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Magnetic Colloidal Supraparticles: Design, Fabrication and Biomedical Applications Jia Guo, Wuli Yang, and Changchun Wang* Dedicated to the 20th Anniversary of the Department of Macromolecular Science of Fudan University

To date, many chemical preparation methods have been developed, such as chemical coprecipitation,[7,8] thermal decomposition,[9–11] sol-gel synthesis,[12] hydrothermal reaction,[13] electrochemical method,[14,15] supercritical fluid method[16] and so on. Based on these methods, the uniform MNPs (size distribution is less than 5%) with tunable sizes, controllable shapes and various compositions can be prepared. Recently, many reviews have elaborately delineated the state-of-the-art progress of the preparation and application of MNPs.[17−20] For biomedical applications, considerable attention is routinely paid on the magnetic properties of MNPs, which is expected to exhibit rapid magnetic responsiveness and low remnant magnetic moment after removal of applied magnetic field. This pivotal performance of MNPs is greatly dependent on their single-domain sizes. From the point of view of theory, the relaxation of magnetic moment orientation of each particle is determined by τ = τ0eKV/2kT, wherein τ is relaxation time at one orientation, K is the particle’s anisotropy constant, V is particle volume, k is the Boltzmann’s constant, and T is temperature.[21,22] When the particle size decreases to a small value, KV becomes comparable to the thermal energy kT, and the magnetic moment starts to fluctuate from one direction to another quickly. Thus the net magnetic moment of the MNP is randomized to zero, leading to the so-called superparamagnetic characteristic. In this status, because the free MNPs are not susceptible to strong magnetic interaction on each other, their colloidal stability in physiological solution is thus improved and beneficial in biomedical applications.[23,24] In order to yield the superparamagnetism, the diameters of MNPs should be limited to less than 30 nm. The small-size MNPs with appropriate functionalities and tailored surface properties are suitable for many biomedical applications, but the weak magnetic responsiveness in solution constrains their practical use in some areas, such as DNA/protein separation, cell sorting and target drug delivery. With the aim to increase the magnetic responsiveness in a controllable manner while retain their superparamagnetic

Magnetic nanoparticles (MNPs) bear many intriguing properties such as superparamagnetism, high specific surface area, remarkable colloidal stability and biocompatibility, which evoke great interest and desire of exploration in biomedical applications. For the use in the complicated physiological environment, MNPs are still being developed to have the enhanced performances and down-to-earth practicality. Engineering of MNPs into hierarchical structures is thus proposed to create a new family of magnetic materials, magnetic colloidal supraparticles (MCSPs), which exhibit collective properties and unique nanomaterial characters. From a biomedical point of view, applicability of MCSPs is somewhat more distinctive in contrast to their primary MNPs, because MCSPs are amenable to modulation of secondary structure, promotion of magnetic responsiveness and ease of function design. As a result, MCSPs have been subject to intense researches in recent years, with the aim to develop outstanding composite materials for biomedical applications. In this review, we embark on an overview of foundational topics that detail the design and fabrication of MCSPs by evaporation-induced emulsion and solvothermal techniques, and continue with a guideline for modification of MCSPs with inorganic oxides and organic polymers. Particular focus is then placed on the biomedical applications of modified MCSPs. Many examples illustrate the latest progress in design of MCSP-based microspheres for magnetic resonance imaging, targeted drug delivery, sensing, and harvesting of peptides/proteins. After these detailed accounts, the current challenges and future development of researches and applications are discussed as a conclusion to the review.

1. Introduction Magnetic nanoparticles (MNPs),[1,2] especially iron oxides, have been subjected to extensive studies in the past few decades owing to their unique size-dependent magnetic properties and promising potentials in biomedical applications.[3–6]

Dr. J. Guo, Prof. W. L. Yang, Prof. C. C. Wang State Key Laboratory of Molecular Engineering of Polymers Department of Macromolecular Science Laboratory of Advanced Materials Fudan University Shanghai 200433, China E-mail: [email protected]

DOI: 10.1002/adma.201301896

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2. Design and Fabrication of Magnetic Colloidal Supraparticles (MCSPs) Magnetic colloidal supraparticles (MCSPs) are featured with high regularity in clustering structure and superior stability as colloids behave in aqueous solution. The synthetic strategies of MCSPs can fall into a multiple-step evaporation-induced route and a one-step solvothermal route. The following discussion will be detailed on this topic, to shed light on the recent advancement in controlled synthesis of MCSPs. 2.1. Evaporation-Induced Preparation of MCSPs from Magnetic Emulsions The evaporation-induced preparation of MCSPs has been widely accepted but adopted just in recent years. The earliest report could be traced back to 1993 by Bibette.[27] Also, Elassari et al. did intense studies in this area during the early stage of the related researches.[28–30] The classic preparation process could be described as follows: (1) synthesis of a stable dispersion of MNPs in organic solvent (ferrofluid), (2) preparation of emulsions with submicron-sized magnetic droplets by controllably shearing a mixture of ferrofluids and surfactants in dispersion medium, and (3) evaporation of solvent in droplets of emulsion if needed. Thanks to a complete repartition of MNP dispersion, the magnetic droplets were a homogeneous single phase and exhibited the regular spherical shape. Their average diameters were around 200 nm with 10% of standard deviation

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Jia Guo completed his Ph.D. in macromolecular chemistry and physics in 2007 at the Fudan University, China. Under the support of JSPS postdoctoral fellowship program, he continued to conduct research in the Institute for Molecular Science, Japan, where he investigated the synthesis of covalent organic frameworks. In 2009, he returned to China and became a lecture at the Fudan University. His scientific interests are the design and construction of porous organic polymers and organicinorganic hybrid nanomaterials for catalytic and biomedical applications.

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characteristic, the strategy of assembly of MNPs into supraparticles has been developed. Recently, a great progress has been made in the development of formulation of secondary structures of colloidal supraparticles. Their uniqueness in microstructure results in prominent properties as a result of a preferable combination of exclusive natures of individual nanoparticles and integrated functionalities of nanoparticle aggregates, which promises great potentials for the development of advanced nanomaterials.[25] In light of the distinctive characters of hierarchical microstructures, magnetic colloidal supraparticles (MCSPs) have attracted mounting interests due to promotion of magnetic responsiveness as well as preservation of the superparamagnetism from the primary MNPs of supraparticles. Moreover, more diverse functionalities are capable of being accomplished by the accurate control over compositions and reactivity of surface functional groups.[26] This review focuses on recent progresses in the design, fabrication and surface modification of the MCSPs and their applications in biomedical fields. The first perspective concerned is relevant to the synthetic tricks of MCSPs, enabling controllability of secondary microstructures with specificity in porosity and surface areas. Some promising technologies, for example, the microwave-assisted synthesis, have been involved in this part. Afterwards, the advancement in surface modification and functionalization of the MCSPs are discussed elaborately. Then a particular emphasis will be given to their applications in magnetic resonance imaging, biomarker sensing, targeted drug delivery, and enrichment and detection of proteins/peptides.

Wuli Yang received his BS degree in 1995, MS degree in 1998 and PhD degree in 2001 from Fudan University. He joined the Department of Macromolecular Science at Fudan University in 2001 as a Lecturer and was promoted to Associate Professor in 2003. In 2010 he was promoted to Full Professor. His research focuses on emulsion polymerization, functional inorganic nanoparticles, functional polymeric composite microspheres and biomedical nanoparticles for diagnostic and drug delivery. Changchun Wang received his PhD in Polymer Chemistry and Physics from Fudan University 1996. He was a visiting scientist 1996-1998 at Eastern Michigan University. He is now the Professor of Department of Macromolecular Science at Fudan University. His research interests are in design and synthesis of various polymer microspheres and magnetic composite nanomaterials with controlled structure and properties for DNA and protein enrichment, biomarker detection and targeting drug delivery.

measured by quasi-elastic light scattering, implying that a narrow size polydispersity could be obtained in the emulsion. As the evaporation-induced emulsion method has universality, tremendous efforts have been dedicated to investigate the construction of monodisperse supraparticles with



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larger than those of the two-end domes. When N was more than ∼80,000, the supraparticles appeared as either irregular-multidomain particles or double-domed cylinders. Following this line, they prepared MCSPs using Fe3O4 nanocubes under thermodynamic control (Figure 2).[33] The resulting MCSPs with unique shapes had exceptional stability upon the arrival of minimized Gibbs free energy. The simple cubic superlattice structure was acquired, and the shape of MCSPs could be tuned between spheres and cubes by varying relative contributions of surface and bulk free energies (Figure 2B). Also, the size-dependent hydration effect played an important role in the formation of highly ordered suparparticles. LCW theory could be applied to predict the formation processes of sphere- and cubeshaped MCSPs. This is the first example for engineering of a well-oriented MCSP through the thermodynamic equilibrium. Since the stabilizers used for MNPs (e.g. oleic acid) prefer to the hydrophobic dropFigure 1. (A) Schematic illustration of evaporation-induced synthesis of MCSPs in emulsion; lets and are compatible to the surfactants or (B) TEM images of MCSPs with controllable compositions, sizes, and shapes: (a) BaCrO4, polymers, thereby, the MNPs can be well dis(b) Ag2Se, (c) PbS, and (d) Fe3O4. Reproduced with permission.[31] persed in O/W emulsion or micelles for generation and manipulation of MCSPs. Comdifferent sizes, shapes and properties by using the dispersible paratively, one-step preparation of MCSPs needs specific stabinanoparticles (NPs) as building blocks.[31] A variety of NPs lizers to control evolution of MCSPs not only in geometry, but (BaCrO4, Ag2Se, PbS and Fe3O4) could be gathered, assembled also in surface and interior properties such as charge density, and fixed simultaneously in the emulsion droplets through dangling group species, and porosity, which will be discussed the hydrophobic interaction of surfactants and ligands of in the following part. NPs (Figure 1A). Upon evaporation of low-boiling solvent in droplets, the colloidal supraparticles were formed in the size 2.2. One-Step Preparation of MCSPs by Solvothermal Method range of 50 nm to 2 μm. Also, the shapes, compositions and surface charges of colloidal supraparticles could be tuned by the pre-designed experiment parameters (Figure 1B), such as One-step solvothermal reaction is considered as a potent, facile surfactant species, concentrations, organic solvents, temperaand time-saving method for preparation of MCSPs.[26] Li and tures, stirring and ultrasonic conditions. Compared with the coworkers described the solvothermal approach to synthesizing early methods, this approach possesses two main advantages: MCSPs by reduction of FeCl3 with ethylene glycol (Figure 3).[34] (1) low-boiling solvent in oil-in-water (O/W) emulsion can be The as-prepared MCSPs had narrowly distributed sizes that easily removed; (2) ligand-stabilized NPs are well dispersed in could be tuned in the range of 200–800 nm, and the standard nonpolar medium as a consequence of phase stability. In addideviation of size distribution was lower than 5%. Albeit without tion, the modified method based on O/W emulsion is available any stabilizers used, the obtained MCSPs could be dispersed for the further modification of supraparticles. in water for more than 1 h, implying their nice dispersibility Within this context, an exciting result has recently been in solution. The solvothermally synthesized MCSPs offer sevreported, which concerned anisotropy-driven self-assembly of eral important advantageous features for biomedical applisemiconducting nanorods into highly ordered colloidal supraparcations: (1) excellent magnetic responsiveness, conducive to ticles with well-defined supercrystalline domains.[32] The prepaconveniently manipulate MCSPs by an external magnetic field; ration process includes two steps: (1) synthesis of water-soluble (2) controllability of particle sizes at the submicrometer scale; nanorod micelles by mixing a chloroform solution of nanorods (3) inexpensive raw materials and high product yields, amewith an aqueous solution of dodecyl trimethylammonium bronable to large-scale production for industrial demand. Since mide and sequentially evaporating chloroform from mixtures, the solvothermal technique was proposed, much attention has and (2) growth of supraparticles from nanorod micelles in an been gained for modulation in secondary structures and funcaqueous solution of ethylene glycol. Varying the total number tionalities of MCSPs, and this method extends to many other (N) of nanorods could flexibly control the configurations and research areas as well. sizes of multiple supercrystalline domains in the supraparticle. As expected, poly(acrylic acid) (PAA) was used as stabilizer When N was less than ∼80,000, the shape of supraparticles was to decorate the MCSPs resulting in the first hydrophilic MCSPs double-domed cylinders, wherein the cylindrical domain was with abundant carboxyl groups on the surface.[35] Zhao and



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REVIEW Figure 2. (A) Representation of self-assembly of iron oxide nanocubes into MCSPs by processes of (i) embryo growth, (ii) crystallization, and (iii) assembly: (a) nanocube micelles, (b, c) MCSP embryos, (d) spherical MCSPs, and (e) cubic MCSPs; (B) TEM images of (a) spherical MCSP, (b) a spherical MCSP viewed along the [001] facet, (c) cubic MCSPs, and (d) a cubic MCSP viewed along the [001] facet. Reproduced with permission.[33] Copyright 2012, American Chemical Society.

coworkers adopted the identical route but utilized sodium citrate instead of PAA to stabilize the MCSPs in aqueous solution.[36] The magnetic responsiveness of the citrate-modified MCSPs was greatly improved compared with the primary MNPs, but the large surface area was sacrificed. Moreover, as the secondary structure was assembled very toughly without any voids, it was thus not suitable for drug storage and delivery. Thereafter, developing a facile way to fabricate MCSPs with large surface area or inner cavity became a big challenge. With these all in mind, we designed and prepared the hollow-core-structured MCSPs by replacing the electrostatic stabilizer NaOAc with NH4OAc in the recipe (Figure 4).[37] Under solvothermal conditions, we found that the NH4OAc played a key role in structural control. The function of NH4OAc could be summarized in the following three aspects: (1) NH4OAc acted as electrostatic stabilizer to

prevent particle agglomeration; (2) NH4OAc assisted ethylene glycol to reduce Fe(OH)3 partially into Fe(OH)2 for the successive dehydration reaction of Fe3O4 nanoparticles; (3) NH4OAc served as structure-directing agent to take effect in the structure transformation from solid to hollow aggregates. The possible reason might lie in that NH4OAc decomposed to HOAc and NH3, and the gaseous NH3 bubbles worked as soft template to manage the evolution of hollow-core structure. Also, the interstitial space was formed during this process in the shells of hollow MCSPs, which was favorable for drug storage and sustained release.[38] As poly(γ-glutamic acid) (PGA) was added in the recipe for preparation of MCSPs, an interesting mesoporous structure was constructed in our consecutive research.[39] As shown in Figure 5A, NH3 bubbles generated in decomposition of

Figure 3. TEM and SEM images of MCSPs of (a, b) Fe3O4, (c, d) MnFe2O4, (e, f) ZnFe2O4, and (g, h) CoFe2O4. The insets of TEM images show the corresponding electron diffraction patterns. Reproduced with permission.[34]

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loidal clusters. As the reaction progressed, the entrapped NH3 bubbles in the initial MCSPs were forced out and left the internal accessible channels, eventually resulting in a distinct mesoporous structure. The obtained MCSPs had large surface areas comparable or superior to that of individual MNPs, as well as high magnetization given by multiple NMPs. It is worth emphasizing that the conjugated PGA stabilizers render the mesoporous MCSPs to have prominent biocompatibility, superior dispersibility and stability, and abundant carboxylate groups available to further surface modification. More importantly, PGA could effectively manipulate the particle sizes of MCSPs as well as the surface areas and pore sizes by varying the feeding amount of PGA (Figure 5B). Besides, the similar mesoporous structures could be obtained for MCSPs using other bio-macroFigure 4. (a) TEM and (b) SEM images of hollow-core-structured MCSPs, (c) enlarged TEM image, and (d) HR TEM image for the marked rectangular area in (c) and SAED pattern of molecules, such as agarose, casein, and soybean protein.[40b] the hollow MCSPs (inset). Reproduced with permission.[37] Copyright 2010, Royal Society of Although the one-pot solvothermal Chemistry. method is advanced in preparation of NH4OAc allowed the PGA globules to reside at the liquid/gas MCSPs, the synthetic conditions are severe, usually requiring a long reaction time (more than 10 h) and high temperainterface, leading to PGA-stabilized bubbles. Then they were ture (up to 200 °C) in the autoclave. To further develop the engineered with the PGA-capped MNPs to form the initial col-

Figure 5. (A) Proposed mechanism of formation of mesoporous MCSPs; (B) Representative TEM and SEM images of the mesoporous MCSPs synthesized with addition of PGA of (a, b) 0.1 g, (c, d) 0.5 g, and (e, f)1.0 g. All scale bars are 200 nm. Reproduced with permission.[39] Copyright 2011, American Chemical Society.

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3. Fabrication of Composite Microspheres from MCSPs Since evaporation-induced method for preparation of MCSPs was reported, the exploration of MCSP-based composite microspheres has been performed coincidently. Investigation of this subject covers issues concerning tunability in microstructure and composition of microspheres and diversity in functionality and applicability. Encapsulation of the MCSPs with inorganic oxides is one of the important modification strategies. Using the sol-gel technique, inorganic coatings, i.e. SiO2,[42] mesoporous SiO2[43] and TiO2,[44] could be readily implemented on the surface of MCSPs. Zhao and coworkers reported a surfactant-templating approach to synthesis of sandwich-structured composite microspheres

with a MCSP@SiO2 core and a mesoporous SiO2 shell that had perpendicularly oriented channels (Figure 6).[45] The obtained microspheres possessed superparamagnetism, high magnetization (53.3 emu g−1), uniform mesopore (2.3 nm), high surface area (365 m2 g−1) and large pore volume (0.29 cm3 g−1). The synthetic procedure is illustrated in Figure 6A. The solvothermally synthesized MCSPs were coated with a thin silica layer through a sol-gel approach, leading to a nonporous MCSP@ SiO2 microsphere. Cetyltrimethylammonium bromide (CTAB) was used as a template to yield a mesostructured CTAB/silica composite on the periphery of MCSP@SiO2 microspheres. Then mesoporous SiO2 shell was generated by acetone extraction of CTAB templates, ultimately resulting in a well-defined core-shell Fe3O4@SiO2@mSiO2 microsphere. Apart from the inorganic coatings, polymer modification have been extensively investigated as well.[20] In this context, organic polymers such as polystyrene (PSt),[46] poly(styrene-b(acrylic acid)),[47] poly(styrene-b-(N-isopropylacryl amide))[48] and so on, have been applied to modify the MCSPs for the different intended uses. The prime factors in determining magnetic contents are polymerization procedure and intrinsic interaction between MCSPs and polymer components. Gu and coworkers synthesized the uniform high-magnetic-content composite microsphere consisting of a Fe3O4/PSt core and a silica shell by using the double-miniemulsion-emulsion technique.[46b] The miniemulsion containing roughly 100-nm droplets of oleic acid-stabilized Fe3O4 NP aggregates was mixed with the

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high-throughout technique, a rapid and environmentallyfriendly microwave assistant reaction has been investigated toward increased output of MCSPs in our group.[41a] In contrast to the traditional solvothermal method, the microwave-aided growth of MCSPs was dramatically speeded up and completed within minutes. The as-prepared MCSPs showed narrow size distribution from 200 to 400 nm. When a structure-directing agent, casein, was added to the reaction, hollow-core-structured MCSPs were formed within 10 min under microwave conditions as well.[41b]

Figure 6. (A) Synthetic procedure of MCSP@SiO2@mSiO2 microspheres; (B) TEM images of (a) MCSPs, (b) MCSP@SiO2, (c–e) MCSP@SiO2@ mSiO2, and (f) SEM image of MCSP@SiO2@mSiO2. Reproduced with permission.[45] Copyright 2008, American Chemical Society.

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Figure 7. (A) Schematic representation of fabrication of (a) MCSP-PMMA microspheres, (b) MCSP-PSt microspheres, (c) MCSP-PMMA core/PSt shell microspheres, and (d) PSt core/MCSP-PMMA shell microspheres; (B) Photographs of (a1) MCSP-PMMA latex, (c1) MCSP-PSt latex, and (a2, c2) core/shell-structured microspheres by polymerization of second monomer, in the absence and presence of a magnet, respectively; TEM images of (b) MCSP-PMMA core/PSt shell microspheres (the inset is the enlarged view of TEM image) and (d) PSt core/MCSP-PMMA shell microspheres (the inset is a TEM image of the ultrathin cross section with a thickness of ∼50 nm). Reproduced with permission.[49]

other emulsion made of styrene (St) monomer droplets with a uniform size of 3.7 μm prepared by membrane emulsification equipment. Since the surfactant concentration (sodium dodecyl sulfate) was limited below the critical micelle concentration and the population of Fe3O4 droplets was four orders of magnitude larger than that of St droplets, the St monomers could diffuse through the water to the Fe3O4 droplets, and, in turn, the polymerization locally occurred upon addition of initiators. The formed Fe3O4/PSt particles were monodispersed and could be coated by silica via a modified Stöber method, resulting in a core/shell-structured magnetic composite microsphere. We employed the modified evaporation-induced method to prepare core-shell MCSP-based microspheres with sitespecific placement of MNPs in either the core or the shell.[49] As displayed in Figure 7, the feeding order of two monomers, St and methyl methacrylate (MMA), were modulated to construct variant core/shell structures via the emulsion polymerization (Figure 7A). When MMA was used as the first monomer and St was added sequentially in the presence of Fe3O4 micelles, the two-step polymerization resulted in a well-defined core-shell structure consisting of a MCSP@ PMMA core and an encapsulating PSt shell (Figure 7B-a,b). In the opposite way, when St was used as the first monomer and MMA was polymerized successively in the presence of Fe3O4 micelles, the anchored Fe3O4 NPs on the surface of PSt cores could be successfully intercalated into the outer PMMA shell to form a unique polymer-magnetite hybrid shell (Figure 7B-c). TEM images confirmed that the Fe3O4 NPs were incorporated selectively into the PMMA shell, but were not present in the PSt core (Figure 7B-d). The main reason for the structure control was that the oleic acid stabilizers of Fe3O4 NPs were miscible with PMMA; this was conducive to accommodation of NPs in PMMA matrix. In contrast, because of the poor miscibility with PSt, Fe3O4 NPs could not be implanted in PSt moiety. To our knowledge, the weak interaction between MNPs and organic polymers possibly impede conjunction with each

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other. Thus an intermediate layer of SiO2 is introduced to build a functionalized surface for polymer deposition. A commonly used path to fabrication of polymer-covered MCSP microspheres includes four steps,[42] (1) solvothermal synthesis of MCSPs, (2) silica encapsulation of MCSPs, (3) modification of silica shells with vinyl groups using silane coupling agents, and (4) coating of polymers on the surface of MCSP@SiO2 particles by seed precipitation polymerization. Alternatively, direct covering of the silane coupling agents also enabled the modified MCSPs to have the pendent vinyl groups for connection of polymer shells.[50] More recently, we found the phenolformaldehyde condensation polymerization that could be performed on the surface of MCSPs through the use of microwave assistance.[51] The obtained MCSP@PF microspheres were uniformly sized and characterized with definitely coreshell microstructure. Distillation–precipitation polymerization is a potent synthetic approach to preparation of varied hydrophilic polymer shells on the basis of silica-modified MCSPs. In our group, the double hydrophilic polymer shell was successfully prepared on the MCSP cores recently (Figure 8A).[52] The approximately 300-nm MCSPs stabilized by citrate were synthesized by a modified solvothermal reaction. Hydration–condensation reaction of silane coupling agent (γ-methacryloxypropyl trimethoxysilane) was undergone on the surface of MCSPs, to give the available vinyl groups. Following two-step distillation-precipitation polymerization, a poly(methylacrylic acid) (PMAA) shell was formed on the modified MCSPs, and sequentially EGMP (ethylene glycol methacrylate phosphate) was polymerized on PMAA shells. We deemed that the interim PMAA layer was crucial for the formation of the outer PEGMP shell; it could shield the interaction between the phosphate group of EGMP and Fe3O4 and thus stabilize the reaction system. Meanwhile, the strong hydrogen bonds between ⫺COOH and–H2PO4 groups facilitated the coating of PEGMP layer over PMAA. The as-prepared MCSP@PMAA@PEGMP composite microspheres


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REVIEW Figure 8. (A) Preparation of Ti4+-immobilized MCSP@PMAA@PEGMP core/shell/shell microspheres; (B) Representative TEM images of (a) MCSPs, (b) MCSP@PMAA, and (c) MCSP@PMAA@PEGMP, respectively (all scale bars are 200 nm); (d) hydrodynamic diameter distributions of (i) MCSP, (ii) MCSP@PMAA, and (iii) MCSP@PMAA@PEGMP. Reproduced with permission.[52]

could coordinate numerous Ti4+ ions, which showed remarkable selectivity for phosphopeptides even at a very low molar ratio of phosphopeptides/nonphosphopeptides (1:500).

4. Biomedical Applications of MCSPs 4.1. MCSP-Based Probes for MR Imaging Exploration of innovative magnetic resonance (MR) contrast agents has aroused considerable interest since MR imaging has become a ubiquitous tool for biomedical imaging and clinic diagnosis. Paramagnetic molecular complex (e.g. GdIII chelates) is the representative MR contrast agent, which exhibits an increase in signal intensity and appear bright in T1-weighted images (“positive” imaging agents).[53] The other class of MR contrast agents is based on nanostructures including paramagnetic-complexes-doped framework nanostructure[54] and inorganic magnetic nanoparticles.[55] Of those members, superparamagnetic Fe3O4 NPs are most commonly used as MR contrast agents in biomedicine.[56] They can generate a decrease in signal intensity and appear dark in T2-weighted images (“negative” imaging agents). Although the recent advancements witness the rapid development on the fabrication and application

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of MNPs with controllable physic-chemical properties such as size, shape, and modified surface nature, the rational design of Fe3O4 MR contrast agents with high relaxivity and sensitivity as well as reduced toxicity is still in high demand thus so far. In comparison to a single-domain MNP, MCSPs are distinctive in relaxivity because their peculiar nanostructures change the proton relaxation effect.[57] As far as is known, two independent relaxation processes, namely, longitudinal and transverse relaxation, are responsible for generating MR imaging. Because of close agglomeration of numerous MNPs, the hierarchical structure of MCSPs is conductive to alter longitudinal (r1) and transverse relaxivities (r2) together.[58] On one hand, the clustering architecture decreases the surface of magnetic nanoparticles in contact with water and hence impairs the longitudinal relaxation effect of the interior MCSPs. On the other hand, the number of MNPs in an assembly and the magnetic moment are both proportional to r2. The overall effects of MCSPs on r1 and r2 thereby lead to the increased ratio of r2/r1 and, in turn, yield the high-efficiency T2 contrast agents. In contrast to a large-size MNP that possesses increased r2, the advantage of MCSPs is that the superparamagnetic character is retained as a result of their inclusion of small-size MNPs (