Silica nanoparticles for cell imaging and intracellular sensing

There is increasing interest in the use of nanoparticles (NPs) for biomedical applications. In particular, nanobiophotonic approaches using fluorescence offers the potential of high sensitivity and selectivity in applications such as cell imaging and intracellular sensing. In this review, we focus primarily on the use of fluorescent silica NPs for these applications and, in so doing, aim to enhance and complement the key recent review articles on these topics. We summarize the main synthetic approaches, namely the Stöber and microemulsion processes, and, in this context, we deal with issues in relation to both covalent and physical incorporation of different types of dyes in the particles. The important issue of NP functionalization for conjugation to biomolecules is discussed and strategies published in the recent literature are highlighted and evaluated. We cite recent examples of the use of fluorescent silica NPs for cell imaging in the areas of cancer, stem cell and infectious disease research, and we review the current literature on the use of silica NPs for intracellular sensing of oxygen, pH and ionic species. We include a short final section which seeks to identify the main challenges and obstacles in relation to the potential widespread use of these particles for in vivo diagnostics and therapeutics.

[1]  E. Gulari,et al.  Monomer-addition growth with a slow initiation step: A growth model for silica particles from alkoxides , 1989 .

[2]  A. Vrij,et al.  Synthesis and characterization of colloidal dispersions of fluorescent, monodisperse silica spheres , 1992 .

[3]  N. Høiby,et al.  Summary and Perspectives , 2011 .

[4]  H. Clark,et al.  Optochemical Nanosensors and Subcellular Applications in Living Cells , 1999 .

[5]  R Y Tsien,et al.  Photochemically generated cytosolic calcium pulses and their detection by fluo-3. , 1989, The Journal of biological chemistry.

[6]  R. Martínez-Zaguilán,et al.  Selection of fluorescent ion indicators for simultaneous measurements of pH and Ca2+. , 1996, Cell calcium.

[7]  Srikanth K. Iyer,et al.  Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma. , 2011, The Journal of clinical investigation.

[8]  Zhiliang Cheng,et al.  Nanometre-sized molecular oxygen sensors prepared from polymer stabilized phospholipid vesicles. , 2006, The Analyst.

[9]  Weihong Tan,et al.  Multicolor FRET silica nanoparticles by single wavelength excitation. , 2006, Nano letters.

[10]  Zongxi Li,et al.  Mesoporous silica nanoparticles in biomedical applications. , 2012, Chemical Society reviews.

[11]  D. Pang,et al.  Covalent conjugation of avidin with dye-doped silica nanopaticles and preparation of high density avidin nanoparticles as photostable bioprobes. , 2012, Biosensors & bioelectronics.

[12]  Brian G. Trewyn,et al.  Mesoporous Silica Nanoparticles for Drug Delivery and Biosensing Applications , 2007 .

[13]  Iseult Lynch,et al.  What the cell "sees" in bionanoscience. , 2010, Journal of the American Chemical Society.

[14]  Raoul Kopelman,et al.  Nanoencapsulation method for high selectivity sensing of hydrogen peroxide inside live cells. , 2010, Analytical chemistry.

[15]  Paras N Prasad,et al.  Dye-concentrated organically modified silica nanoparticles as a ratiometric fluorescent pH probe by one- and two-photon excitation. , 2006, Chemical communications.

[16]  E. Herz,et al.  Cellulose Acetate Fibers with Fluorescing Nanoparticles for Anti-counterfeiting and pH-sensing Applications , 2010 .

[17]  Kazuya Kikuchi,et al.  Design, synthesis and biological application of chemical probes for bio-imaging. , 2010, Chemical Society reviews.

[18]  L. Benning,et al.  Quantification of initial steps of nucleation and growth of silica nanoparticles: An in-situ SAXS and DLS study , 2009 .

[19]  B. Tang,et al.  A highly selective and sensitive nanoprobe for detection and imaging of the superoxide anion radical in living cells. , 2012, Chemical communications.

[20]  Kenneth A. Dawson,et al.  In vitro evaluation of cytotoxic and inflammatory properties of silica nanoparticles of different sizes in murine RAW 264.7 macrophages , 2011 .

[21]  L. Prodi,et al.  A versatile strategy for signal amplification based on core/shell silica nanoparticles. , 2011, Chemistry.

[22]  Jinho Park,et al.  Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy , 2012, Theranostics.

[23]  D. Pang,et al.  MUC-1 aptamer-conjugated dye-doped silica nanoparticles for MCF-7 cells detection. , 2013, Biomaterials.

[24]  Kai Johnsson,et al.  Localizable and highly sensitive calcium indicator based on a BODIPY fluorophore. , 2010, Analytical chemistry.

[25]  Yufang Xu,et al.  Ratiometric and reusable fluorescent nanoparticles for Zn2+ and H2PO4− detection in aqueous solution and living cells , 2010 .

[26]  Taeghwan Hyeon,et al.  Designed Fabrication of Silica‐Based Nanostructured Particle Systems for Nanomedicine Applications , 2008 .

[27]  Jong Hwa Jung,et al.  Fluorescein-functionalized silica nanoparticles as a selective fluorogenic chemosensor for Cu2+ in living cells , 2010 .

[28]  R. Kopelman,et al.  Ratiometric Singlet Oxygen Nano-optodes and Their Use for Monitoring Photodynamic Therapy Nanoplatforms , 2005, Photochemistry and photobiology.

[29]  Vincent M. Rotello,et al.  Applications of Nanoparticles in Biology , 2008 .

[30]  Kemin Wang,et al.  Noninvasive monitoring of intracellular pH change induced by drug stimulation using silica nanoparticle sensors , 2007, Analytical and bioanalytical chemistry.

[31]  Michihiro Nakamura Approaches to the Biofunctionalization of Spherical Silica Nanomaterials , 2010 .

[32]  G. Mohr,et al.  Two‐Dye Core/Shell Zeolite Nanoparticles: A New Tool for Ratiometric pH Measurements , 2009 .

[33]  David E. Williams,et al.  A comparison of mono and multivalent linkers and their effect on the colloidal stability of nanoparticle and immunoassays performance. , 2010, Talanta.

[34]  D. R. Bae,et al.  A selective fluoroionophore based on BODIPY-functionalized magnetic silica nanoparticles: removal of Pb2+ from human blood. , 2009, Angewandte Chemie.

[35]  V. Lamer,et al.  Theory, Production and Mechanism of Formation of Monodispersed Hydrosols , 1950 .

[36]  Osseo-Asare,et al.  Synthesis of Nanosize Silica in a Nonionic Water-in-Oil Microemulsion: Effects of the Water/Surfactant Molar Ratio and Ammonia Concentration. , 1999, Journal of colloid and interface science.

[37]  Weihong Tan,et al.  Ultrasensitive detection of biomolecules with fluorescent dye-doped nanoparticles. , 2004, Analytical biochemistry.

[38]  Kemin Wang,et al.  Imaging breast cancer cells and tissues using peptide-labeled fluorescent silica nanoparticles. , 2008, Journal of nanoscience and nanotechnology.

[39]  J. Aylott Optical nanosensors--an enabling technology for intracellular measurements. , 2003, The Analyst.

[40]  Kevin Burgess,et al.  Fluorescent indicators for intracellular pH. , 2010, Chemical reviews.

[41]  Angel Orte,et al.  Fluorescent nanoparticles for intracellular sensing: a review. , 2012, Analytica chimica acta.

[42]  Ivana Fenoglio,et al.  Multiple aspects of the interaction of biomacromolecules with inorganic surfaces. , 2011, Advanced drug delivery reviews.

[43]  R. Zenobi,et al.  Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for identifying the composition of labeled proteins. , 1999, Analytical biochemistry.

[44]  M. Mcshane,et al.  Nanoscale internally referenced oxygen sensors produced from self-assembled nanofilms on fluorescent nanoparticles. , 2005, Journal of biomedical optics.

[45]  G. Daston,et al.  Toxicology of nanoparticles. , 2012, Advanced drug delivery reviews.

[46]  Jonathan S Dordick,et al.  Silica nanoparticle size influences the structure and enzymatic activity of adsorbed lysozyme. , 2004, Langmuir : the ACS journal of surfaces and colloids.

[47]  Jinlong Zhang,et al.  The Institute of Chemistry of Great Britain and Ireland. Journal and Proceedings. 1920. Part I , 1920 .

[48]  Charles F. Zukoski,et al.  Preparation of monodisperse silica particles: control of size and mass fraction , 1988 .

[49]  Fabrizio Mancin,et al.  Amplified fluorescence response of chemosensors grafted onto silica nanoparticles. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[50]  L. Lévy,et al.  Overview of the main methods used to combine proteins with nanosystems: absorption, bioconjugation, and encapsulation , 2009, International journal of nanomedicine.

[51]  E. Rampazzo,et al.  A Fluorescence Nanosensor for Cu2+ on Silica Particles. , 2004 .

[52]  M. Schäferling,et al.  Luminescent probes for detection and imaging of hydrogen peroxide , 2011 .

[53]  Raoul Kopelman,et al.  Room-temperature preparation and characterization of poly (ethylene glycol)-coated silica nanoparticles for biomedical applications. , 2003, Journal of biomedical materials research. Part A.

[54]  Wenwan Zhong,et al.  Nanomaterials in fluorescence-based biosensing , 2009, Analytical and bioanalytical chemistry.

[55]  Veeren M. Chauhan,et al.  Dual-fluorophore ratiometric pH nanosensor with tuneable pKa and extended dynamic range. , 2011, The Analyst.

[56]  Kenneth A. Dawson,et al.  Nanobiotechnology: nanoparticle coronas take shape. , 2011, Nature nanotechnology.

[57]  K. Osseo-asare,et al.  CONTROLLED HYDROLYSIS OF TETRAETHOXYSILANE IN A NONIONIC WATER-IN-OIL MICROEMULSION : A STATISTICAL MODEL OF SILICA NUCLEATION , 1999 .

[58]  Weihong Tan,et al.  Watching Silica Nanoparticles Glow in the Biological World , 2006 .

[59]  Zongxi Li,et al.  Biocompatibility, biodistribution, and drug-delivery efficiency of mesoporous silica nanoparticles for cancer therapy in animals. , 2010, Small.

[60]  Kemin Wang,et al.  Dye-doped nanoparticles for bioanalysis , 2007 .

[61]  N. Jana Design and development of quantum dots and other nanoparticles based cellular imaging probe. , 2011, Physical chemistry chemical physics : PCCP.

[62]  Raoul Kopelman,et al.  Real-time measurements of dissolved oxygen inside live cells by organically modified silicate fluorescent nanosensors. , 2004, Analytical chemistry.

[63]  Monty Liong,et al.  Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery. , 2008, ACS nano.

[64]  Clemens Burda,et al.  The unique role of nanoparticles in nanomedicine: imaging, drug delivery and therapy. , 2012, Chemical Society reviews.

[65]  R. Nooney,et al.  Optimization of size, morphology and colloidal stability of fluorescein dye-doped silica NPs for application in immunoassays , 2012, Analytical and Bioanalytical Chemistry.

[66]  Nicholas A Peppas,et al.  Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. , 2006, International journal of pharmaceutics.

[67]  Xu Hun,et al.  Preparation of a novel fluorescence nanosensor based on calcein-doped silica nanoparticles, and its application to the determination of calcium in blood serum , 2007 .

[68]  Hong-Wei Li,et al.  Dual-emission fluorescent silica nanoparticle-based probe for ultrasensitive detection of Cu2+. , 2011, Analytical chemistry.

[69]  J. Aylott,et al.  Dual fluorescent labelling of cellulose nanocrystals for pH sensing. , 2010, Chemical communications.

[70]  Sara Linse,et al.  Understanding the nanoparticle–protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles , 2007, Proceedings of the National Academy of Sciences.

[71]  Kemin Wang,et al.  Preparation of luminescent Cy5 doped core-shell SFNPs and its application as a near-infrared fluorescent marker. , 2007, Talanta.

[72]  Reinhard Niessner,et al.  Review: bioanalytical applications of biomolecule-functionalized nanometer-sized doped silica particles. , 2009, Analytica chimica acta.

[73]  David E Williams,et al.  Kinetics of immunoassays with particles as labels: effect of antibody coupling using dendrimers as linkers. , 2011, The Analyst.

[74]  Timothy Thatt Yang Tan,et al.  Robust, Non‐Cytotoxic, Silica‐Coated CdSe Quantum Dots with Efficient Photoluminescence , 2005 .

[75]  V. Shmanai,et al.  Oriented antibody immobilization to polystyrene macrocarriers for immunoassay modified with hydrazide derivatives of poly(meth)acrylic acid , 2001, BMC Biotechnology.

[76]  W. D. de Jong,et al.  Cytotoxic effects in 3T3-L1 mouse and WI-38 human fibroblasts following 72 hour and 7 day exposures to commercial silica nanoparticles. , 2012, Toxicology and applied pharmacology.

[77]  N. Rosenzweig,et al.  Synthesis and application of submicrometer fluorescence sensing particles for lysosomal pH measurements in murine macrophages. , 2000, Analytical chemistry.

[78]  F. Guillemin,et al.  Specific fluorescent tracers. Imaging and applications for photodynamic therapy. , 2002, Comptes rendus biologies.

[79]  Jinlong Zhang,et al.  Ratiometric pH sensor based on mesoporous silica nanoparticles and Förster resonance energy transfer. , 2010, Chemical communications.

[80]  H. Youn,et al.  Canine mesenchymal stem cells are effectively labeled with silica nanoparticles and unambiguously visualized in highly autofluorescent tissues , 2012, BMC Veterinary Research.

[81]  Yu Chen,et al.  Nuclear-targeted drug delivery of TAT peptide-conjugated monodisperse mesoporous silica nanoparticles. , 2012, Journal of the American Chemical Society.

[82]  S. Maiti,et al.  Dendritic effect of ligand-coated nanoparticles: enhanced apoptotic activity of silica-berberine nanoconjugates. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[83]  Jonathan W Aylott,et al.  A facile method to clickable sensing polymeric nanoparticles. , 2009, Chemical communications.

[84]  Saji George,et al.  Polyethyleneimine coating enhances the cellular uptake of mesoporous silica nanoparticles and allows safe delivery of siRNA and DNA constructs. , 2009, ACS nano.

[85]  Prabuddha Sengupta,et al.  Core/Shell fluorescent silica nanoparticles for chemical sensing: towards single-particle laboratories. , 2006, Small.

[86]  Jürgen Lademann,et al.  Skin penetration and cellular uptake of amorphous silica nanoparticles with variable size, surface functionalization, and colloidal stability. , 2012, ACS nano.

[87]  Timothy Thatt Yang Tan,et al.  Size control, shape evolution, and silica coating of near-infrared-emitting PbSe quantum dots , 2007 .

[88]  Zheng Xie,et al.  Highly Luminescent Organosilane‐Functionalized Carbon Dots , 2011 .

[89]  Bin Qiu,et al.  Preparation of novel core-shell silica particles for pH sensing using ratiometric fluorescence approach , 2012 .

[90]  W. Tan,et al.  Development of novel dye-doped silica nanoparticles for biomarker application. , 2001, Journal of biomedical optics.

[91]  Ingo Klimant,et al.  Optical nanosensors--smart tools in bioanalytics. , 2008, The Analyst.

[92]  W. Tan,et al.  Conjugation of biomolecules with luminophore-doped silica nanoparticles for photostable biomarkers. , 2001, Analytical chemistry.

[93]  Huimao Zhang,et al.  Incorporating anionic dyes into silica nanoparticles by using a cationic polyelectrolyte as a bridge , 2011 .

[94]  Hooisweng Ow,et al.  Bright and stable core-shell fluorescent silica nanoparticles. , 2005, Nano letters.

[95]  Charles F. Zukoski,et al.  Studies of the kinetics of the precipitation of uniform silica particles through the hydrolysis and condensation of silicon alkoxides , 1991 .

[96]  Osseo-Asare,et al.  Growth Kinetics of Nanosize Silica in a Nonionic Water-in-Oil Microemulsion: A Reverse Micellar Pseudophase Reaction Model. , 1999, Journal of colloid and interface science.

[97]  Ingo Klimant,et al.  Intracellular O2 sensing probe based on cell-penetrating phosphorescent nanoparticles. , 2011, ACS nano.

[98]  Linlin Li,et al.  Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery , 2012, Advanced materials.

[99]  S. Dutz,et al.  Magnetic and fluorescent core–shell nanoparticles for ratiometric pH sensing , 2011, Nanotechnology.

[100]  E. Gulari,et al.  Dynamics of Growth of Silica Particles from Ammonia-Catalyzed Hydrolysis of Tetra-ethyl-orthosilicate , 1988 .

[101]  R. O'Kennedy,et al.  Synthesis and characterization of a Noble metal Enhanced Optical Nanohybrid (NEON): a high brightness detection platform based on a dye-doped silica nanoparticle. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[102]  W. Stöber,et al.  Controlled growth of monodisperse silica spheres in the micron size range , 1968 .

[103]  C. Zukoski,et al.  Uniform Silica Particle Precipitation : An Aggregative Growth Model , 1991 .

[104]  Barbara Sennino,et al.  Labeling Human Mesenchymal Stem Cells with Fluorescent Contrast Agents: the Biological Impact , 2010, Molecular Imaging and Biology.

[105]  J. Schlager,et al.  In vitro cytotoxicity of nanoparticles in mammalian germline stem cells. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[106]  Kemin Wang,et al.  In vivo study of biodistribution and urinary excretion of surface-modified silica nanoparticles. , 2008, Analytical chemistry.

[107]  Zeev Rosenzweig,et al.  Novel fluorescent oxygen indicator for intracellular oxygen measurements. , 2002, Journal of biomedical optics.

[108]  Fabrizio Mancin,et al.  Sensing with fluorescent nanoparticles. , 2011, Nanoscale.

[109]  C. Naumann,et al.  Biofunctionalization of Fluorescent Nanoparticles , 2007 .

[110]  Changfeng Wu,et al.  Multicolor conjugated polymer dots for biological fluorescence imaging. , 2008, ACS nano.

[111]  L. Basabe‐Desmonts,et al.  From particle to platelet: optimization of a stable, high brightness fluorescent nanoparticle based cell detection platform. , 2013, Nanomedicine : nanotechnology, biology, and medicine.

[112]  Weihong Tan,et al.  Fluorescent nanoparticles for multiplexed bacteria monitoring. , 2007, Bioconjugate chemistry.

[113]  Improving colloidal properties of quantum dots with combined silica and polymer coatings for in vitro immuofluorenscence assay , 2011 .

[114]  B. MacCraith,et al.  Experimental and theoretical studies of the optimisation of fluorescence from near-infrared dye-doped silica nanoparticles , 2009, Analytical and bioanalytical chemistry.

[115]  M. Tan,et al.  Development of functionalized terbium fluorescent nanoparticles for antibody labeling and time-resolved fluoroimmunoassay application. , 2004, Talanta.

[116]  S. Dutz,et al.  Magnetic core-shell fluorescent pH ratiometric nanosensor using a Stöber coating method. , 2011, Analytica chimica acta.

[117]  A. Vrij,et al.  Monodisperse Colloidal Silica Spheres from Tetraalkoxysilanes: Particle Formation and Growth Mechanism , 1992 .

[118]  Fabrizio Mancin,et al.  Silica nanoparticles for fluorescence sensing of Zn(II): exploring the covalent strategy. , 2007, Chemistry.

[119]  M. Bissell,et al.  A Rapid Bioassay for Single Bacterial Cell Quantitation Using Bioconjugated Nanoparticles , 2006 .

[120]  Fabrizio Mancin,et al.  A cell-penetrating ratiometric nanoprobe for intracellular chloride. , 2012, Organic letters.

[121]  Igor L. Medintz,et al.  Biosensing with Luminescent Semiconductor Quantum Dots , 2006, Sensors (Basel, Switzerland).

[122]  Shichong Wang,et al.  Effects of nano-sized silicon dioxide on the structures and activities of three functional proteins. , 2010, Journal of hazardous materials.

[123]  E. Hall,et al.  Ratiometric pH-dot ANSors. , 2010, The Analyst.

[124]  J. Aylott,et al.  A real-time ratiometric method for the determination of molecular oxygen inside living cells using sol-gel-based spherical optical nanosensors with applications to rat C6 glioma. , 2001, Analytical chemistry.

[125]  Erik Herz,et al.  Dye structure-optical property correlations in near-infrared fluorescent core-shell silica nanoparticles , 2009 .

[126]  K. Dawson,et al.  Effects of Transport Inhibitors on the Cellular Uptake of Carboxylated Polystyrene Nanoparticles in Different Cell Lines , 2011, PloS one.

[127]  Weihong Tan,et al.  Aptamer-conjugated nanoparticles for cancer cell detection. , 2011, Analytical chemistry.

[128]  A. Tsourkas,et al.  Size, charge and concentration dependent uptake of iron oxide particles by non-phagocytic cells. , 2008, Biomaterials.

[129]  Victor S-Y Lin,et al.  Effect of surface functionalization of MCM-41-type mesoporous silica nanoparticles on the endocytosis by human cancer cells. , 2006, Journal of the American Chemical Society.

[130]  Kenneth A. Dawson,et al.  Effects of the presence or absence of a protein corona on silica nanoparticle uptake and impact on cells. , 2012, ACS nano.

[131]  Indrajit Roy,et al.  Covalently dye-linked, surface-controlled, and bioconjugated organically modified silica nanoparticles as targeted probes for optical imaging. , 2008, ACS nano.

[132]  Alexander V. Zhdanov,et al.  A Phosphorescent Nanoparticle‐Based Probe for Sensing and Imaging of (Intra)Cellular Oxygen in Multiple Detection Modalities , 2012 .

[133]  Chin-Tu Chen,et al.  Near‐Infrared Mesoporous Silica Nanoparticles for Optical Imaging: Characterization and In Vivo Biodistribution , 2009 .

[134]  H. Goesmann,et al.  Nanoparticulate functional materials. , 2010, Angewandte Chemie.

[135]  Kenneth A. Dawson,et al.  Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts , 2008, Proceedings of the National Academy of Sciences.

[136]  Jeffrey I. Zink,et al.  Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery , 2010, BiOS.

[137]  H Szmacinski,et al.  Fluorescence lifetime imaging of intracellular calcium in COS cells using Quin-2. , 1994, Cell calcium.

[138]  G. Mohr,et al.  Ratiometric pH-nanosensors based on rhodamine-doped silica nanoparticles functionalized with a naphthalimide derivative. , 2009, Journal of colloid and interface science.

[139]  Michael R Hamblin,et al.  Imidazole metalloporphyrins as photosensitizers for photodynamic therapy: role of molecular charge, central metal and hydroxyl radical production. , 2009, Cancer letters.

[140]  Feng Gao,et al.  A fluorescence ratiometric nano-pH sensor based on dual-fluorophore-doped silica nanoparticles. , 2007, Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.

[141]  Kevin D. Belfield,et al.  Folate receptor targeting silica nanoparticle probe for two-photon fluorescence bioimaging , 2010, Biomedical optics express.

[142]  Daniel K. Bonner,et al.  Large stokes-shift fluorescent silica nanoparticles with enhanced emission over free dye for single excitation multiplexing. , 2009, Macromolecular rapid communications.

[143]  D. Hall,et al.  Investigation of nonspecific effects of different dyes in the screening of labeled carbohydrates against immobilized proteins. , 2005, The Journal of organic chemistry.

[144]  Ahmed A. Heikal,et al.  Silica Nanoparticle Architecture Determines Radiative Properties of Encapsulated Fluorophores , 2008 .

[145]  Iseult Lynch,et al.  Designing the nanoparticle-biomolecule interface for "targeting and therapeutic delivery". , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[146]  T. Xia,et al.  Understanding biophysicochemical interactions at the nano-bio interface. , 2009, Nature materials.

[147]  K. Dawson,et al.  Quantifying size-dependent interactions between fluorescently labeled polystyrene nanoparticles and mammalian cells , 2012, Journal of Nanobiotechnology.

[148]  T. Tatsumi,et al.  Mechanism of Formation of Uniform-Sized Silica Nanospheres Catalyzed by Basic Amino Acids , 2009 .

[149]  Earl J. Bergey,et al.  Organically Modified Silica Nanoparticles Are Biocompatible and Can Be Targeted to Neurons In Vivo , 2012, PloS one.

[150]  Weihong Tan,et al.  Surface modification of silica nanoparticles to reduce aggregation and nonspecific binding. , 2006, Langmuir : the ACS journal of surfaces and colloids.

[151]  Guiying Xu,et al.  The control of size and morphology of nanosized silica in Triton X-100 based reverse micelle , 2008 .

[152]  Huan Meng,et al.  Mesoporous silica nanoparticles: A multifunctional nano therapeutic system. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[153]  F. Gao,et al.  Core-shell fluorescent silica nanoparticles for sensing near-neutral pH values , 2011 .

[154]  H. Clark,et al.  Optical nanosensors for chemical analysis inside single living cells. 2. Sensors for pH and calcium and the intracellular application of PEBBLE sensors. , 1999, Analytical chemistry.

[155]  Huang-Hao Yang,et al.  Nanometer fluorescent hybrid silica particle as ultrasensitive and photostable biological labels. , 2003, The Analyst.

[156]  E. Rampazzo,et al.  Surface modification of silica nanoparticles: a new strategy for the realization of self-organized fluorescence chemosensors , 2005 .

[157]  Dermot Kelleher,et al.  Activation of stress-related signalling pathway in human cells upon SiO2 nanoparticles exposure as an early indicator of cytotoxicity , 2011, Journal of nanobiotechnology.

[158]  D. Kang,et al.  A highly sensitive and selective turn-on fluorogenic and chromogenic sensor based on BODIPY-functionalized magnetic nanoparticles for detecting lead in living cells. , 2010, Chemistry.

[159]  K. Oka,et al.  Design and synthesis of Mg2+-selective fluoroionophores based on a coumarin derivative and application for Mg2+ measurement in a living cell. , 2002, Analytical chemistry.

[160]  M. Al-Rawi,et al.  Uptake and intracellular localization of submicron and nano-sized SiO2 particles in HeLa cells , 2011, Archives of Toxicology.

[161]  Barry L. Mordike,et al.  Distribution of Ion-Implanted Nitrogen in Iron Alloys Investigated by AES , 2000, Microchimica Acta.

[162]  Feng Gao,et al.  A Novel Nano-Sensor Based on Rhodamine-β-Isothiocyanate – Doped Silica Nanoparticle for pH Measurement , 2005 .

[163]  Alfons van Blaaderen,et al.  Dispersions of Rhodamine-Labeled Silica Spheres: Synthesis, Characterization, and Fluorescence Confocal Scanning Laser Microscopy , 1994 .

[164]  Paul L Houston,et al.  Functional Tomographic Fluorescence Imaging of pH Microenvironments in Microbial Biofilms by Use of Silica Nanoparticle Sensors , 2009, Applied and Environmental Microbiology.

[165]  Asim Bhaumik,et al.  Selective Zinc(II)‐Ion Fluorescence Sensing by a Functionalized Mesoporous Material Covalently Grafted with a Fluorescent Chromophore and Consequent Biological Applications , 2009 .

[166]  Feng Gao,et al.  A novel nonenzymatic fluorescent sensor for glucose based on silica nanoparticles doped with europium coordination compound. , 2009, Talanta.

[167]  Iseult Lynch,et al.  Physical-chemical aspects of protein corona: relevance to in vitro and in vivo biological impacts of nanoparticles. , 2011, Journal of the American Chemical Society.

[168]  K. Dawson,et al.  Time and space resolved uptake study of silica nanoparticles by human cells. , 2011, Molecular bioSystems.

[169]  Shanshan Huang,et al.  MCM-41 functionalized with YVO4:Eu3+: a novel drug delivery system , 2007 .

[170]  杨朝勇 Optimization of dye-doped silica nanoparticles prepared using a reverse microemulsion method , 2004 .

[171]  Toshiyuki Yokoi,et al.  Periodic arrangement of silica nanospheres assisted by amino acids. , 2006, Journal of the American Chemical Society.

[172]  N. Erathodiyil,et al.  Functionalization of inorganic nanoparticles for bioimaging applications. , 2011, Accounts of chemical research.

[173]  Gyu-Chul Yi,et al.  Cetuximab-conjugated magneto-fluorescent silica nanoparticles for in vivo colon cancer targeting and imaging. , 2010, Cancer letters.

[174]  Weihong Tan,et al.  Highly fluorescent dye-doped silica nanoparticles increase flow cytometry sensitivity for cancer cell monitoring , 2009 .

[175]  Jiahuai Han,et al.  Dual colored mesoporous silica nanoparticles with pH activable rhodamine-lactam for ratiometric sensing of lysosomal acidity. , 2011, Chemical communications.

[176]  Jim E Riviere,et al.  An index for characterization of nanomaterials in biological systems. , 2010, Nature nanotechnology.

[177]  Kemin Wang,et al.  Uptake of silica-coated nanoparticles by HeLa cells. , 2005, Journal of nanoscience and nanotechnology.

[178]  F. Chien,et al.  Surface charge effect in intracellular localization of mesoporous silica nanoparticles as probed by fluorescent ratiometric pH imaging , 2012 .

[179]  Clemens Burda,et al.  The unique role of nanoparticles in nanomedicine : imaging , drug delivery and therapy , 2012 .

[180]  D. Kessel,et al.  On the use of fluorescence probes for detecting reactive oxygen and nitrogen species associated with photodynamic therapy. , 2010, Journal of biomedical optics.

[181]  Luca Prodi,et al.  Luminescent silica nanoparticles: extending the frontiers of brightness. , 2011, Angewandte Chemie.

[182]  B. MacCraith,et al.  Novel multiparametric approach to elucidate the surface amine-silanization reaction profile on fluorescent silica nanoparticles. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[183]  Victor S-Y Lin,et al.  A polyamidoamine dendrimer-capped mesoporous silica nanosphere-based gene transfection reagent. , 2004, Journal of the American Chemical Society.

[184]  Marc Schneider,et al.  Synthesis and characterization of human transferrin-stabilized gold nanoclusters , 2011, Nanotechnology.

[185]  Colette McDonagh,et al.  Dextran-coated silica nanoparticles for calcium-sensing. , 2011, The Analyst.

[186]  Andrew A. Burns,et al.  Fluorescent core-shell silica nanoparticles: towards "Lab on a Particle" architectures for nanobiotechnology. , 2006, Chemical Society reviews.

[187]  S. Parveen,et al.  Nanoparticles: a boon to drug delivery, therapeutics, diagnostics and imaging. , 2012, Nanomedicine : nanotechnology, biology, and medicine.

[188]  W. Xiong,et al.  Poly(l‐lysine)‐modified silica nanoparticles for the delivery of antisense oligonucleotides , 2004, Biotechnology and applied biochemistry.

[189]  H. S. Fogler,et al.  Controlled Formation of Silica Particles from Tetraethyl Orthosilicate in Nonionic Water-in-Oil Microemulsions , 1997 .

[190]  K. Osseo-Asare,et al.  Preparation of SiO2 nanoparticles in a non-ionic reverse micellar system , 1990 .

[191]  Colette McDonagh,et al.  Intracellular sensing and cell diagnostics using fluorescent silica nanoparticles , 2012 .

[192]  Chin-Tu Chen,et al.  Tri-functionalization of mesoporous silica nanoparticles for comprehensive cancer theranostics—the trio of imaging, targeting and therapy , 2010 .

[193]  Ashutosh Kumar Singh,et al.  Silica nanodisks as platforms for fluorescence lifetime-based sensing of pH , 2011 .

[194]  Susan L. R. Barker,et al.  Subcellular optochemical nanobiosensors: probes encapsulated by biologically localised embedding (PEBBLEs) , 1998 .

[195]  D. E. Aston,et al.  8-aminoquinoline functionalized silica nanoparticles: a fluorescent nanosensor for detection of divalent zinc in aqueous and in yeast cell suspension. , 2011, ACS applied materials & interfaces.