonance in medicine.

[31]  Kai Yang,et al.  Perfluorocarbon‐Loaded Hollow Bi2Se3 Nanoparticles for Timely Supply of Oxygen under Near‐Infrared Light to Enhance the Radiotherapy of Cancer , 2016, Advanced materials.

[32]  Sumaira Ashraf,et al.  In vivo degeneration and the fate of inorganic nanoparticles. , 2016, Chemical Society reviews.

[33]  Keishiro Tomoda,et al.  Biodistribution of colloidal gold nanoparticles after intravenous administration: effect of particle size. , 2008, Colloids and surfaces. B, Biointerfaces.

[34]  Kai Yang,et al.  Facile preparation of multifunctional upconversion nanoprobes for multimodal imaging and dual-targeted photothermal therapy. , 2011, Angewandte Chemie.

[35]  Grigory Tikhomirov,et al.  Caspase-responsive smart gadolinium-based contrast agent for magnetic resonance imaging of drug-induced apoptosis. , 2014, Chemical science.

[36]  G. Brudvig,et al.  Biocompatible and pH-sensitive PLGA encapsulated MnO nanocrystals for molecular and cellular MRI. , 2011, ACS nano.

[37]  L. Lartigue,et al.  Biotransformations of magnetic nanoparticles in the body , 2016 .

[38]  S. Nie,et al.  Reexamining the Effects of Particle Size and Surface Chemistry on the Magnetic Properties of Iron Oxide Nanocrystals: New Insights into Spin Disorder and Proton Relaxivity , 2008 .

[39]  Kai Yang,et al.  Catalase‐Loaded TaOx Nanoshells as Bio‐Nanoreactors Combining High‐Z Element and Enzyme Delivery for Enhancing Radiotherapy , 2016, Advanced materials.

[40]  Patrick Couvreur,et al.  Magnetic nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications. , 2012, Chemical reviews.

[41]  R. Reilly,et al.  What nephrologists need to know about gadolinium , 2007, Nature Clinical Practice Nephrology.

[42]  Jianlin Shi,et al.  Silica coated upconversion nanoparticles: a versatile platform for the development of efficient theranostics. , 2015, Accounts of chemical research.

[43]  Marc Vendrell,et al.  Intracellular glutathione detection using MnO(2)-nanosheet-modified upconversion nanoparticles. , 2011, Journal of the American Chemical Society.

[44]  Gang Bao,et al.  The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. , 2016, Nanomedicine.

[45]  Mark D Pagel,et al.  A review of responsive MRI contrast agents: 2005-2014. , 2015, Contrast media & molecular imaging.

[46]  Weihong Tan,et al.  Activatable fluorescence/MRI bimodal platform for tumor cell imaging via MnO2 nanosheet-aptamer nanoprobe. , 2014, Journal of the American Chemical Society.

[47]  P. Perriat,et al.  Hybrid gadolinium oxide nanoparticles: multimodal contrast agents for in vivo imaging. , 2007, Journal of the American Chemical Society.

[48]  Ick Chan Kwon,et al.  Multifunctional nanoparticles for multimodal imaging and theragnosis. , 2012, Chemical Society reviews.

[49]  G. Bao,et al.  Size-Dependent Heating of Magnetic Iron Oxide Nanoparticles. , 2017, ACS nano.

[50]  Liangzhu Feng,et al.  Intelligent Albumin–MnO2 Nanoparticles as pH‐/H2O2‐Responsive Dissociable Nanocarriers to Modulate Tumor Hypoxia for Effective Combination Therapy , 2016, Advanced materials.

[51]  Yang Sun,et al.  Manganese oxide-based multifunctionalized mesoporous silica nanoparticles for pH-responsive MRI, ultrasonography and circumvention of MDR in cancer cells. , 2012, Biomaterials.

[52]  M. Hoehn,et al.  Polyelectrolyte coating of iron oxide nanoparticles for MRI-based cell tracking. , 2012, Nanomedicine : nanotechnology, biology, and medicine.

[53]  Mauro Ferrari,et al.  Geometrical confinement of gadolinium-based contrast agents in nanoporous particles enhances T1 contrast , 2010, Nature nanotechnology.

[54]  Xiaoyuan Chen,et al.  Rethinking cancer nanotheranostics. , 2017, Nature reviews. Materials.

[55]  Jie Zheng,et al.  PEGylation and zwitterionization: pros and cons in the renal clearance and tumor targeting of near-IR-emitting gold nanoparticles. , 2013, Angewandte Chemie.

[56]  R. Pei,et al.  Gadolinium-based nanoscale MRI contrast agents for tumor imaging. , 2017, Journal of materials chemistry. B.

[57]  Jin-Sil Choi,et al.  Distance-dependent magnetic resonance tuning as a versatile MRI sensing platform for biological targets. , 2017, Nature materials.

[58]  S. Laurent,et al.  High Relaxivities and Strong Vascular Signal Enhancement for NaGdF4 Nanoparticles Designed for Dual MR/Optical Imaging , 2013, Advanced healthcare materials.

[59]  Daniela A Wilson,et al.  Manipulation of micro- and nanostructure motion with magnetic fields. , 2014, Soft matter.

[60]  I. Aoki,et al.  A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. , 2016, Nature nanotechnology.

[61]  B. Bay,et al.  Ultrasmall Ferrite Nanoparticles Synthesized via Dynamic Simultaneous Thermal Decomposition for High-Performance and Multifunctional T1 Magnetic Resonance Imaging Contrast Agent. , 2017, ACS nano.

[62]  Erik Kampert,et al.  Tuning of the size of Dy2O3 nanoparticles for optimal performance as an MRI contrast agent. , 2008, Journal of the American Chemical Society.

[63]  Anna Moore,et al.  In vivo magnetic resonance imaging of transgene expression , 2000, Nature Medicine.

[64]  Arno C Gutleb,et al.  Influence of Size and Shape on the Anatomical Distribution of Endotoxin-Free Gold Nanoparticles. , 2017, ACS nano.

[65]  Hakho Lee,et al.  Recent Developments in Magnetic Diagnostic Systems. , 2015, Chemical reviews.

[66]  R. Lauffer,et al.  Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. , 1999, Chemical reviews.

[67]  E. Gianolio,et al.  An MRI Method To Map Tumor Hypoxia Using Red Blood Cells Loaded with a pO2-Responsive Gd-Agent. , 2015, ACS nano.

[68]  R. V. Van Duyne,et al.  Localized surface plasmon resonance spectroscopy and sensing. , 2007, Annual review of physical chemistry.

[69]  Dong Chen,et al.  The shape effect of mesoporous silica nanoparticles on biodistribution, clearance, and biocompatibility in vivo. , 2011, ACS nano.

[70]  Controlled clustering of superparamagnetic nanoparticles using block copolymers: design of new contrast agents for magnetic resonance imaging. , 2005, Journal of the American Chemical Society.

[71]  S. Hurley,et al.  Multifunctional stable and pH-responsive polymer vesicles formed by heterofunctional triblock copolymer for targeted anticancer drug delivery and ultrasensitive MR imaging. , 2010, ACS nano.

[72]  Wenpei Fan,et al.  Real-time in vivo quantitative monitoring of drug release by dual-mode magnetic resonance and upconverted luminescence imaging. , 2014, Angewandte Chemie.

[73]  Hsuan-Liang Liu,et al.  Preparation of ICG-FePt nanoparticles promising for magnetic resonance imaging contrast agent and hyperthermia applications , 2016 .

[74]  S. Moon,et al.  Ultrathin Interface Regime of Core-Shell Magnetic Nanoparticles for Effective Magnetism Tailoring. , 2017, Nano letters.

[75]  Enzo Terreno,et al.  Lanthanide(III) chelates for NMR biomedical applications , 1998 .

[76]  Taeghwan Hyeon,et al.  Designed synthesis of uniformly sized iron oxide nanoparticles for efficient magnetic resonance imaging contrast agents. , 2012, Chemical Society reviews.

[77]  Shelton D Caruthers,et al.  Revisiting an old friend: manganese-based MRI contrast agents. , 2011, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[78]  Shuming Nie,et al.  Single chain epidermal growth factor receptor antibody conjugated nanoparticles for in vivo tumor targeting and imaging. , 2008, Small.

[79]  In Su Lee,et al.  Mn(2+)-doped silica nanoparticles for hepatocyte-targeted detection of liver cancer in T1-weighted MRI. , 2013, Biomaterials.

[80]  R. Prosser,et al.  Water-Soluble GdF3 and GdF3/LaF3 NanoparticlesPhysical Characterization and NMR Relaxation Properties , 2006 .

[81]  Weili Lin,et al.  Mesoporous silica nanospheres as highly efficient MRI contrast agents. , 2008, Journal of the American Chemical Society.

[82]  Zhen Cheng,et al.  Effects of nanoparticle size on cellular uptake and liver MRI with polyvinylpyrrolidone-coated iron oxide nanoparticles. , 2010, ACS nano.

[83]  Scott E. Fraser,et al.  In vivo visualization of gene expression using magnetic resonance imaging , 2000, Nature Biotechnology.

[84]  Dwight G Nishimura,et al.  FeCo/graphitic-shell nanocrystals as advanced magnetic-resonance-imaging and near-infrared agents , 2006, Nature materials.

[85]  Xiaolian Sun,et al.  Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment. , 2017, Chemical Society reviews.

[86]  Taeghwan Hyeon,et al.  Large-scale synthesis of uniform and extremely small-sized iron oxide nanoparticles for high-resolution T1 magnetic resonance imaging contrast agents. , 2011, Journal of the American Chemical Society.

[87]  Liangping Zhou,et al.  Ultrasmall NaGdF4 Nanodots for Efficient MR Angiography and Atherosclerotic Plaque Imaging , 2014, Advanced materials.

[88]  Yongmin Chang,et al.  Paramagnetic ultrasmall gadolinium oxide nanoparticles as advanced T1 MRI contrast agent: account for large longitudinal relaxivity, optimal particle diameter, and in vivo T1 MR images. , 2009, ACS nano.

[89]  Han Lin,et al.  Metalloporphyrin-Encapsulated Biodegradable Nanosystems for Highly Efficient Magnetic Resonance Imaging-Guided Sonodynamic Cancer Therapy. , 2017, Journal of the American Chemical Society.

[90]  Yongmin Chang,et al.  Paramagnetic dysprosium oxide nanoparticles and dysprosium hydroxide nanorods as T₂ MRI contrast agents. , 2012, Biomaterials.

[91]  Rui Tian,et al.  Artificial local magnetic field inhomogeneity enhances T2 relaxivity , 2017, Nature Communications.

[92]  Lianzhou Wang,et al.  Break‐up of Two‐Dimensional MnO2 Nanosheets Promotes Ultrasensitive pH‐Triggered Theranostics of Cancer , 2014, Advanced materials.

[93]  Taeghwan Hyeon,et al.  Ultra-large-scale syntheses of monodisperse nanocrystals , 2004, Nature materials.

[94]  Eun-Kyung Lim,et al.  pH‐Triggered Drug‐Releasing Magnetic Nanoparticles for Cancer Therapy Guided by Molecular Imaging by MRI , 2011, Advanced materials.

[95]  M. Hiraoka,et al.  Monitoring of biological one-electron reduction by (19)F NMR using hypoxia selective activation of an (19)F-labeled indolequinone derivative. , 2009, Journal of the American Chemical Society.

[96]  B. Sitharaman,et al.  Water-soluble gadofullerenes: toward high-relaxivity, pH-responsive MRI contrast agents. , 2005, Journal of the American Chemical Society.

[97]  Hui Mao,et al.  Improving the Magnetic Resonance Imaging Contrast and Detection Methods with Engineered Magnetic Nanoparticles , 2012, Theranostics.

[98]  Bing Xu,et al.  Multifunctional yolk-shell nanoparticles: a potential MRI contrast and anticancer agent. , 2008, Journal of the American Chemical Society.

[99]  R. Wu,et al.  Integrating Anatomic and Functional Dual-Mode Magnetic Resonance Imaging: Design and Applicability of a Bifunctional Contrast Agent. , 2016, ACS nano.

[100]  Jie Zheng,et al.  Clearance Pathways and Tumor Targeting of Imaging Nanoparticles. , 2015, ACS nano.

[101]  Mingyuan Gao,et al.  Magnetic/upconversion fluorescent NaGdF4:Yb,Er nanoparticle-based dual-modal molecular probes for imaging tiny tumors in vivo. , 2013, ACS nano.

[102]  A. Almutairi,et al.  Compact Micellization: A Strategy for Ultrahigh T1 Magnetic Resonance Contrast with Gadolinium-Based Nanocrystals. , 2016, ACS nano.

[103]  Jianlin Shi,et al.  PEGylated NaHoF4 nanoparticles as contrast agents for both X-ray computed tomography and ultra-high field magnetic resonance imaging. , 2016, Biomaterials.

[104]  A. Koretsky,et al.  The use of silica coated MnO nanoparticles to control MRI relaxivity in response to specific physiological changes. , 2012, Biomaterials.

[105]  Goran Angelovski,et al.  What We Can Really Do with Bioresponsive MRI Contrast Agents. , 2016, Angewandte Chemie.

[106]  Ming Zhao,et al.  Non-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent , 2001, Nature Medicine.

[107]  Taeghwan Hyeon,et al.  Theranostic Probe Based on Lanthanide‐Doped Nanoparticles for Simultaneous In Vivo Dual‐Modal Imaging and Photodynamic Therapy , 2012, Advanced materials.

[108]  M. Busquets,et al.  Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents , 2015, International journal of nanomedicine.

[109]  Sung Tae Kim,et al.  Development of a T1 contrast agent for magnetic resonance imaging using MnO nanoparticles. , 2007, Angewandte Chemie.

[110]  A. Sherry,et al.  Oxidative Conversion of a Europium(II)-Based T1 Agent into a Europium(III)-Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging. , 2016, Angewandte Chemie.

[111]  Y. Gossuin,et al.  MnO-labeled cells: positive contrast enhancement in MRI. , 2012, The journal of physical chemistry. B.

[112]  Aiguo Wu,et al.  Iron Oxide Nanoparticle Based Contrast Agents for Magnetic Resonance Imaging. , 2017, Molecular pharmaceutics.

[113]  S. Zou,et al.  Engineered gadolinium-doped carbon dots for magnetic resonance imaging-guided radiotherapy of tumors. , 2017, Biomaterials.

[114]  Giorgio Russolillo,et al.  Partial least squares algorithms and methods , 2013 .

[115]  Xiaoxia Du,et al.  Silica‐Coated Manganese Oxide Nanoparticles as a Platform for Targeted Magnetic Resonance and Fluorescence Imaging of Cancer Cells , 2010 .

[116]  K. Zhong,et al.  Casp3/7-Instructed Intracellular Aggregation of Fe3O4 Nanoparticles Enhances T2 MR Imaging of Tumor Apoptosis. , 2016, Nano letters.

[117]  Lianzhou Wang,et al.  Multifunctional Graphene Oxide‐based Triple Stimuli‐Responsive Nanotheranostics , 2014 .

[118]  Chenjie Xu,et al.  Ultrasmall c(RGDyK)-coated Fe3O4 nanoparticles and their specific targeting to integrin alpha(v)beta3-rich tumor cells. , 2008, Journal of the American Chemical Society.

[119]  A. Lu,et al.  Magnetic nanoparticles: synthesis, protection, functionalization, and application. , 2007, Angewandte Chemie.

[120]  Xiue Jiang,et al.  MnO2 Gatekeeper: An Intelligent and O2‐Evolving Shell for Preventing Premature Release of High Cargo Payload Core, Overcoming Tumor Hypoxia, and Acidic H2O2‐Sensitive MRI , 2017 .

[121]  A. Roch,et al.  Superparamagnetic colloid suspensions: Water magnetic relaxation and clustering , 2005 .

[122]  Yan Zhang,et al.  Single-Phase Dy2O3:Tb3+ Nanocrystals as Dual-Modal Contrast Agent for High Field Magnetic Resonance and Optical Imaging , 2011 .

[123]  M. Botta,et al.  Substituent effects on Gd(III)-based MRI contrast agents: optimizing the stability and selectivity of the complex and the number of coordinated water molecules. , 2006, Inorganic chemistry.

[124]  J. Morrow,et al.  A redox-activated MRI contrast agent that switches between paramagnetic and diamagnetic states. , 2013, Angewandte Chemie.

[125]  Sik-Yum Lee,et al.  Bayesian structural equation model , 2014 .

[126]  S. H. Koenig,et al.  Transverse relaxation of solvent protons induced by magnetized spheres: Application to ferritin, erythrocytes, and magnetite , 1987, Magnetic resonance in medicine.

[127]  L. Helm,et al.  Water exchange on metal ions: experiments and simulations , 1999 .

[128]  Oliver T. Bruns,et al.  A highly effective, nontoxic T1 MR contrast agent based on ultrasmall PEGylated iron oxide nanoparticles. , 2009, Nano letters.

[129]  S. Gambhir,et al.  Nanomaterials for In Vivo Imaging. , 2017, Chemical reviews.

[130]  J. Duerk,et al.  Magnetite‐Loaded Polymeric Micelles as Ultrasensitive Magnetic‐Resonance Probes , 2005 .

[131]  Ming Ma,et al.  Structure-property relationships in manganese oxide--mesoporous silica nanoparticles used for T1-weighted MRI and simultaneous anti-cancer drug delivery. , 2012, Biomaterials.

[132]  Teruyuki Kondo,et al.  Size‐Controlled and Biocompatible Gd2O3 Nanoparticles for Dual Photoacoustic and MR Imaging , 2012, Advanced healthcare materials.

[133]  Chad A Mirkin,et al.  Multimodal gadolinium-enriched DNA-gold nanoparticle conjugates for cellular imaging. , 2009, Angewandte Chemie.

[134]  R. Weissleder,et al.  Molecular imaging in drug discovery and development , 2003, Nature Reviews Drug Discovery.

[135]  Xiaoyuan Chen,et al.  Color-tunable Gd-Zn-Cu-In-S/ZnS quantum dots for dual modality magnetic resonance and fluorescence imaging , 2014, Nano Research.

[136]  Xiaoqun Gong,et al.  Impact of Surface Polyethylene Glycol (PEG) Density on Biodegradable Nanoparticle Transport in Mucus ex Vivo and Distribution in Vivo. , 2015, ACS nano.

[137]  Chung-Yuan Mou,et al.  Mesoporous silica nanoparticles as a delivery system of gadolinium for effective human stem cell tracking. , 2008, Small.

[138]  Meng-Lin Li,et al.  Infrared-active quadruple contrast FePt nanoparticles for multiple scale molecular imaging. , 2016, Biomaterials.

[139]  Stefan Vogt,et al.  DNA-TiO2 nanoconjugates labeled with magnetic resonance contrast agents. , 2007, Journal of the American Chemical Society.

[140]  Oliver T. Bruns,et al.  Size and surface effects on the MRI relaxivity of manganese ferrite nanoparticle contrast agents. , 2007, Nano letters.

[141]  Taeghwan Hyeon,et al.  Mesoporous Silica-Coated Hollow Manganese Oxide Nanoparticles as Positive T1 Contrast Agents for Labeling and MRI Tracking of Adipose-Derived Mesenchymal Stem Cells , 2011, Journal of the American Chemical Society.

[142]  R. Brooks,et al.  On T2‐shortening by strongly magnetized spheres: A partial refocusing model , 2002, Magnetic resonance in medicine.

[143]  Z. Fayad,et al.  Clearance of Iron Oxide Particles in Rat Liver: Effect of Hydrated Particle Size and Coating Material on Liver Metabolism , 2006, Investigative radiology.

[144]  Chunhua Yan,et al.  PAA-capped GdF3 nanoplates as dual-mode MRI and CT contrast agents , 2015 .

[145]  Xiaogang Liu,et al.  Preparation of core-shell NaGdF4 nanoparticles doped with luminescent lanthanide ions to be used as upconversion-based probes , 2014, Nature Protocols.

[146]  Zijian Zhou,et al.  Geometrically confined ultrasmall gadolinium oxide nanoparticles boost the T(1) contrast ability. , 2016, Nanoscale.

[147]  Jianlin Shi,et al.  Chemical Design and Synthesis of Functionalized Probes for Imaging and Treating Tumor Hypoxia. , 2017, Chemical reviews.

[148]  Jianlin Shi,et al.  "Manganese Extraction" Strategy Enables Tumor-Sensitive Biodegradability and Theranostics of Nanoparticles. , 2016, Journal of the American Chemical Society.

[149]  Qingfeng Xiao,et al.  Dual-targeting upconversion nanoprobes across the blood-brain barrier for magnetic resonance/fluorescence imaging of intracranial glioblastoma. , 2014, ACS nano.

[150]  P. Callaghan,et al.  Simple synthesis and functionalization of iron nanoparticles for magnetic resonance imaging. , 2011, Angewandte Chemie.

[151]  Yong-Min Huh,et al.  Urchin-shaped manganese oxide nanoparticles as pH-responsive activatable T1 contrast agents for magnetic resonance imaging. , 2011, Angewandte Chemie.

[152]  Francis Vocanson,et al.  Gadolinium chelate coated gold nanoparticles as contrast agents for both X-ray computed tomography and magnetic resonance imaging. , 2008, Journal of the American Chemical Society.

[153]  Jinwoo Cheon,et al.  Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging , 2007, Nature Medicine.

[154]  Laura M Ensign,et al.  PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. , 2016, Advanced drug delivery reviews.

[155]  Lianzhou Wang,et al.  Positive and Negative Lattice Shielding Effects Co‐existing in Gd (III) Ion Doped Bifunctional Upconversion Nanoprobes , 2011 .

[156]  Efstathios Karathanasis,et al.  Shaping cancer nanomedicine: the effect of particle shape on the in vivo journey of nanoparticles. , 2014, Nanomedicine.

[157]  Yuancheng Li,et al.  Exerting Enhanced Permeability and Retention Effect Driven Delivery by Ultrafine Iron Oxide Nanoparticles with T1-T2 Switchable Magnetic Resonance Imaging Contrast. , 2017, ACS nano.

[158]  A. Alivisatos Semiconductor Clusters, Nanocrystals, and Quantum Dots , 1996, Science.

[159]  Warren C W Chan,et al.  The effect of nanoparticle size, shape, and surface chemistry on biological systems. , 2012, Annual review of biomedical engineering.

[160]  Matthias Ernst,et al.  Cancer research: past, present and future , 2011, Nature Reviews Cancer.

[161]  Teri W. Odom,et al.  Shape-Dependent Relaxivity of Nanoparticle-Based T1 Magnetic Resonance Imaging Contrast Agents. , 2016, The journal of physical chemistry. C, Nanomaterials and interfaces.

[162]  Jianlin Shi On the synergetic catalytic effect in heterogeneous nanocomposite catalysts. , 2013, Chemical reviews.

[163]  Armando J. Marenco,et al.  Design and Regulation of NaHoF4 and NaDyF4 Nanoparticles for High-Field Magnetic Resonance Imaging , 2016 .

[164]  Elke Debroye,et al.  Towards polymetallic lanthanide complexes as dual contrast agents for magnetic resonance and optical imaging. , 2014, Chemical Society reviews.

[165]  Boguslaw Tomanek,et al.  NaDyF4 Nanoparticles as T2 Contrast Agents for Ultrahigh Field Magnetic Resonance Imaging. , 2012, The journal of physical chemistry letters.

[166]  Alke Petri-Fink,et al.  Form Follows Function: Nanoparticle Shape and Its Implications for Nanomedicine. , 2017, Chemical reviews.

[167]  Yaming Zhou,et al.  Single Molecular Wells–Dawson‐Like Heterometallic Cluster for the In Situ Functionalization of Ordered Mesoporous Carbon: A T 1‐ and T 2‐Weighted Dual‐Mode Magnetic Resonance Imaging Agent and Drug Delivery System , 2017 .

[168]  Ralph Weissleder,et al.  Magnetic relaxation switches capable of sensing molecular interactions , 2002, Nature Biotechnology.

[169]  Ioannis Lavdas,et al.  CXCR4-Targeted and MMP-Responsive Iron Oxide Nanoparticles for Enhanced Magnetic Resonance Imaging** , 2014, Angewandte Chemie.

[170]  F. Fang,et al.  NaGdF4 nanoparticle-based molecular probes for magnetic resonance imaging of intraperitoneal tumor xenografts in vivo. , 2013, ACS Nano.

[171]  Joop A. Peters,et al.  MRI contrast agents based on dysprosium or holmium. , 2011, Progress in nuclear magnetic resonance spectroscopy.

[172]  C. Yeh,et al.  Synthesis of Gd doped CdSe nanoparticles for potential optical and MR imaging applications , 2010 .

[173]  Jianlin Shi,et al.  Hypoxia Induced by Upconversion-Based Photodynamic Therapy: Towards Highly Effective Synergistic Bioreductive Therapy in Tumors. , 2015, Angewandte Chemie.

[174]  F. Fang,et al.  Rational design of multifunctional magnetic mesoporous silica nanoparticle for tumor-targeted magnetic resonance imaging and precise therapy. , 2016, Biomaterials.

[175]  Kajsa Uvdal,et al.  Synthesis and characterization of PEGylated Gd2O3 nanoparticles for MRI contrast enhancement. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[176]  Chen Chang,et al.  High-contrast paramagnetic fluorescent mesoporous silica nanorods as a multifunctional cell-imaging probe. , 2008, Small.

[177]  Jinwoo Cheon,et al.  Nanoscale size effect of magnetic nanocrystals and their utilization for cancer diagnosis via magnetic resonance imaging. , 2005, Journal of the American Chemical Society.

[178]  T. Hyeon,et al.  Paramagnetic inorganic nanoparticles as T1 MRI contrast agents. , 2014, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[179]  Feng Chen,et al.  Biodegradable and Renal Clearable Inorganic Nanoparticles , 2015, Advanced science.

[180]  Liming Nie,et al.  T1-T2 Dual-Modal Magnetic Resonance Imaging: From Molecular Basis to Contrast Agents. , 2017, ACS nano.

[181]  Dong Chen,et al.  The effect of the shape of mesoporous silica nanoparticles on cellular uptake and cell function. , 2010, Biomaterials.

[182]  H. Daldrup-Link,et al.  Magnetic resonance imaging of stem cell apoptosis in arthritic joints with a caspase activatable contrast agent. , 2015, ACS Nano.

[183]  I. Solomon Relaxation Processes in a System of Two Spins , 1955 .

[184]  Wenyong Hu,et al.  The properties of Gd2O3-assembled silica nanocomposite targeted nanoprobes and their application in MRI. , 2012, Biomaterials.

[185]  Ichio Aoki,et al.  Manganese‐enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations , 2004, NMR in biomedicine.

[186]  Mathieu L. Viger,et al.  Collective activation of MRI agents via encapsulation and disease-triggered release. , 2013, Journal of the American Chemical Society.

[187]  Seung-Min Park,et al.  Towards clinically translatable in vivo nanodiagnostics. , 2017, Nature reviews. Materials.

[188]  Yaping Li,et al.  Ultrasmall Confined Iron Oxide Nanoparticle MSNs as a pH‐Responsive Theranostic Platform , 2014 .

[189]  S. Choi,et al.  Synthesis of Uniformly Sized Manganese Oxide Nanocrystals with Various Sizes and Shapes and Characterization of Their T1 Magnetic Resonance Relaxivity , 2012 .

[190]  Greg J. Stanisz,et al.  Size-Tunable, Ultrasmall NaGdF4 Nanoparticles: Insights into Their T1 MRI Contrast Enhancement , 2011 .

[191]  Himanshu Tyagi,et al.  Iron oxide nanorods as high-performance magnetic resonance imaging contrast agents. , 2015, Nanoscale.

[192]  Chung-Yuan Mou,et al.  Size effect on cell uptake in well-suspended, uniform mesoporous silica nanoparticles. , 2009, Small.

[193]  Teri W. Odom,et al.  High relaxivity Gd(III)-DNA gold nanostars: investigation of shape effects on proton relaxation. , 2015, ACS nano.

[194]  R. Brooks,et al.  On T2‐shortening by weakly magnetized particles: The chemical exchange model † , 2001, Magnetic resonance in medicine.

[195]  M. Botta,et al.  A Multinuclear NMR Study on the Structure and Dynamics of Lanthanide(III) Complexes of the Poly(amino carboxylate) EGTA4- in Aqueous Solution , 1997 .

[196]  Jinwoo Cheon,et al.  Chemical design of nanoparticle probes for high-performance magnetic resonance imaging. , 2008, Angewandte Chemie.

[197]  Konstantin Nikolaou,et al.  25 Years of Contrast-Enhanced MRI: Developments, Current Challenges and Future Perspectives , 2016, Advances in Therapy.

[198]  Kazunori Kataoka,et al.  PEGylated Nanoparticles for Biological and Pharmaceutical Applications , 2003 .

[199]  Lehui Lu,et al.  Fluorescence-enhanced gadolinium-doped zinc oxide quantum dots for magnetic resonance and fluorescence imaging. , 2011, Biomaterials.

[200]  Klaas Nicolay,et al.  Quantum dots with a paramagnetic coating as a bimodal molecular imaging probe. , 2006, Nano letters.

[201]  Yang Sun,et al.  Multifunctional mesoporous composite nanocapsules for highly efficient MRI-guided high-intensity focused ultrasound cancer surgery. , 2011, Angewandte Chemie.

[202]  Shouheng Sun,et al.  Recent Advances in Chemical Synthesis, Self‐Assembly, and Applications of FePt Nanoparticles , 2006 .

[203]  Sophie Laurent,et al.  Contrast agents: magnetic resonance. , 2008, Handbook of experimental pharmacology.

[204]  C. Yeh,et al.  Bifunctional Gd2O3/C Nanoshells for MR Imaging and NIR Therapeutic Applications , 2009 .

[205]  D. Arifin,et al.  MRI-detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted cell viability , 2012, Nature materials.

[206]  Y. Hsiao,et al.  A new and facile method to prepare uniform hollow MnO/functionalized mSiO₂ core/shell nanocomposites. , 2011, ACS nano.

[207]  J. Martinelli,et al.  Cleavable β-cyclodextrin nanocapsules incorporating Gd(III)-chelates as bioresponsive MRI probes. , 2011, Chemical communications.

[208]  Robert Sinclair,et al.  Redox-Triggered Self-Assembly of Gadolinium-Based MRI Probes for Sensing Reducing Environment , 2014, Bioconjugate chemistry.

[209]  Dar-Bin Shieh,et al.  In vitro and in vivo studies of FePt nanoparticles for dual modal CT/MRI molecular imaging. , 2010, Journal of the American Chemical Society.

[210]  Marco Pedroni,et al.  PEG-capped, lanthanide doped GdF3 nanoparticles: luminescent and T2 contrast agents for optical and MRI multimodal imaging. , 2012, Nanoscale.

[211]  Jinwoo Cheon,et al.  Critical enhancements of MRI contrast and hyperthermic effects by dopant-controlled magnetic nanoparticles. , 2009, Angewandte Chemie.

[212]  Dongmei Wu,et al.  Core-shell NaYF4:Yb3+,Tm3+@FexOy nanocrystals for dual-modality T2-enhanced magnetic resonance and NIR-to-NIR upconversion luminescent imaging of small-animal lymphatic node. , 2011, Biomaterials.

[213]  Tao Yang,et al.  Size-Tunable Gd2O3@Albumin Nanoparticles Conjugating Chlorin e6 for Magnetic Resonance Imaging-Guided Photo-Induced Therapy , 2017, Theranostics.

[214]  Jianlin Shi,et al.  Oxygen Vacancy Enables Markedly Enhanced Magnetic Resonance Imaging-Guided Photothermal Therapy of a Gd3+-Doped Contrast Agent. , 2017, ACS nano.

[215]  Arezou A Ghazani,et al.  Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. , 2006, Nano letters.

[216]  Gang Bao,et al.  Coating optimization of superparamagnetic iron oxide nanoparticles for high T2 relaxivity. , 2010, Nano letters.

[217]  Prachi Pandit,et al.  Controlled self-assembling of gadolinium nanoparticles as smart molecular magnetic resonance imaging contrast agents. , 2011, Angewandte Chemie.

[218]  Zhi Ping Xu,et al.  Manganese‐Based Layered Double Hydroxide Nanoparticles as a T1‐MRI Contrast Agent with Ultrasensitive pH Response and High Relaxivity , 2017, Advanced materials.

[219]  H. Grüll,et al.  Bioresponsive probes for molecular imaging: concepts and in vivo applications. , 2015, Contrast media & molecular imaging.

[220]  Thierry Epicier,et al.  Toward an image-guided microbeam radiation therapy using gadolinium-based nanoparticles. , 2011, ACS nano.

[221]  Harald Ittrich,et al.  Exceedingly small iron oxide nanoparticles as positive MRI contrast agents , 2017, Proceedings of the National Academy of Sciences.

[222]  Wenpei Fan,et al.  Intelligent MnO2 Nanosheets Anchored with Upconversion Nanoprobes for Concurrent pH‐/H2O2‐Responsive UCL Imaging and Oxygen‐Elevated Synergetic Therapy , 2015, Advanced materials.

[223]  S. Haam,et al.  Redoxable heteronanocrystals functioning magnetic relaxation switch for activatable T1 and T2 dual-mode magnetic resonance imaging. , 2016, Biomaterials.