Edouard Alphandéry
email: edouardalphandery@hotmail.com

Light-Interacting Iron-Based Nanomaterial For Localized Cancer Detection and Treatment

Keywords: Iron-based nanomaterials, oncology, cancer, optical methods, fluorescence, nano, fluorescent nanoparticles, nanomedicine. ABREVIATIONS Alexa fluor, AFM: Atomic force microscopy, BBB: Blood brain barrier, BP: Body part, CAs: Cerebral aneurysms, CCD: Charge-coupled device, CD: carbon dot, Cy: Cyanine, ctDNA: cicrculating tumor DNA, CT: computed tomography, CTDR: Cell Tracker Deep Red, CM: confocal microscopy, CTC: Circulating tumor cells

To improve the prognosis of cancer patients, methods of local cancer detection and treatment could be implemented. For that, iron-based nanomaterials (IBN) are particularly well-suited due to their biocompatibility and the various ways in which they can specifically target a tumor, i.e. through passive, active or magnetic targeting. Furthermore, when it is needed, IBN can be associated with well-known fluorescent compounds, such as dyes, clinically approved ICG, fluorescent proteins, or quantum dots. They may also be excited and detected using well-established optical methods, relying on scattering or fluorescent mechanisms, depending on whether IBN are associated with a fluorescent compound or not. Systems combining IBN with optical methods are diverse, thus enabling tumor detection in various ways.. In addition, these systems provide a wealth of information, which is inaccessible with more standard diagnostic tools, such as single tumor cell detection, in particular by combining IBN with near-field scanning optical microscopy, dark-field microscopy, confocal microscopy or super-resolution microscopy, or the highlighting of certain dynamic phenomena such as the diffusion of a fluorescent compound in an organism, e.g. using fluorescence lifetime imaging, fluorescence resonance energy transfer, fluorescence anisotropy, or fluorescence tomography. Furthermore, they can in some cases be complemented by a therapeutic approach to destroy tumors, e.g. when the fluorescent compound is a drug, or when a technique such as photo-thermal or photodynamic therapy is employed. This review brings forward the idea that iron-based nanomaterials may be associated with various optical techniques to form a commercially available toolbox, which can serve to locally detect or treat cancer with a better efficacy than more standard medical approaches.

INTRODUCTION

To improve the prognostic of cancer patients, two inter-connected aspects deserve to be considered, i.e. first, cancer should be detected at the earliest possible stage, and second, tumors should be treated locally when they are sufficiently small, non-invasive, and non-metastatic. This double aim can be achieved by using nanomaterials that specifically target tumor cells and are detected or excited locally by various optical methods, [START_REF] Yang | Optically Active Nanomaterials for Bioimaging and Targeted Therapy[END_REF]. Among the different types of markers, iron based nanomaterials (IBN) present a large number of advantages characterized by: i) their ability to detect a wide range of different cancer biomarkers, e.g. tumor cells, Protein, ctDNA, microRNA, DNA methylation, circulating tumor cells, [START_REF] Zhang | Nanotechnology in cancer diagnosis: progress, challenges and opportunities[END_REF],

ii) their contrasting properties in various traditional cancer detection techniques, such as computed tomography (CT), Magnetic Resonance Imaging (MRI), Ultrasound (US), where they yield improved sensitivity, [START_REF] Padmanabhan | Nanoparticles in practice for molecular-imaging applications: An overview[END_REF], iii) their faculty to act as multimodal imaging tools, [START_REF] Alphandéry | Iron oxide nanoparticles as multimodal imaging tools[END_REF], notably in magnetic resonance imaging (MRI), [START_REF] Shen | Iron Oxide Nanoparticle Based Contrast Agents for Magnetic Resonance Imaging[END_REF], single-photon emission computed tomography (SPECT), [START_REF] Bouziotis | Radiolabeled Iron Oxide Nanoparticles As Dual-Modality SPECT/MRI and PET/MRI Agents[END_REF], X-Ray diffraction (XRD), [START_REF] Song | Synthesis and Characterization of Iron Oxide Nanoparticles Prepared by Electrical Explosion of Fe Wire in ArO2 Gas Mixtures[END_REF][START_REF] Kim | A new method for the identification and quantification of magnetite-maghemite mixture using conventional X-ray diffraction technique[END_REF], or Small-Angle X-Ray Scattering (SAXS), [START_REF] Rosenfeldt | Probing the Nanostructure and Arrangement of Bacterial Magnetosomes by Small-Angle X-Ray Scattering[END_REF], iv) their biocompatibility, i.e. they were safely administered to humans and used in the clinic either as contrast agents, or for the treatment of iron anemia diseases, [START_REF] Alphandéry | Biodistribution and targeting properties of iron oxide nanoparticles for treatments of cancer and iron anemia disease[END_REF], v) their capability to locally heat tumors, e.g. through magnetic hyperthermia (MHT), [START_REF] Maier-Hauff | Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme[END_REF][START_REF] Maier-Hauff | Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: Results of a feasibility study on patients with glioblastoma multiforme[END_REF], or photo-thermal therapy (PTT), [START_REF] Estelrich | Iron Oxide Nanoparticles in Photothermal Therapy[END_REF], vi) their movement in the organism that can be adjusted via the application of an external magnetic field, [START_REF] Israel | Magnetic iron oxide nanoparticles for imaging, targeting and treatment of primary and metastatic tumors of the brain[END_REF], vii) their potential to target tumor, e.g. through passive targeting via enhanced permeability and retention (EPR) effect or active targeting by attaching to IBN a molecule that specifically recognizes a tumor cell receptor, [START_REF] Jayapaul | FMNcoated fluorescent iron oxide nanoparticles for RCP-mediated targeting and labeling of metabolically active cancer and endothelial cells[END_REF], and viii) their capacity to carry a chemotherapeutic drug or photosensitizer (PS) to tumor site, [START_REF] Shen | Doxorubicin and indocyanine green loaded superparamagnetic iron oxide nanoparticles with PEGylated phospholipid coating for magnetic resonance with fluorescence imaging and chemotherapy of glioma[END_REF]. Two types of IBN can be distinguished. The first one consists of non-fluorescent IBN, whose properties are reviewed elsewhere both for naturally and chemically synthesized IBN, [START_REF] Alphandéry | Natural Metallic Nanoparticles for Application in Nano-Oncology[END_REF][START_REF] Zhao | Multifunctional magnetic iron oxide nanoparticles: an advanced platform for cancer theranostics[END_REF]. They can be used as nanoscale local detector tools operating through a light scattering mechanism. The second one, designated as FIBN, comprises iron-based nanomaterials associated with a fluorescent compound. FIBN can be used in various fluorescence imaging techniques and are most often conceived to avoid fluorescence quenching by iron oxide, e.g. by introducing an intercalating material between the fluorescent compound and the iron complex, which is characterized by a wide band gap or a thickness that is sufficiently thick to avoid electron transfer between the fluorescent compound and the iron-based nanomaterial, [START_REF] Lacroix | New generation of magnetic and luminescent nanoparticles for in vivo real-time imaging[END_REF][START_REF] Lartigue | Luminophore and Magnetic Multicore Nanoassemblies for Dual-Mode MRI and Fluorescence Imaging[END_REF][START_REF] García | Recent Progress in Synthesis and Functionalization of Multimodal Fluorescent-Magnetic Nanoparticles for Biological Applications[END_REF]. Recent studies have also introduced FIBN working through another mechanism of fluorescence de-quenching upon release of the fluorescence substance from FIBN magnetic core, [START_REF] Alphande Ŕy | Nanoprobe Synthesized by Magnetotactic Bacteria, Detecting Fluorescence Variations under Dissociation of Rhodamine B from Magnetosomes following Temperature, pH Changes, or the Application of Radiation[END_REF][START_REF] Alphandéry | Fluorescent magnetosomes for controlled and repetitive drug release under the application of an alternating magnetic field under conditions of limited temperature increase[END_REF]. It enables visualizing the release of the fluorescence substance from the nanoparticle, a mechanism that is especially interesting when the fluorescence substance is a drug whose activity is triggered upon release. Here, the various types of light detection methods operating in combination with IBN/FIBN are described as well as their applications in the oncology field. Most of them operate in the infrared (IR), since fluorescent compounds often absorb/emit light within this range of wavelengths, light tissue penetration is enhanced at IR long wavelengths, and tissue absorption can be partly avoided in the IR, specifically between 650 and 900 nm, where tissue autofluorescence and water/hemoglobin absorptions are minimized, [START_REF] Shcherbakova | Near-infrared fluorescent proteins engineered from bacterial phytochromes[END_REF]. In addition to being able to optically detect tumors, FIBN can be used in light-induced cancer treatment, essentially through PDT or PTT. This review covers the description of optical methods operating within the tissular/cellular environment in the visible/infrared region for which most scattering/fluorescent mechanisms are reported to occur. Characterizations methods used to estimate IBN sizes, shapes, compositions outside of their biological environment, such as X-RD, [START_REF] Fischer | Structural purity of magnetite nanoparticles in magnetotactic bacteria[END_REF][START_REF] Kim | A new method for the identification and quantification of magnetite-maghemite mixture using conventional X-ray diffraction technique[END_REF][START_REF] Mahadevan | Size distribution of magnetic iron oxide nanoparticles using Warren-Averbach XRD analysis[END_REF][START_REF] Rosenfeldt | Probing the Nanostructure and Arrangement of Bacterial Magnetosomes by Small-Angle X-Ray Scattering[END_REF][START_REF] Song | Synthesis and Characterization of Iron Oxide Nanoparticles Prepared by Electrical Explosion of Fe Wire in ArO2 Gas Mixtures[END_REF][START_REF] Sun | Synthesis of nanometer-size maghemite particles from magnetite, Colloids and Surfaces A: Physicochem[END_REF], SAXS, [START_REF] Szczerba | SAXS analysis of single-and multi-core iron oxide magnetic nanoparticles[END_REF], dynamic light scattering (DLS), [START_REF] Lim | Characterization of magnetic nanoparticle by dynamic light scattering[END_REF][START_REF] Yang | Dynamic light scattering-based method to determine primary particle size of iron oxide nanoparticles in simulated gastrointestinal fluid[END_REF][START_REF] Carvalho | Application of Light Scattering Techniques to Nanoparticle Characterization and Development[END_REF], FT-IR, [START_REF] Wang | Biodegradable magnetic fluorescent magnetite/poly(DL-lactic acid-co-a,b-malic acid) composite nanoparticles for stem cell labeling[END_REF][START_REF] Rao | Epirubicin-Loaded Superparamagnetic Iron-Oxide Nanoparticles for Transdermal Delivery: Cancer Therapy by Circumventing the Skin Barrier[END_REF][START_REF] Azadmanjiri | Phase reduction of coated maghemite (g-Fe2O3) nanoparticles under microwave-induced plasma heating for rapid heat treatment[END_REF], or optical-based techniques operating in the UV or radio-frequency wavelength range, such as SPECT, CT, or MRI, are described in other detailed reviews, [START_REF] Alphandéry | Iron oxide nanoparticles as multimodal imaging tools[END_REF].

I. OPTICAL PROPERTIES OF IRON OXIDE NANOPARTICLES

Iron oxide nanoparticles (IONP), composed of maghemite (Fe2O3) or magnetite (Fe3O4), are the most commonly studied IBN. Generally, they significantly absorb light between 200 and 600-800 nm, and display an absorption strength that strongly increases with decreasing wavelength, displaying specific absorption bands at 400 and 420 nm for Fe3O4 and 300 nm for Fe2O3, [START_REF] Lesiak | Surface Study of Fe3O4 Nanoparticles Functionalized With Biocompatible Adsorbed Molecules[END_REF]. In addition, IONP can yield photoluminescence (PL), although such effect was rarely reported, most probably due to a weak PL signal.

In one study, IONP with sizes lying between 10 nm and 5 μm were observed to display PL peaks at 560 nm, 695 nm, and 840 nm, under excitation at 350 and 407 nm. These peaks were attributed to various recombination of electrons at IONP tetrahedral and octahedral sites, [START_REF] Shi | Photo-fluorescent and magnetic properties of iron oxide nanoparticles for biomedical applications[END_REF]. Furthermore, IONP has a band structure that directly impacts its fluorescence properties. Indeed, the presence of an unfilled shell of Fe 3+

and Fe 2+ at IONP surface, [START_REF] Loudet | BODIPY dyes and their derivatives: syntheses and spectroscopic properties[END_REF], where electrons can transfer from the fluorescent compound (FC) attached to them, leads to a mechanism of fluorescence quenching under laser excitation, [START_REF] Yu | Magnetite Nanoparticle-Induced Fluorescence Quenching of Adenosine Triphosphate-BODIPY Conjugates: Application to Adenosine Triphosphate and Pyrophosphate Sensing[END_REF]. As described in the next section, strategies have been employed to develop various FIBN, in which this quenching mechanism is suppressed. Light interaction with IBN can also lead to a scattering phenomenon, which is enhanced when the incident light couples with so-called surface plasmon waves. This is the reason why, when the detection of a scattering signal is sought for, the surface of IBN is often adjusted to result in an efficient surface plasmon wave effect. To this end, it was suggested to design mixed structures containing iron with a plasmonic material (gold or silver), i.e. by incorporating iron in Au NP (nanoparticle), [START_REF] Amendola | Superior plasmon absorption in iron-doped gold nanoparticles[END_REF], by designing gold-iron oxide Janus magnetic-plasmonic nanoparticles, [START_REF] Reguera | Janus plasmonic-magnetic gold-iron oxide nanoparticles as contrast agents for multimodal imaging[END_REF], by coating IBN with gold, [START_REF] Levin | Magnetic-Plasmonic Core-Shell Nanoparticles[END_REF],

or silver, [START_REF] Ramade | Environmental Plasmonic Spectroscopy of Silver-Iron Nanoparticles: Chemical Ordering under Oxidizing and Reducing Conditions[END_REF]. Although the nature of the material located at IBN surface appears crucial to optimize the plasmonic effect, other parameters should also be taken into consideration for such endeavor, such as the shape, size, and type of assembly/interactions of IBN, [START_REF] Noguez | Surface Plasmons on Metal Nanoparticles: The Influence of Shape and Physical Environment[END_REF].

II. DIFFERENT TYPES OF FLUORESCENT IRON-BASED NANOMATERIALS

Fluorescent iron-based nanomaterials (FIBN), whose composition, type of assembly, fluorescent

properties, and various operating mechanisms are summarized in table 1 and Figure 1, consist of a first metallic part, which is composed of Fe2O3 (maghemite) or Fe3O4 (magnetite), or of an alloy made of iron mixed with different metals, such as cobalt ferrite, FePt, or Zinc ferrite. Concerning pure iron oxides, although most studies report that they are composed of magnetite, it is possible that they in fact consist of maghemite, since on the one hand magnetite should oxidize into maghemite in the absence of a specific treatment/layer protecting magnetite against oxidation, and on the other hand magnetite and maghemite structures are very close to each other, i.e. their electron diffraction patterns are very similar, [START_REF] Alphandéry | Difference between the Magnetic Properties of the Magnetotactic Bacteria and Those of the Extracted Magnetosomes: Influence of the Distance between the Chains of Magnetosomes[END_REF], making these two structures difficult to distinguish one from the other in the absence of a specific characterization method such as Raman scattering, [START_REF] Testa-Anta | Raman spectroscopy to unravel the magnetic properties of iron oxide nanocrystals for biorelated applications[END_REF]. Maghemite is very stable and should not be prone to a phase transition in the absence of a specific harsh treatment such as heating at 900 °C, which can oxidize maghemite into hematite, [START_REF] Azadmanjiri | Phase reduction of coated maghemite (g-Fe2O3) nanoparticles under microwave-induced plasma heating for rapid heat treatment[END_REF]. Cobalt ferrite composition presents the advantage of yielding improved magnetic properties, [START_REF] Dutz | Biocompatible Magnetic Fluids of Co-Doped Iron Oxide Nanoparticles with Tunable Magnetic Properties[END_REF]. Although preliminary assessment of the toxicity of cobalt doped IBN led to a reassuring safety profile, [START_REF] Dutz | Biocompatible Magnetic Fluids of Co-Doped Iron Oxide Nanoparticles with Tunable Magnetic Properties[END_REF], it is not certain that regulatory agencies will allow their administration to humans due to the well-known toxicity of cobalt, [START_REF] Leyssens | Cobalt toxicity in humans-A review of the potential sources and systemic health effects[END_REF]. FePt has shown good biocompatibility, resistance to oxidation, and high chemical stability [368], while the doping of ferrite with zinc increases IBN magnetization values, [START_REF] Byrne | Biosynthesis of Zinc Substituted Magnetite Nanoparticles with Enhanced Magnetic Properties[END_REF].

Besides their metallic portion, FIBN comprise a fluorescent part that can be classified in four different categories. The first one consists of classic fluorescent compounds, mainly dyes or fluorescent proteins, e.g. ICG, [START_REF] Shen | Doxorubicin and indocyanine green loaded superparamagnetic iron oxide nanoparticles with PEGylated phospholipid coating for magnetic resonance with fluorescence imaging and chemotherapy of glioma[END_REF], RhB, [49-,51], RITC, [START_REF] Cho | Cetuximab-conjugated magneto-fluorescent silica nanoparticles for in vivo colon cancer targeting and imaging[END_REF][START_REF] Hwang | Smart Magnetic Fluorescent Nanoparticle Imaging Probes to Monitor MicroRNAs[END_REF][START_REF] Magro | Charge binding of rhodamine derivative to OH stabilized nanomaghemite: Universal nanocarrier for construction of magnetofluorescent biosensors[END_REF][START_REF] Verma | Fluorescent magnetic iron oxide nanoparticles for cardiac precursor cell selection from stromal vascular fraction and optimization for magnetic resonance imaging[END_REF], Cy, [START_REF] Fu | Fluorescent Magnetic Nanoparticles for Magnetically Enhanced Cancer Imaging and Targeting in Living Subjects[END_REF][START_REF] Levy | Bioactive magnetic near Infra-Red fluorescent core-shell iron oxide/human serum albumin nanoparticles for controlled release of growth factors for augmentation of human mesenchymal stem cell growth and differentiation[END_REF][START_REF] Perillo | Synthesis and in vitro evaluation of fluorescent and magnetic nanoparticles functionalized with a cell penetrating peptide for cancer theranosis[END_REF], ATTO, [START_REF] Lehmann | Fluorescent-Magnetic Hybrid Nanoparticles Induce a Dose-Dependent Increase in Proinflammatory Response in Lung Cells in vitro Correlated with Intracellular Localization[END_REF][START_REF] Howes | Magnetic Conjugated Polymer Nanoparticles as Bimodal Imaging Agents[END_REF], fluorescein/FITC, [START_REF] Chekina | Fluorescent magnetic nanoparticles for biomedical applications[END_REF][START_REF] Ebrahiminezhad | Preparation of novel magnetic fluorescent nanoparticles using amino acids[END_REF][START_REF] Ge | Fluorescence Modified Chitosan-Coated Magnetic Nanoparticles for High-Efficient Cellular Imaging[END_REF][START_REF] Kaewsaneha | Immobilization of fluorescein isothiocyanate on magnetic polymeric nanoparticle using chitosan as spacer[END_REF][START_REF] Lu | Fluorescent-magnetic poly(poly(ethyleneglycol)monomethacrylate)-grafted Fe3O4 nanoparticles from post-atom-transferradical-polymerization modification: synthesis, characterization, cellular uptake and imaging[END_REF][START_REF] Pinheiro | Fluorescent Magnetic Bioprobes by Surface Modification of Magnetite Nanoparticles[END_REF][START_REF] Torkpur-Biglarianzadeh | Multilayer fluorescent magnetic nanoparticles with dual thermoresponsive and pH-sensitive polymeric nanolayers as anti-cancer drug carriers[END_REF][START_REF] Wan | Incorporation of magnetite nanoparticle clusters in fluorescent silica nanoparticles for high-performance brain tumor delineation[END_REF],

which usually emit/absorb in the visible, near infrared or far infrared, i.e. mainly between 380 and 1000 nm. Among all these compounds, ICG presents the advantage of being authorized for human injection for a number of imaging applications, [START_REF] Alander | A Review of Indocyanine Green Fluorescent Imaging in Surgery[END_REF], hence suggesting that FIBN comprising ICG may be authorized for clinical application provided their safety is established. The second one is made of quantum/carbon dots, [START_REF] Chen | Magneto-Fluorescent Core-Shell Supernanoparticles[END_REF][START_REF] Cho | Superparamagnetic Nanospheres for Drug Storage, Targeting, and Imaging:AMultifunctional Nanocarrier System for Cancer Diagnosis and Treatment[END_REF][START_REF] Cho | Characterization and Optimization of the Fluorescence of Nanoscale Iron Oxide/Quantum Dot Complexes[END_REF][START_REF] Ding | Chitosan-based magnetic/fluorescent nanocomposites for cell labelling and controlled drug release[END_REF][START_REF] Gui | Encapsulating magnetic and fluorescent mesoporous silica into thermosensitive chitosan microspheres for cell imaging and controlled drug release in vitro[END_REF][START_REF] Hong | Fabrication of Magnetic Luminescent Nanocomposites by a Layer-by-Layer Self-assembly Approach[END_REF][START_REF] Insin | Incorporation of Iron Oxide Nanoparticles and Quantum Dots into Silica Microspheres[END_REF][START_REF] Jha | Direct one-pot synthesis of glutathione capped hydrophilic FePt-CdS nanoprobe for efficient bimodal imaging application[END_REF][START_REF] Koc | Synthesis and characterization of ZnS@Fe3O4 fluorescentmagnetic bifunctional nanospheres[END_REF][START_REF] Koktysh | Fluorescent magnetic hybrid nanoprobe for multimodal bioimaging[END_REF][START_REF] Li | Conjugated Polymer Based Nanoparticles as Dual-Modal Probes for Targeted In Vivo Fluorescence and Magnetic Resonance Imaging[END_REF][START_REF] Lou | Functionalized magneticfluorescent hybrid nanoparticles for cell labelling[END_REF][START_REF] Vargas | Synthesis and characterization of core/shell Fe3O4/ZnSe fluorescent magnetic nanoparticles[END_REF][START_REF] Wang | Superparamagnetic Fe2O3 Beads-CdSe/ZnS Quantum Dots Core-Shell Nanocomposite Particles for Cell Separation[END_REF][START_REF] Wang | BRCAA1 monoclonal antibody conjugated fluorescent magnetic nanoparticles for in vivo targeted magnetofluorescent imaging of gastric cancer[END_REF][START_REF] Wen | Fluorescent/magnetic micro/nano-spheres based on quantum dots and/or magnetic nanoparticles: preparation, properties, and their applications in cancer studies[END_REF][START_REF] Ye | Biodegradable polymeric vesicles containing magnetic nanoparticles, quantum dots and anticancer drugs for drug delivery and imaging[END_REF][START_REF] Yin | A multifunctional mesoporous Fe3O4/SiO2/CdTe magneticfluorescent composite nanoprobe[END_REF], whose absorption/emission wavelengths vary between 200 and 800 nm depending on their composition and size. These materials present the advantages of displaying absorption/emission peaks with wavelengths that can be tuned through size adjustment and stock shifts that are often larger than for dyes due to light quantum confinement. These properties yield efficient imaging. However, some of these materials also suffer from the presence of toxic elements in their composition, e.g. CdSe, [START_REF] Cho | Characterization and Optimization of the Fluorescence of Nanoscale Iron Oxide/Quantum Dot Complexes[END_REF][START_REF] Gao | Intracellular Spatial Control of Fluorescent Magnetic Nanoparticles[END_REF][START_REF] Jha | Direct one-pot synthesis of glutathione capped hydrophilic FePt-CdS nanoprobe for efficient bimodal imaging application[END_REF][START_REF] Sun | Synthesis of magnetic and fluorescent multifunctional hollow silica nanocomposites for live cell imaging[END_REF],

CdTe, [START_REF] Gao | Graphene oxide-based magnetic fluorescent hybrids for drug delivery and cellular imaging[END_REF][START_REF] Gaponik | Luminescent Polymer Microcapsules Addressable by a Magnetic Field[END_REF][START_REF] Jha | Direct one-pot synthesis of glutathione capped hydrophilic FePt-CdS nanoprobe for efficient bimodal imaging application[END_REF][START_REF] Hong | Fabrication of Magnetic Luminescent Nanocomposites by a Layer-by-Layer Self-assembly Approach[END_REF], CdSe/CdS, [START_REF] Chen | Magneto-Fluorescent Core-Shell Supernanoparticles[END_REF], CdSe/ZnS, [START_REF] Cho | Characterization and Optimization of the Fluorescence of Nanoscale Iron Oxide/Quantum Dot Complexes[END_REF][START_REF] Wang | Superparamagnetic Fe2O3 Beads-CdSe/ZnS Quantum Dots Core-Shell Nanocomposite Particles for Cell Separation[END_REF], CdTe/ZnS, [START_REF] Ding | Chitosan-based magnetic/fluorescent nanocomposites for cell labelling and controlled drug release[END_REF], CdTe/CdSe, [START_REF] Insin | Incorporation of Iron Oxide Nanoparticles and Quantum Dots into Silica Microspheres[END_REF],

CdTe/CdS, [START_REF] Koktysh | Fluorescent magnetic hybrid nanoprobe for multimodal bioimaging[END_REF], ZnS, [START_REF] Lou | Functionalized magneticfluorescent hybrid nanoparticles for cell labelling[END_REF], and from a blinking effect, i.e. intermittent light emission, [START_REF] Efros | Origin and control of blinking in quantum dots[END_REF]. The third type of fluorescent materials consists of luminescence up-conversion compounds such as Yb 3+ /Er 3 + , [START_REF] Gai | Synthesis of Magnetic, Up-Conversion Luminescent, and Mesoporous Core-Shell-Structured Nanocomposites as Drug Carriers[END_REF], Yb 3 + /Tm 3+ co-doped NaYF4, [START_REF] Gai | Synthesis of Magnetic, Up-Conversion Luminescent, and Mesoporous Core-Shell-Structured Nanocomposites as Drug Carriers[END_REF], NaYF4:Yb, Er, [START_REF] Mi | Multifunctional nanocomposites of superparamagnetic (Fe3O4) and NIR-responsive rare earth-doped up-conversion fluorescent (NaYF4 : Yb,Er) nanoparticles and their applications in biolabeling and fluorescent imaging of cancer cells[END_REF], which emit light at shorter wavelength than their excitation wavelength. The use of long excitation wavelengths with large tissue penetration paves the way towards deep in vivo fluorescence. Fourth, metallic compounds different from iron such as chromium can be incorporated in FIBN, e.g. in Cr2O3 FIBN, and yield fluorescent properties with emission/absorption at 460 nm/360 nm, [START_REF] Borgohain | A new CoFe2O4-Cr2O3-SiO2 fluorescent magnetic nanocomposite[END_REF].

Metallic and fluorescent compounds are assembled together to form a complex in the following different manners. In most cases, a fluorescent compound is attached to the metallic part of the complex, either directly, i.e. without an intermediate layer [START_REF] Cho | Characterization and Optimization of the Fluorescence of Nanoscale Iron Oxide/Quantum Dot Complexes[END_REF][START_REF] Gao | Intracellular Spatial Control of Fluorescent Magnetic Nanoparticles[END_REF][START_REF] Magro | Charge binding of rhodamine derivative to OH stabilized nanomaghemite: Universal nanocarrier for construction of magnetofluorescent biosensors[END_REF], or via a coating made of various organic layers such as chitosan, [START_REF] Ge | Fluorescence Modified Chitosan-Coated Magnetic Nanoparticles for High-Efficient Cellular Imaging[END_REF], carboxy-methyl-chitosan, [START_REF] Ge | Fluorescence Modified Chitosan-Coated Magnetic Nanoparticles for High-Efficient Cellular Imaging[END_REF][START_REF] Ding | Chitosan-based magnetic/fluorescent nanocomposites for cell labelling and controlled drug release[END_REF], dextran, [START_REF] Koktysh | Fluorescent magnetic hybrid nanoprobe for multimodal bioimaging[END_REF], DMSA, [START_REF] Bertorelle | Fluorescence-Modified Superparamagnetic Nanoparticles: Intracellular Uptake and Use in Cellular Imaging[END_REF], PEI, [START_REF] Wang | A Magnetic Nanoparticle-Based Multiple-Gene Delivery System for Transfection of Porcine Kidney Cells[END_REF],

polyelectrolytes, [START_REF] Hong | Fabrication of Magnetic Luminescent Nanocomposites by a Layer-by-Layer Self-assembly Approach[END_REF], PLMA, [START_REF] Wang | Biodegradable magnetic fluorescent magnetite/poly(DL-lactic acid-co-a,b-malic acid) composite nanoparticles for stem cell labeling[END_REF], PEG, [START_REF] Shen | Doxorubicin and indocyanine green loaded superparamagnetic iron oxide nanoparticles with PEGylated phospholipid coating for magnetic resonance with fluorescence imaging and chemotherapy of glioma[END_REF][START_REF] Verma | Fluorescent magnetic iron oxide nanoparticles for cardiac precursor cell selection from stromal vascular fraction and optimization for magnetic resonance imaging[END_REF], or inorganic compounds such as SiO2, [START_REF] Borgohain | A new CoFe2O4-Cr2O3-SiO2 fluorescent magnetic nanocomposite[END_REF][START_REF] Chen | Modification of magnetic silica/iron oxide nanocomposites with fluorescent polymethacrylic acid for cancer targeting and drug delivery[END_REF][START_REF] Chen | Magneto-Fluorescent Core-Shell Supernanoparticles[END_REF][START_REF] Cho | Cetuximab-conjugated magneto-fluorescent silica nanoparticles for in vivo colon cancer targeting and imaging[END_REF][START_REF] Gai | Synthesis of Magnetic, Up-Conversion Luminescent, and Mesoporous Core-Shell-Structured Nanocomposites as Drug Carriers[END_REF][START_REF] Huang | Photosensitizer-conjugated magnetic nanoparticles for in vivo simultaneous magnetofluorescent imaging and targeting therapy[END_REF][START_REF] Pfaff | Magnetic and Fluorescent Glycopolymer Hybrid Nanoparticles for Intranuclear Optical Imaging[END_REF]. The coating can be made of a single layer/matrix, e.g. of silica, [100], or of several layers, e.g. polyelectrolytes of opposite charges within a so-called layer by layer assembly, [START_REF] Gallagher | Bimodal magneticfluorescent nanostructures for biomedical applications[END_REF]. The coating material surrounds the metallic part of the complex and the fluorescence substance is attached at its surface. In some cases, a coating, which is fluorescent by nature, such as a carbon shell, is used to stabilize the metallic part of the IBN complex,[101]. Moreover, a coating composed of mesoporous silica was suggested to enable the insertion of fluorescence substance within its inner pores, [START_REF] Chen | Modification of magnetic silica/iron oxide nanocomposites with fluorescent polymethacrylic acid for cancer targeting and drug delivery[END_REF][START_REF] Huang | Photosensitizer-conjugated magnetic nanoparticles for in vivo simultaneous magnetofluorescent imaging and targeting therapy[END_REF]. In addition to a fluorescent compound, IBN can comprise a targeting agent and a chemotherapeutic drug such as folic acid and β-cyclodextrin, [102], providing additional functionalities to IBN but making this complex more difficult to fabricate under pharmaceutical standards. The distance between the fluorescent compound and the iron-based metallic part is often maintained sufficiently large to prevent fluorescence quenching and below a certain threshold to avoid the loss of the complex stability. When the fluorescent substance is an inorganic QD, it is possible to grow it directly on top of IBN external surface, and hence to avoid the presence of an organic coating, [START_REF] Cho | Characterization and Optimization of the Fluorescence of Nanoscale Iron Oxide/Quantum Dot Complexes[END_REF][START_REF] Gao | Intracellular Spatial Control of Fluorescent Magnetic Nanoparticles[END_REF][START_REF] Magro | Charge binding of rhodamine derivative to OH stabilized nanomaghemite: Universal nanocarrier for construction of magnetofluorescent biosensors[END_REF]. Finally, different types of super-structures have been proposed, which are composed of micelles, [103], filled or empty vesicles/spheres, [START_REF] Gaponik | Luminescent Polymer Microcapsules Addressable by a Magnetic Field[END_REF][START_REF] Gui | Encapsulating magnetic and fluorescent mesoporous silica into thermosensitive chitosan microspheres for cell imaging and controlled drug release in vitro[END_REF][START_REF] Sun | Synthesis of magnetic and fluorescent multifunctional hollow silica nanocomposites for live cell imaging[END_REF][START_REF] Ye | Biodegradable polymeric vesicles containing magnetic nanoparticles, quantum dots and anticancer drugs for drug delivery and imaging[END_REF],

matrix, [START_REF] Cho | Superparamagnetic Nanospheres for Drug Storage, Targeting, and Imaging:AMultifunctional Nanocarrier System for Cancer Diagnosis and Treatment[END_REF], nanowires, [104], graphene oxide, [START_REF] Gao | Graphene oxide-based magnetic fluorescent hybrids for drug delivery and cellular imaging[END_REF], inside or at the surface which FIBN are inserted or attached. Such super-structures maintain several FIBN complexes on or within the same support, hence providing a means to collectively send several FIBN towards a desired location, e.g. a tumor, hence possibly improving the targeting efficacy compared with a strategy relying on the movement of individual FIBN.

Most often, the FIBN complex is designed to prevent the release of the fluorescent compound and hence to ensure that the fluorescence remains stable as a function of time, e.g. by attaching the fluorescent compound (FC) by strong/covalent bonds to the coating of IBN metallic part,[102,[START_REF] Bertorelle | Fluorescence-Modified Superparamagnetic Nanoparticles: Intracellular Uptake and Use in Cellular Imaging[END_REF][START_REF] Chekina | Fluorescent magnetic nanoparticles for biomedical applications[END_REF][START_REF] Chen | Modification of magnetic silica/iron oxide nanocomposites with fluorescent polymethacrylic acid for cancer targeting and drug delivery[END_REF][START_REF] Ge | Fluorescence Modified Chitosan-Coated Magnetic Nanoparticles for High-Efficient Cellular Imaging[END_REF][START_REF] Huang | Photosensitizer-conjugated magnetic nanoparticles for in vivo simultaneous magnetofluorescent imaging and targeting therapy[END_REF][START_REF] Koktysh | Fluorescent magnetic hybrid nanoprobe for multimodal bioimaging[END_REF][START_REF] Levy | Bioactive magnetic near Infra-Red fluorescent core-shell iron oxide/human serum albumin nanoparticles for controlled release of growth factors for augmentation of human mesenchymal stem cell growth and differentiation[END_REF][START_REF] Lu | Fluorescent-magnetic poly(poly(ethyleneglycol)monomethacrylate)-grafted Fe3O4 nanoparticles from post-atom-transferradical-polymerization modification: synthesis, characterization, cellular uptake and imaging[END_REF][START_REF] Verma | Fluorescent magnetic iron oxide nanoparticles for cardiac precursor cell selection from stromal vascular fraction and optimization for magnetic resonance imaging[END_REF][START_REF] Wan | Incorporation of magnetite nanoparticle clusters in fluorescent silica nanoparticles for high-performance brain tumor delineation[END_REF][START_REF] Wang | Superparamagnetic Fe2O3 Beads-CdSe/ZnS Quantum Dots Core-Shell Nanocomposite Particles for Cell Separation[END_REF][START_REF] Wang | Biodegradable magnetic fluorescent magnetite/poly(DL-lactic acid-co-a,b-malic acid) composite nanoparticles for stem cell labeling[END_REF][START_REF] Wang | BRCAA1 monoclonal antibody conjugated fluorescent magnetic nanoparticles for in vivo targeted magnetofluorescent imaging of gastric cancer[END_REF]105,106], or by maintaining the FC inside the FIBN complex by encapsulating it inside a vesicle, [START_REF] Gaponik | Luminescent Polymer Microcapsules Addressable by a Magnetic Field[END_REF]. However, in one recent case, it was suggested to maintain a weak bond between FC and FIBN, [START_REF] Alphande Ŕy | Nanoprobe Synthesized by Magnetotactic Bacteria, Detecting Fluorescence Variations under Dissociation of Rhodamine B from Magnetosomes following Temperature, pH Changes, or the Application of Radiation[END_REF][START_REF] Alphandéry | Fluorescent magnetosomes for controlled and repetitive drug release under the application of an alternating magnetic field under conditions of limited temperature increase[END_REF], to allow the operation of the probe through the release of FC from the FIBN complex, hence yielding an increase of the fluorescence intensity of FC through a de-quenching mechanism, i.e. the fluorescence of FC is initially quenched when FC is attached to FIBN and is then dequenched when FC is released from FIBN, [START_REF] Alphande Ŕy | Nanoprobe Synthesized by Magnetotactic Bacteria, Detecting Fluorescence Variations under Dissociation of Rhodamine B from Magnetosomes following Temperature, pH Changes, or the Application of Radiation[END_REF][START_REF] Alphandéry | Fluorescent magnetosomes for controlled and repetitive drug release under the application of an alternating magnetic field under conditions of limited temperature increase[END_REF]. This method was conceived to yield enhanced sensitivity, due its operating conditions relying on the detection of fluorescence increase instead of constant fluorescence. In addition, it can detect the release of a fluorescent anti-cancerous drug, e.g. Doxorubicin, paclitaxel, or bleomycin, [107], hence possibly enabling the monitoring of chemotherapeutic drug activity when the latter is triggered upon release of the drug from FIBN.

Several types of FIBN are commercially available, at prices that differ depending on the product between 7 and 300 euros per mg of FIBN. FIBN are available in the following different configurations : i) dyes are covalently bound to FIBN, eventually coated with dextran/hyroxyl-starch, i.e. Absolute Mag from CD, Magdye from Ocean Nanotech, nanomag®-CLD-redF and synomag®-CLD-far redF from Micromod, MP25/350-FC/RB/Cy3/Cy5/Cy5.5 from NANOCS, ii) dyes are sandwiched between a magnetic core and a polysaccharide matrix, i.e. nano-screen MAG (affinity) from Chemicell, iii) dyes are comprised in a polystyrene/silica matrix surrounding FIBN magnetic core, i.e. SPHERO™ Carboxyl Fluorescent Magnetic Particles from Spherotech, iv) dyes are weakly bound to magnetosome surface and could be released from this surface under the application of a stimulus to yield an increase in fluorescence intensity (table 1).

III. DETECTION METHODS OF NON-FLUORESCENT IRON-BASED NANOMATERIALS

Dark-field optical microscopy (DFM), is a relatively cheap/simple method that can image IBN down to single IBN resolution, using a microscope shining light, e.g. white one, on IBN with the help of a condenser to ensure accurate light focusing, and the scattered light then travels through an objective lens before being observed/recorded. In DFM, the light scattered by IBN is recorded at localized surface plasmon resonance (LSPR) wavelength, e.g. using a spectrometer connected to a CCD camera, [108].

DFM relies on Rayleigh scattering by IBN, which occurs under conditions where the wavelength of the incident light beam is large compared with IBN sizes resulting in elastic interactions between this beam and IBN and in an absence of energy loss. This method can be used to visualize an assembly of IBN through an image built from the intensity of light scattered by this assembly after removal of un-scattered light. The region, which surrounds IBN and where scattering does not occur in the absence of a scattering object should appear dark in the image, shedding light on the name ''dark-field microscopy''. To reach a high scattering efficacy, a material with strong surface plasmonic resonance, i.e. essentially gold, can be added at the surface of IBN, [101]. Hence, nanoparticle complexes made of Au nano-seeds organized at IBN surface were brought into the presence of human fibroblast cells. It was possible to observe assemblies of these IBN in these cells using a dark-field microscope, apparently with a better resolution than the bright field microscope although this aspect was not discussed in this study, [109].

Near Field Scanning Optical Microscopy (NSOM) uses laser light that travels through an aperture with a diameter smaller than the laser wavelength to create an evanescent field, which then excites and images IBN down to individual IBN level. NSOM presents the double advantage of reaching very high resolution down to 10 nm, [110], which is well below the diffraction limit of /2 estimated for an objective with numerical aperture of 1, and of enabling to extract topographical information of the measured sample when NSOM is combined with atomic force microscopy (AMF). NSOM microscopes usually consist of a laser light beam, which travels through an optical fiber, whose ending part, which serves to illuminate IBN and to collect the scattered light, i.e. the so-called scanning tip, is coated with a metal, pulled or stretched. The laser light beam further crosses a polarizer and a beam splitter to remove light not interacting with FIBN from the scattered light.

IV. DETECTION METHODS OF FLUORESCENT IRON-BASED NANOMATERIALS

The methods described in the previous section, which don't necessitate the presence of a fluorescent Furthermore, CM, which is a widely used microscopy technique, enabled to distinguish the various blocks of a FIBN complex consisting of SPION (block 1), PEG (block 2), and antibody (block 3), where blocks 1, 2, and 3 appeared in black, green, and red, respectively, hence clearly showing the different locations of these blocks within the nanoparticulate complex, [START_REF] Cho | Cetuximab-conjugated magneto-fluorescent silica nanoparticles for in vivo colon cancer targeting and imaging[END_REF].

To reach a microscopic resolution below 200 nm, super-resolution light microscopy, (SRM), can be used, Fluorescence resonance energy transfer (FRET) relies on the detection of the variation of fluorescence of a donor induced by the appearance or disappearance of a transfer of electrons between so-called donors and acceptors in close proximity, i.e. typically separated by less than 10 nm. To carry out optimal FRET measurements, specific properties are required both for the microscope used for imaging and for the FRET pair. On the one hand, most inverted microscopes could in principle be used for FRET microscopy, provided that they include a camera, which is sensitive enough to detect the fluorescence signal of FIBN, e.g. a high-resolution CCD camera, as well as interference filters allowing to block the light not arising from the fluorescence signal of FIBN. On the other hand, the FRET pair contained in FIBN should be characterized by: i) a well-adjusted ratio between the concentration of donors and acceptors, ii) an absence of photobleaching, iii) a sufficient overlap between donor fluorescence emission and acceptor absorption, iv) a minimal overlap between donor absorption and donor emission, v) no excitation of acceptor at donor excitation wavelength, v) a sufficiently long donor lifetime, and vi) a low donor polarization anisotropy.

Most interestingly, these properties can be optimized in FIBN, e.g. by accurately selecting the FC, by adjusting the distance between the FC and IBN magnetic core through a tuning of the coating thickness, by controlling the number/position of FC bound to IBN magnetic core. In most FRET studies, a FRET-based IBN complex was activated through the binding of FC to IBN or via the structural change of the Fluorescence anisotropy (FA) is a light detection method, which measures fluorescence anisotropy, i.e.

the intensity of fluorescence for different light emission directions. Its mechanism is based on the existence of photon polarization in light emitted by a FC when the exciting photons are polarized in a specific direction. Hence, a microscope used for FA measurements contains polarizers to polarize the light illuminating FIBN and to record the strength of the fluorescence intensity signal as a function of the light polarization direction. FA further relies on the principle that a molecule leads to less FA when it is in movement than when it is immobilized, since a molecule can more easily emit light in all directions when it is free to rotate than when it is fixed. Thus, this method was first used to measure the melting temperature of the membrane of a liposome containing IONP, by making such membrane fluorescent and by measuring FA as a function of increasing temperature under alternating magnetic field application, [128].

It could also be employed to determine the heating mechanism of IBN during magnetic hyperthermia. For example, IBN encapsulated in a silica matrix were shown to heat through a dominating Néèl contribution [129].

Two-photon microscopy (TPM) usually requires the use of a fluorescence microscope containing a laser of sufficiently large power, e.g. a femtosecond pulsed laser, with typical emission in the near infrared. It has been developed to image FIBN in regions that are inaccessible/too deep for the microscopy methods described above. Its principle relies on the use of an excitation light source with a wavelength that is twice that of single photon excitation (SPE). Two-photon excitation (TPE) presents the advantage of limiting tissue light scattering due to the use of long wavelengths, thus making it possible to image tissues at a certain penetration depth, i.e. typically 1 mm compared with only a few micrometers for single photon microscopy. The power required for TPE is however much larger than for SPE, requiring the use of a pulsed laser, since the number of photons reaching the region to be imaged should be sufficiently large so that the probability for the energies of two photons of energies E/2 to be simultaneously absorbed by the FC and result in its excitation, should be sufficiently large for fluorescence excitation to occur. As an example, FeS QD conjugated with HER2 antibodies were injected intravenously in mice bearing MCF7

subcutaneous tumors, and their presence in the tumor was revealed by TPE at 800 nm at a depth of up to 500 µm by a cyan color due to FeS QD fluorescence, [130]. Some FIBN such as FePt NP associated with NOPS fluorescent dye, which are non-fluorescent under SPE due to fluorescence quenching, can be made fluorescent under TPE and used for in vivo imaging, e.g. to image the mouse neocortex, [131].

Interestingly, it was suggested that TPE efficacy could be optimized, not necessarily by choosing an adapted dye that is incorporated in FIBN, which is always a complex thing to do, specially to reach a good FIBN stability, but by tailoring the surface of FIBN to make this material a strong absorber of NIR-IR light, as demonstrated for Fe3O4 NP with a surface modified by trimesic acid (TMA) [132].

To follow the fate of FIBN in an organism, fluorescence tomography (FT) can be used. In FT, the body part of a small animal (rat, mouse) in which FIBN are located is trans-illuminated with an IR/NIR laser.

The fluorescent light transmitted through the animal is then detected after removal of the excitation signal

IV. FLUORESCENT IRON OXIDE NANOPARTICLES FOR DETECTING TUMOR

MICRO-ENVIRONMENT

The tumor micro-environment consists of a wide range of different molecules, cells, or entities contained in tumor, such as angiogenic blood vessels, immune cells or fibroblasts, various signaling molecules, or the extracellular matrix. Its detection is important to yield accurate tumor diagnosis. In an interesting study, a probe was fabricated to detect metalloprotease-9 (MMP-9), which are known to be activated in TME. Such probe consisted of Fe3O4 NP linked to a Cy5.5 through a bond that was cleaved in the presence of MMP-9, thus suppressing the FRET mechanism between the NP and Cy5.5. In other words, this probe indirectly enabled to detect the TME by highlighting the loss of FRET, a method that was then elegantly applied for the detection of colon cancer, [136].

V. RECENT INNOVATIONS OF LIGHT INTERACTING IRON-BASED

NANOMATERIALS IN ONCOLOGY

In addition to the fluorescent probes already described, which operate through a fluorescence dequenching mechanism, [START_REF] Alphande Ŕy | Nanoprobe Synthesized by Magnetotactic Bacteria, Detecting Fluorescence Variations under Dissociation of Rhodamine B from Magnetosomes following Temperature, pH Changes, or the Application of Radiation[END_REF][START_REF] Alphandéry | Fluorescent magnetosomes for controlled and repetitive drug release under the application of an alternating magnetic field under conditions of limited temperature increase[END_REF], and studies which are in line with or complement older works, [137][138][139][140][141][142][143][144][145][146][147], some recent papers in the field of FIBN have brought to light some remarkable innovations. First, radio-luminescent FIBN produce a luminescence intensity proportional to the x-ray dose at which they are exposed. They could therefore potentially be used to monitor the doses of X-rays administered to a cancer patient, [148]. Secondly, an original detection system for cathepsin L was

VI. TOWARDS CLINICAL APPLICATIONS OF VISIBLE AND INFRA-RED LIGHT DETECTION METHODS COMBINED WITH IRON-BASED NANOMATERIALS:

Early cancer detection, which is needed to yield efficient cancer prognosis, relies on certain detection methods, which could be made more sensitive by using FIBN. First, liquid biopsy (LB), which consists in an analysis of certain blood components such as circulating tumor cells (CTC) and extracellular vesicles, has a strong cancer predictive power, since it can in principle highlight at the same time cancer occurrence, cancer heterogeneity, and cancer evolution, as demonstrated for lung, colorectal, prostate, melanoma, breast and pancreatic cancers, [152,153]. In addition, it is less invasive than tissue biopsy. LB can be carried out using an apparatus that detects and identifies by fluorescence the presence of extracellular vesicles. It has been shown that FIBN consisting of fluorescent magnetic mesoporous silica nanoparticles conjugated to the antibody of epithelial cell adhesion molecule (EpCAM) could enable to isolate and then detect CTC, hence demonstrating its utility in LB, [154]. Second, a system of detection of superficial tumors such as those of the skin, typically consisting in a fiber optic-based fluorimeter,

[155], could yield improved efficacy in the presence of FIBN, as demonstrated when SPION covalently conjugated to anti-cancer drug Epirubicin (EPI) with red fluorescence properties were shown to cross the derma under magnetic field application, enter and destroy skin WM266-4 metastatic human melanoma cells, as well as specifically release EPI through a pH dependent release mechanism, which takes advantage of the acidic tumor microenvironment, [START_REF] Azadmanjiri | Phase reduction of coated maghemite (g-Fe2O3) nanoparticles under microwave-induced plasma heating for rapid heat treatment[END_REF]. Third, fluorescent endoscopy could be carried on Fourth, colonoscopy, which is a similar method than endoscopy but specifically targets colon tumors and requires the patients to follow a specific preparatory treatment before imaging to clear out the colon, i.e. by drinking cleansing solutions/laxatives/enemas and by observing a diet.

Among the innovations in this field, it is worth mentioning a colonoscopy imaging endoscopic system that eliminates tissue autofluorescence and can distinguish between FIBN with different absorption/fluorescent properties. It combines a cysto-urethroscope, a multi-spectral imaging system, a CCD camera, a Xenon lamp, as well as lenses/optical fibers to carry the exciting/emitted light between the apparatus and colon tumor, [162]. Furthermore, using FIBN during colonoscopy can yield a reduction in dye photobleaching as well as the specific imaging of colon tumors when FIBN are bound to a tumortargeting ligand such as peanut agglutinin and anti-carcinoembryonic antigen antibodies (αCEA), [163].

One of the main interests of using FIBN in combination with optical methods resides in the faculty of these nanomaterials to specifically target tumors, hence enabling to improve tumor detection/treatment.

Passive targeting, i.e. via the well-known enhanced permeability and retention effect (EPR), [164], is the most common employed strategy. Its efficacy seems to depend on the nature of the body part. On the one hand, it was shown that FIBN associated with pH-activatable NIR dyes could accumulate in 4T1 tumors three hours after their injection and trigger a fluorescence signal in these tumors due to their acid environment, which persisted for 24 hours, [165]. On the other hand, when tumors are poorly vascularized, the EPR effect is not pronounced. This is the case for SKOV3 tumors, where other methods than passive targeting, e.g. magnetic targeting, need to be used to reach FIBN tumor accumulation, [167].

Targeting could also be achieved by using FIBN associated with a molecule that targets the region of interest, as was shown first for fluorescent iron oxide-carbon hybrid nanomaterials conjugated with CD44 monoclonal antibodies that specifically reach 4T1 breast cancer cells, yielding fluorescence of these cells,

[167], second for FIBN associated with a protein targeting riboflavin, which is overexpressed/activated in cancer/endothelial cells, and a fluorescent moiety (flavin mononucleotide), demonstrating efficient fluorescence of PC-3, DU-145, LnCap cancer cells and activated HUVEC endothelial cells, [START_REF] Jayapaul | FMNcoated fluorescent iron oxide nanoparticles for RCP-mediated targeting and labeling of metabolically active cancer and endothelial cells[END_REF], third for FIBN associated with fluorescent dye and folic acid that target KB cancer cells as demonstrated in vitro through fluorescence experiments, [168]. The targeting molecules incorporated in IBN and their associated cellular targets form pairs, whose list is provided elsewhere, [169,170]. The presence of iron in FIBN makes these materials sensitive to the application of an external magnetic field. Thus, it was

shown that FIBN administered intravenously to GBM bearing mice could be magnetically retained in tumor neovasculature and surrounding tumor tissues, using a magnetic field applied on the tumor via a micromesh, [START_REF] Fu | Fluorescent Magnetic Nanoparticles for Magnetically Enhanced Cancer Imaging and Targeting in Living Subjects[END_REF]. Interestingly, it was shown that FIBN could be captured by certain cells carrying FIBN to a location that needs to be imaged. For example, when FIBN were associated with ICG and injected intravenously to rats suffering from cerebral aneurysms (CAs), they were captured by macrophages that [183][184][185][186]. When they are covered with a plasmonic material, such as gold or silver, the light diffusion that they generate under the effect of a radiation makes it possible to detect tumor cells, which contain them, in particular with the help of dark field, Raman or near-field scanning optical microscopy. A more important number of applications can be foreseen when IBN are combined with a fluorescent compound.

For example, tumor cells, which are made fluorescent by the presence of FIBN, can be detected with wide-field epi-fluorescence microscopy. The sensitivity of the detection can further be improved by using confocal or super-resolution microscopy. Moreover, dynamic phenomena such as FIBN diffusion can be monitored by various microscopic methods, which measure the variation as a function of time and FIBN location of certain fluorescence parameters such as fluorescence lifetime, intensity, or anisotropy, using FRET, FLIM or FA microscopy. A method has also recently been developed to detect the release of a fluorescent drug from iron-based nanoparticles by monitoring a dequenching mechanism, i.e. the fluorescence of FIBN is initially quenched in the absence of excitation/perturbation and then de-quenched after FC release. TF imaging is another microscopy tool for imaging FIBN at a certain tissular depth, hence providing a tool to detect non-superficial tumors. Finally, although this method is currently reserved to small animals (rats, mice), fluorescence tomography can be used to visualize FIBN within the whole organism, thus making it possible to follow FIBN trajectory inside/outside a tumor. In combination with these various optical methods, FIBN can be used in liquid biopsy to improve the detection in blood of certain cancer biomarkers, they can serve to detect superficial tumors, e.g. those of the skin, or to improve the resolution of fluorescence imaging in endoscopic/colonoscopic tumor tissue examination. FIBN can also be employed in the context of cancer treatment, where they can guide the surgeon by illuminating tumor edges, and thus potentially allow him to increase the size of the tumor portion that he can remove at tumor margin. FIBN can directly destroy the tumor, either through heat, i.e. when FIBN are exposed to a laser beam of suitable wavelength and sufficient power to produce a temperature increase via PTT, or by generating singlet oxygen, i.e. when FIBN are associated with a photosensitizer and exposed to a laser beam to yield PDT. As a whole, iron-based nanomaterials appear to be very interesting and promising materials to fight cancers when they are combined with various optical methods to yield early cancer detection and localized tumor treatment. first category, the fluorescent compound (FC) is either attached to the NP magnetic core, embedded in a matrix (mesoporous or not) embedding the NP magnetic sore, or sandwiched between an external layer and the NP magnetic core. In a second category, FC is weakly bound to the NP magnetic core. In the first case, FC is sufficiently strongly associated to the NP magnetic core to prevent its dissociation and the fluorescence intensity of FC remains stable over time. In the second case, the weak interaction between FC and the NP magnetic core enables FC dissociation under various physico-chemical disturbance, such as pH, temperature variation or the application of a radiation, yielding a de-quenching mechanism and an increase of the fluorescence intensity. Table 1: For various FIBN described in the literature, magnetic composition, type of fluorescence substance that it contains, size, magnetization, coercivity, stability, type of complex that it is made of, fluorescent properties, and various applications.

FIGURES AND TABLE:

  -thermal therapy; PVLA: Polyvinylbenzyl-O-beta-D-galactopyranosyl-D-gluconamide; QD: Quantum dot; RhB: Rhodamine B; RITC: Rhodamine B isothiocyanate; SAXS: Small angle X-ray diffraction; SERS: Surface enhanced Raman spectroscopy; SIM: Structured illumination microscopy; SPECT: Single photon emission computed tomography; SPM: Single photon microscopy; SPION: Superparamagnetic iron oxide nanoparticle; TPM: Two photon microscopy; US: Ultrasound; WFEM: Wide field epifluorescence microscopy; XRD: X-ray diffraction;

  compound associated with IBN, can be of insufficient resolution to observe individual or weakly concentrated IBN. Thus, to improve the signal quality, visible/infra-red light detection methods have been developed in which FIBN are excited by an incident light beam, resulting in light emission used for reconstituting a fluorescence image. The description of the different existing types of fluorescent microscopy (FM) are reviewed elsewhere,[116]. With FIBN, certain drawbacks of FM can be overcome such as fluorophore photobleaching[117], weak dye quantum yield[118], and a narrow absorption band of many fluorescent compounds, (FC),[119]. Indeed, FIBN enable the attachment of several FC to a single FIBN hence increasing their concentration, a strong absorption in particular below 500 nm, the adjustment of fluorescence mechanisms through the design of the nanoparticulate complex, which can result in the presence or absence of electron transfer between the crystalized part of FIBN and the fluorescent compound and in FC being associated to the FIBN complex by weak or strong bonds, depending on whether or not the release of FC is desired.Wide field epifluorescence microscopy (WFEM) is the easiest fluorescent imaging method. Following laser light illumination, it yields a fluorescent image of FIBN, which is a superposition of images obtained at all different focal planes. WFEM contrasts with confocal microscopic images, where fluorescence originates from a specific focal plane. WFEM loses in resolution as the sample gets thicker and is best suited for thin sample with minimal autofluorescence, such as FIBN internalized in cells. It also requires the removal with adequate filters of laser light not originating from FIBN fluorescence. It can be combined with FIBN to yield efficient imaging at sub-cellular level, as has been shown for DMSA coated FIBN covalently attached to dyes, which produced membranous fluorescence when FIBN adsorbed on cell membrane and intracellular vesicular fluorescence when FIBN internalized inside cells, where these two distinct types of fluorescence could be achieved by varying FIBN incubation time and by deciding to apply (or not) a magnetic field,[START_REF] Bertorelle | Fluorescence-Modified Superparamagnetic Nanoparticles: Intracellular Uptake and Use in Cellular Imaging[END_REF].To further improve the detection of FIBN position within cells, confocal microscopy (CM) may be used.In CM, the combination of a microscope objective and a pinhole enables to focus a laser light beam on different focal planes localized at various depths of a sample containing FIBN, a method called optical sectioning. It yields a series of images from which a three-dimensional sample image can be reconstructed.In CM, the fluorescence originating from other planes than the focal one, is removed, hence resulting in a sharper and better resolved image with enhanced resolution compared with WFEM, i.e. typically 160-180 nm and 600 nm in lateral and vertical directions. Depending on FIBN sizes, on FIBN fluorescent properties, and on the optical quality of the used confocal microscope, such resolution could in principle allow the detection of a minimum of 1 to 100 FIBN. Using this method, it was clearly shown that fluorescent PVLA-coated FIBN were located inside hepatocyte cells and not at cell surface,[120].

[

  121]. The term SRM encompasses a large number of different techniques, an example of which being structured illumination microscopy (SIM). SIM can reach a resolution of 100 nm in lateral directions by reconstructing an image, which is a superposition of images obtained for illuminations at different phases and angles. Due to its high resolution, SRM enables to obtain images in 3D of FIBN in interaction with cells, cell compartments or cell membrane, using different colors for labeling various entities at nanometer scale,[121]. To obtain highly contrasted images with this method, fluorescent CTDR and DAPI compounds were directly mixed with Hela cells, leading to beautiful images of the cell nucleus and its surrounding with IBN appearing in the reflectance mode as white dots localized inside (blue) and around (red) cell nucleus,[122].

  not due to fluorescence, hence enabling to reconstruct a 2D or 3D fluorescence image (depending on FT apparatus) of a body part (BP) containing FIBN by gathering the fluorescence of different portions of the BP recorded at different angles. In this case, fluorescence is generated by a fluorescence compound associated to FIBN, e.g. Cy5.5 or NIR emitting semiconducting polymer with excitation/emission wavelengths of 670/695 nm, [133], or 360/660 nm, [134], respectively. Thus, when FIBN associated with specific targeting agents such as anti-EGFR, [135] or folic acid, [134] were administered intravenously to mice, they specifically targeted MDA-MB-231 breast and A549 lung subcutaneous tumors, [133, 134], reaching maximum FIBN tumor accumulation at 6 and 36 hours following FIBN administration, as revealed by the strongest fluorescent signal observed at these time points, [133, 134].

  described. It operates by detecting the fluorescence quenching caused by the aggregation of FIBN associated with polymer dots in the presence of cathepsin, [149]. Thirdly, IBN associated with thermo-responsive fluorescent polymer (TFP) which can release DOX in response to temperature changes, were shown to be taken up by prostate/skin tumor, resulting in tumor fluorescence that could serve for their detection. Furthermore, DOX release led to efficient tumor cell destruction at 41 °C. Hence, such nano-systems displayed a controlled drug release mechanism, which could be monitored by fluorescence, [150]. The presence of a fluorescence probe in ION was also shown to enable the detection of the specific tumor targeting of these NP or their internalization in tumor cells, using a variety of different types of FIBN, [151].

  various cancers, e.g. gastrointestinal, [156], pancreatic, [157], gastric/stomach, [158], esophageal, [159], or kidney, [160] cancers. Combining standard endoscopic fluorescent apparatus with FIBN associated to a targeting moiety (amino-terminal fragment) could improve the quality of the fluorescence signal due to the specific tumor targeting and imaging of FIBN, [157]. In the same spirit, it was shown that the position of FIBN encapsulated in a hydrogel with upconverting materials could be adjusted via magnetic targeting to enable the fluorescent compound of FIBN to reach the desired target, hence resulting in an improved endoscopic image, [161].

Figure 1 :

 1 Figure 1: A schematic diagram showing examples of fluorescent iron-based nanomaterials (FIBN). In a

Figure 2 :

 2 Figure 2: The different methods of light interaction with iron-based nanomaterials as a function of

Figure 3 :

 3 Figure 3: Various applications of light-interacting iron-based nanomaterials for cancer treatment and

  The scattered signal is further detected by standard optical detectors, such as avalanche photodiode, photomultiplier tube (PMT) or CCD camera. A so-called feedback mechanism can be used to achieve high resolution images without artifacts. Thus, it was demonstrated that IBN internalized in MCF7 breast cancer cells could be visualized by NSOM, giving rise to dark spots in transmission NSOM images, resulting from IBN light absorption at 488 nm. leads to surface enhanced Raman spectroscopy (SERS) effect, i.e. an amplification of the Raman signal due to plasmonic resonance at NP surface. Without such mechanism, it may be difficult to record a Raman spectrum with good resolution/sensitivity. By using various SERS based IBN, ultrasensitive detection of various cancer biomarkers could be reached, e.g. Fe3O4@Ag NP associated with DNA

	detected miRNA let-7b down to 0.3 fM, [113], SPION-PEI associated with Au NP and Folic Acid enabled
	the detection of a single HeLa cell per mL of collected blood, [114], while a sandwiched type
	immunoassay, consisting of Fe3O4 IONP coated by a silica shell attached to antibodies capturing tumor
	exosomes enabled to reach rapid detection, i.e. within 2 hours, of tumor exosomes via a SERS signal,
	[115].

Furthermore, AFM images, which displayed the geography of the cell surface through which IBN were engulfed, were also provided as sisters images of NSOM images,

[111]

.

Raman spectroscopy (RS) is another method, whose principle relies on inelastic light scattering by a nanomaterial notably following light energy absorption through lattice vibration of this material. It consists in recording a Raman Spectrum, whose peaks positions and intensities depend on the composition/structure of the studied material, further highlighting its presence or absence. Raman phenomena can be triggered by several different laser sources operating within a wide range of different wavelengths, i.e. typically between 488 nm (Argon laser) and 1064 nm (Nd:YAG laser), where a tradeoff between long wavelengths resulting in the most efficient tissue/cell penetration and low wavelength yielding the strongest Raman signal, which is proportional to 1/ 4 , should be determined,

[112]

. A Raman microscope typically contains a laser for IBN excitation, filters to remove laser light not interacting with IBN, a spectrometer or monochromator for scanning the different wavelengths of the scattered light, and standard detectors for measuring the strength of the scattered light. It measures so-called Raman Shifts, resulting from the light scattered by IBN, and operates either in standard or hyperspectral mode, where it detects wavenumber(s) associated with one or several type(s) of IBN, further providing images determining IBN location. Carrying out RS in the presence of IBN covered by a plasmonic material such as gold,

  FRET IBN complex, which took place without FC release from IBN. FIBN can contain FRET pairs consisting of a donor such as GFP,[123], Carbon dots, [124], FITC, [125], PFR,[126], and an acceptor such as CdTe QD,[123], Au[124, 126], or iron oxide nanoparticle (IONP),[125]. When FC gets linked to IBN to form a FRET IBN complex, it yields a fluorescence decrease of the FC donor and the binding of FC to this complex can then be detected. Hence, FRET can be used to detect the binding of a substance of interest such as sarcosine, [123], histamine,[124], thiol, [126], to IBN with a high sensitivity, i.e.

	typically in the nM range, [123], resulting in a highly sensitive diagnostic test. FRET can also serve to
	monitor the release of a cancer drug such as platinum (IV), following the action of an enzyme triggering
	such mechanism in the presence of FITC whose fluorescence changes are measured with FITC
	detachment from IBN, [125].
	provide a method for FRET measurement described above, which does not rely on fluorescence intensity
	but on fluorescence lifetime, hence making FRET outcome potentially less dependent on tissular
	environment. FLIM measurements on FIBN consisting of an iron oxide core coated by polymers bound
	covalently via imine bonds to DOX and incubated (or not) with MCF-7 breast / H1299 lung cancer cells
	showed that DOX lifetime was lower for incubated FIBN complexes, i.e. ∼1 ns, than for non-incubated

Although microscopic techniques often allow to obtain well-resolved images, they can hardly monitor very localized phenomena at the nanometer scale and suffer from the dependence of the fluorescence intensity on tissue light absorption/scattering. To overcome this hurdle, fluorescence lifetime imaging (FLIM) was developed. FLIM provides microscopic images, in which each pixel intensity is determined by the fluorescent decay rate (FDR) of the material that it contains, hence allowing to clearly differentiate between materials of different FDR through a contrast in the FLIM image. FLIM could be used to detect FIBN associated with photosensitizers inside tumor cells or FIBN internalized in tumors. It could also FIBN complexes, i.e. 4.6 ns. Such behavior may be attributed to DOX release from FIBN complexes under acidic intracellular pH,

[127]

.

  transported the nanoparticulate complex to CAs, hence providing a means to image CAs,[171]. It can be taken advantage of the imaging capacity of FIBN to efficiently deliver a molecule of therapeutic interest, e.g. FIBN surrounded by a mesoporous silica shell containing siRNA were efficiently carried to Hela cells under magnetic guidance and visualized by FI[172].Most interestingly, FIBN can also be used in the context of cancer treatments. First, the well-established and valuable method of fluorescence guided surgery (FGS), which is most commonly used on brain tumors to improve tumor resection, avoid tumor re-growth, and prevent removal of healthy tissues, could benefit from the presence of FIBN. Practically, FGS operates under infra-red (IR) light illumination with relatively deep tissue penetration of 1-2 cm,[173]. Hence, it can serve to excite/detect FIBN that can be made fully operational in the IR range of wavelengths. As an example, FIBN associated with DiI were combine PTT with fluorescence imaging (FI) to determine FIBN localization. For example, FIBN made of an assembly of iron oxide and carbon NP associated with fluorescent ICG enabled reaching ICG photostability and efficient long-term FI and PTT capability, i.e. intravenous injection of these FIBN on mice bearing 4T1 subcutaneous tumors followed by tumor illumination at 808 nm and 2 W/cm 2 for 5 minutes led to tumor temperature elevation up to a maximum temperature of 47 °C and to full tumor disappearance. Interestingly, the fate of FIBN after its injection in mouse organism could be followed by FI excited at 704 nm using an ex in vivo imaging system. FI nicely helped determining the lapse of time following FIBN injection that yielded maximal FIBN tumor accumulation, i.e. 8-10 hours,[178]. The practical application of PTT combined with IF can be made even more efficient by incorporating in FIBN a fluorescent compound with adjustable emission/excitation wavelengths and a releasable chemotherapeutic drug, as demonstrated for FIBN associated with carbon dots and DOX that yielded efficient imaging and destruction of mouse melanoma B16F10 cells through a synergy between chemotherapeutic and heating anti-tumor activity,[START_REF] Wang | A Magnetic Nanoparticle-Based Multiple-Gene Delivery System for Transfection of Porcine Kidney Cells[END_REF]. The use of IBN with PTT further enables NP minutes laser applications at 670 nm and 4 mW/cm 2 , [179], third for mice having subcutaneous gastric cancer tumors administered intravenously with FIBN associated with Ce-6, for which the combination of FI and PDT was reported under similar laser excitation conditions at 630 and 633 nm, enabling to monitor FIBN tumor localization before, during, and after tumor treatment,[181]. These three treatments led to tumor growth retardation, but not to full tumor disappearance. Figure3summarizes the various applications of light-interacting iron-based nanomaterials.CONCLUSIONThe detection and treatment of cancer are major public health issues. These two concepts are closely linked to each other, i.e. in general the earlier or the more precisely a cancer is detected in the body, the greater the chances of treating it effectively. Based on this observation, it appears interesting to develop methods that can improve detection and treatment of tumors through local approaches. When combined with various optical methods, iron-based nanomaterials achieve this double objective. Indeed, they are biocompatible and can target tumors by various mechanisms, i.e. passive, active, and magnetic targeting,

	concentration at tumor cell location via the application of a magnetic field, as highlighted for IBN
	used to label certain microglial BV2 cells, resulting in FIBN efficiently crossing the BBB and then
	incorporated in PLA microcapsules functionalized with graphene oxide that were heated by a 808 nm
	imaging by fluorescence tumor border demarcation for a prolonged period of 4 to 24 h following FIBN
	laser of 2 W/cm 2 during 10 minutes in the presence of Hella cancer cells, resulting in more efficient cancer
	administration through the carotid artery in an orthotopic glioblastoma mouse model. In this case, FIBN
	cell destruction in the presence than in the absence of magnetic field application for optimal IBN
	also led to an inhibition of M2 markers (arginase-1 and CD206), possibly reducing immunosuppressive
	concentration of 0.5 and 1 mg/mL, [179]. Third, Photodynamic therapy (PDT) is another modality of
	effects induced by M2-like phenotype of microglial cells, [174]. Compared to other types of NIR
	cancer treatment that can be implemented using iron-based nanomaterials associated with a
	nanoparticulate fluorescent materials foreseen for this application, such as carbon dots, CuInSe QD,
	photosensitizer (IBN-PS), which trigger anti-tumor activity via singlet oxygen generation under infra-red
	cornell dots, Up-converting NP, aggregation-induced emission NP, FIBN present the advantage of being
	light excitation, and is currently in use in the clinic to treat several cancers, [180]. IBN-PS was reported
	bio-compatible and orientable through the application of an external magnetic field, [175]. Second, FIBN
	to yield better PS solubility and more efficient tumor targeting compared with free PS, hence improving
	could be heated via a method called photothermal therapy (PTT), and trigger heat-induced anti-tumor
	PDT efficacy. The latter has been demonstrated, first for mice bearing 4T1 tumors injected intravenously
	activity, [176]. Thus, FIBN conjugated with certain dyes (MHI-148) were injected in subcutaneous SCC7

mouse tumors and heated during 10 minutes at a maximum temperature of 50 °C under the application of a 808 nm laser of 1 W/cm 2 , resulting in full tumor disappearance after 8 days,

[177]

. Furthermore, it is possible to with Ce6-FIBN followed by tumor light exposure at 650 nm and 75 mW/cm 2 during 30 minutes,

[181]

, second for mice with A539 xenograft tumors receiving intravenously IBN conjugated with thiolated heparin-pheophorbide, which is a PS designated to be specifically activated at tumor site, followed by several 30

and Nanoglioma E11778), the AIR program (''aide à l'innovation responsable'') from the region of Paris (A1401025Q), the ANR (''Agence Nationale de la Recherche'') Méfisto, as well as the Universities Paris 6 and Paris 11. We also would like to thank the Nomis Foundation and Markus Reinhard for their support.