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Review

Cite This: ACS Appl. Bio Mater. 2020, 3, 121−142 www.acsabm.org

Polymer-Assisted Magnetic Nanoparticle Assemblies for Biomedical Applications # † ‡ # † ⊥ † ‡ ⊥ ‡ ⊥ Yuhuan Li, , , Nan Wang, , Xumin Huang, Fangyuan Li, Thomas P. Davis, , Ruirui Qiao,*, , † Δ and Daishun Ling*, , † Δ Institute of Pharmaceutics and Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China ‡ ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia ⊥ ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia

ABSTRACT: Magnetic nanoparticle (MNP) assemblies have demonstrated great potential in biomedical applications due to their controllable magnetic properties and collective functions. Among the versatile approaches to obtaining MNP assemblies, polymer-assisted assembling methods offer unique advances, by which the assembled nanostructures could exert the merits of both the inorganic magnetic nanoparticles and organic polymeric materials to realize combined advantages for medical diagnosis and treatment. Precise control over the interactions among different building moieties and spatial organization of magnetic nanoparticles with the aid of polymers provides promising strategies in manipulating the physical, chemical, and biological properties of nanoassemblies for biomedical applications. In this review, we summarize the recent progress of polymer-assisted MNP assemblies, which include the mutual interactions between building blocks, architectural diversity of the assemblies, and their synthetic strategies along with biomedical applications. The current review provides a comprehensive insight into controlled and intelligent nanomedicines, which shall facilitate the development of next-generation high-performance theranostic agents based on MNP assemblies. KEYWORDS: magnetic nanoparticle assembly, polymer, interaction force, architecture, biomedical application

fi 1. INTRODUCTION relaxation switching or signi cant T2 enhancement through 11−13 Magnetic nanoparticles (MNPs) have received growing the tailoring of interparticle distance and interaction, or controlled drug release at the targeted diseased sites with

Downloaded via 130.194.147.111 on March 17, 2020 at 04:41:59 (UTC). attention for their promising applications in disease diagnosis 1,2 minimized systemic side effects. Consequently, improved and therapy. Recent advances in chemical synthesis and performance with increased signal-to-noise (S/N) ratios characterization allow the production of MNPs with controlled through the targeted delivery and amplified MRI signals or shape, size distribution, and magnetism, while surface controlled drug release at the disease lesions can be achieved See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. engineering strategies endow particles with water dispersibility, for precision medicine and theranostic applications.14,15 colloidal stability, and biocompatibility in biological environ- − Recently, a number of techniques have been reported for the ments.3 5 Currently, the manipulation of the assembling/ constructions of assembly structures through self-organization, disassembling process has been demonstrated to be an effective directed-, or templated-assisted conformation arrangement by and facile approach to alter the physiochemical properties of introduced external fields,16 and various moieties including 6,7 − − MNPs, paving the way for breakthroughs in various research small molecules,17 biomolecules,18 20 inorganic materials,21 24 fields including drug delivery and targeted biological 25,26 8−10 as well as organic polymers. Precise spatial organization of imaging. For instance, compared with isolated magnetic nanoparticles (NPs) in the assemblies can lead to multiple nanoparticles, the MNP assemblies with higher magnetic structures including spherical, worm-like, and other template- ff − moment a ord a considerable enhancement in the detection guided structures (Scheme 1).27 30 Among these assembly sensitivity of magnetic resonance imaging (MRI). Moreover, moieties, polymer-based materials present a huge potential in the conjugation of therapeutics or imaging agents mediated by polymers or coassembling with MNPs enables the simulta- neous implementation of therapeutics and/or multiple imaging Special Issue: Young Investigator Forum modalities in one system. Especially, the responsive assembly/ Received: September 27, 2019 disassembly of MNPs upon specific endogenous conditions or Accepted: November 8, 2019 externally applied stimulus could impart a typical T2/T1 Published: November 8, 2019

© 2019 American Chemical Society 121 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Scheme 1. Schematic Illustration of Approaches, Interactions, and the Resulting Multilevel Structures for the Polymer-Assisted a MNP Assemblies

aThe preparation approaches of the assemblies were composed of template-free and template-based assembly via weak noncovalent bindings, including hydrophobic interaction, hydrogen bonding, electrostatic interaction, and other interactions. The obtained MNP assemblies have a wide diversity of hierarchically complex multilevel structures, such as magnetic polymersome, magnetomicelle, condensed cluster, nanoworm/nanowire, magnetic array/gel, etc. The incorporation of MNPs and variegated polymers greatly enriches the biomedical applications of MNP assemblies in imaging, drug delivery, and various therapeutic patterns. terms of facilitating various biomedical applications since their of polymer-assisted MNP assemblies, and then, we focus on properties can be well controlled by manipulating the the recent progress of MNP assemblies in medical imaging, construction including chemical constitution, molecular drug/gene delivery, and therapy. Finally, we will provide a brief weight, chain length, and electric charge,10 as well as the overview of the challenges and potential opportunities for ability to accommodate various ingredients. The diverse and future MNPs research in the biomedical field. easy manipulation of polymers endows the MNPs with possibilities to be precisely modified or structurally rearranged 2. ASSEMBLY OF MAGNETIC NANOSTRUCTURE in the assemblies to meet the rapidly rising demands for DIRECTED BY POLYMERS preclinical studies and clinical applications. The controlled assembly of MNPs directed by polymers is a Through a typical encapsulation method, MNPs could easily dynamical process of recognition and arrangement of structural coassemble with amphiphilic block copolymers into a broad units to form multilevel architectures, resulting in complex range of hierarchically complex nanostructures. The spatial hierarchical constructions via different interactions of the distribution of MNPs in the polymeric assemblies is tunable building blocks (Scheme 1). through the adjustment of the hydrophobic and hydrophilic 2.1. Interactions between the Building Blocks. Since block ratio of the copolymers, capping ligands and grafting most MNPs are synthesized in organic media, the original density on the surface of inorganic MNPs, solubility of the hydrophobic ligands limit their dispersion in aqueous solution assembly blocks in the solvents, etc.31 Nowadays, many efforts for direct biological applications. Although the early generation have been dedicated to controlling the fundamental properties of water-soluble MNPs could be achieved through coprecipi- of polymers and to designing the functionally responsive tation method, the as-synthesized MNPs are often polydisperse polymers using different polymerization techniques or and unstable, resulting in the form of aggregates.33,34 In spite of modification methods, which makes polymers highly attractive different methods used to disperse aggregates or avoid the for nanoengineering.32 To date, the development of polymeric reaggregation,35,36 the obtained nanoparticles are not sat- science in versatile designing and chemical synthesis methods isfactory in clinical applications. It is noted that particle for polymers, together with the recent advances in the aggregation is mainly induced by the imbalance of attractive controlled synthesis of MNPs, and the various strategies in and repulsive colloidal forces acting between particles.37 encapsulating inorganic NPs into the block copolymer Therefore, the tight control over the colloidal forces, which matrixes, place great promise for preparation and application mainly include van der Waals forces, electrical double-layer of the polymer-assisted MNP assemblies in the biomedical steric interactions, hydrophobic and solvation forces for field. In this review, we summarize the methods and principles particle stabilization, is highly demanded.38,39 Commonly, it

122 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Figure 1. Formation of water-dispersible NPs through multiple-interaction ligands. Reproduced with permission from ref 55. Copyright 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. is well-accepted that one of the most practical methods for imaging detection. The polymer shell, constituted of stabilizing stabilizing the nanoparticle dispersion in aqueous solution is to dispersants and solubilizers, effectively decreased the high use polymeric surfactants during or after the synthesis of surface energy and alleviated aggregation of the individual MNPs for finely balancing the colloidal forces through the nanoparticles, making the polymer-modified MNPs or their minimization of Gibbs free energy.32,40 In addition, polymeric assemblies counterparts much more stable compared to the coating can also prevent the formation of large aggregates bare ones in aqueous media.32 Moreover, a mussel-inspired − when exposed to the biological system.41 43 Among the multiple-interaction ligand (MIL) was developed by Ling and reported methods up to now, the ligand exchange44 and co-workers55 for the improvement of NPs stability in aqueous physical assembly/encapsulation approaches3 are often con- media. The MIL was composed of PEG, polyethylenimine sidered to be effective ways for the surface coating of (PEI), and poly(L-3,4-dihydroxyphenylalanine) (polyDOPA) nanoparticles with functional polymers. To date, a number of moieties to stabilize various metals and metal oxide nano- biocompatible copolymers such as poly (ethylene glycol) particles via multibinding reactions including coordinate (PEG), poly (ethylene glycol)-poly (acrylic acid) (PEG- binding between catechol and amine groups, micelle formation PAA),45 polyvinylpyrrolidone (PVP),46 poly lactic-co-glycolic via hydrophobic interactions, and electrostatic interaction acid (PLGA),47 or poly(vinyl alcohol) (PVA)48 have been between positively charged moieties of the ligands and the widely used as coating materials for MNPs in aqueous negatively charged nanoparticle surface (Figure 1). Among the suspension. In addition, amphiphilic block copolymers with three synthesized ligands with different L-DOPA ratios (MIL0, multifarious compositions such as poly(acrylic acid)-b- MIL1, MIL2), MIL2 exhibited the best performance for 29 polystyrene (PAA-b-PS), poly(ethylene oxide)-b-polystyrene stabilizing nanoparticles of Fe3O4, MnO, and Au in various (PEO-b-PS), poly(4-vinylpyridine)-b-polystyrene (P4VP-b- harsh aqueous environments, especially in highly acidic and PS),49 poly(ε-caprolactone)-b-poly(ethylene glycol) (PCL-b- basic media, concentrated NaCl solutions, and even in boiling PEG),50 or Pluronic F68 (PF68)51 are also frequently used as water. coating materials. Notably, these amphiphilic block copolymers Currently, many contemporary studies on the MNPs are attracted great attention especially for their ability to focusing on the manipulation and organization of individual coassemble with MNPs into complex nanocomposites for components into new nanoscale hierarchical architectures with biological applications, where rational modification of func- novel and fascinating functions.56,57 Compared to the chaotic tional groups in the copolymers supplies extra fascinating aggregation, the MNP assemblies with a controlled and biological functionalities.52 At this point, more representative ordered spatial arrangement of MNPs are much more examples for the polymers used as coating materials or imperative in bioapplications,58 since the as-constructed assembling modules can be referred to previously published nanocomposites with well-defined sizes, shapes, or conforma- reviews.32,53 tions can not only increase their in vivo circulation time,59,60 On the basis of the above principles, Qiao et al.54 utilized but also change the interactions between the individual MNP dibromomaleimide (DBM)-terminated poly(oligoethylene gly- in the nanoassemblies, which will in turn improve the col) methyl ether acrylate (poly(OEGA)) homopolymer for magnetization and MRI performance. It is known that the the surface modification of MNPs to achieve enhanced introduced external magnetic field could guide or control the colloidal stability and biocompatibility for the fluorescence assembling processes, sizes, morphologies, and structures of

123 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Figure 2. Three distinct MNP self-assembly structures in different solvents formed by controlling the solvent−nanoparticle and polymer− nanoparticle interactions. STEM images, Fe intensity line scans and structure schematic plots for (a) magneto-core−shell assemblies formed in DMF/THF, and a monolayer of MNPs were entrapped at the interface between the polymer core and the shell; (b) magneto-micelles formed in THF, and MNPs were homogeneously distributed in the polymer matrix; (c) magneto-polymersomes formed in dioxane/THF (96.8% dioxane), and MNPs were distributed in the polymersome wall; (d) magneto-micelles formed in dioxane/THF (96.8% dioxane) and the MNPs were homogeneously distributed in the polymer matrix. Light gray lines, dark gray lines, and red dots represent PAA, PS, and nanoparticles, respectively. Reproduced with permission from ref 29. Copyright 2011 American Chemical Society. the MNP assemblies via magnetostatic dipole−dipole inter- Besides, other strong chemical bonds inspired from the action, which plays a vital role as the predominant driving force stimuli-responsive polymers could also offer a high degree of in the course of self-assembling and enables the long-range control to direct the assembly process.68 Instead of organization of the MNPs.61,62 Although it is possible to form summarizing all achievements in the interactions between the magnetic assemblies with the help of an external magnetic MNPs and polymers, we next focus on the formation of the field, the biocompatible materials, such as silica and polymer, multilevel structured MNP assemblies assisted by polymers. are often required in the formation of the MNP assemblies for 2.2. Architectural Diversity of Magnetic Nanoparticle biomedical applications.62,63 In this regard, the assemblies of Assemblies. The architecture plays an important role in MNPs assisted by polymers render more opportunities to the regulating the characteristics and performance of the polymer- facial fabrication with desired and diverse functionalities. based hybrid materials. For example, the detection sensitivity Since the assembling behavior of NPs with copolymers in of MNP assemblies in MRI depends not only on the aqueous solvents is a process for balancing the enthalpic and magnetism of individual MNP but also on their spatial entropic contributions,31 the assembly construction can be organization. On the basis of the above principles, the magnetically assembled systems with architectural diversity achieved by altering the interaction forces between the ff blocking units or with the solvents. The inherent forces in o er more possibilities and unique properties, which makes them extremely attractive as building blocks for nano- the assembling process can mainly refer to the hydrophobic medicine.5 Some typical hybrid superstructures prepared by interaction, hydrogen bonding, electrostatic interaction, and operating the localization of MNPs in the polymer matrix are other strong chemical reactions between the building blocks shown in Scheme 1, including spherical structures, 1D worm/ (Scheme 1).16,64 By means of the aforementioned colloidal ring-like structures, and 2D arrays. These nanocomposites can forces, desired multilevel structures with nanoscopically be constructed through two representative methods; one is in confined geometries could be obtained. For example, the − situ method based on the template via chemical reactions, most common magnetic core shell structures could be easily while the other one is ex situ method, which is referring to the achieved via hydrophobic interactions between the hydro- coassembling or encapsulating the MNPs and copolymers by phobic components in amphiphilic polymer segments and − 65,66 coprecipitation, emulsion, heating cooling and other meth- organic capping ligands on the surface of MNPs. ods.31 Herein, we first introduce the fabrication of polymeric Moreover, the ordinarily electrostatic attractive forces between MNP assemblies based on the ex situ method for that it the ligands capping on the surface of MNPs and the segments provides facile approaches for precise control over the size or with opposite electric charges in the polymer also assist MNPs position of MNPs in the copolymer matrix. assembling. For instance, the integration of super-paramagnetic By virtue of the ex situ method, multiple magnetic spherical iron oxide (SPIO) clusters assisted by polysaccharide polymer structures, including magnetic polymersomes,14 magneto- was initiated by the electrostatic interaction between micelles,69 and condensed clusters70,71 could be obtained ammonium cations of glycol chitosan/acryl/biotin and through regulating the hydrophobic/hydrophilic ratio of carboxylic anions on the surface of SPIO.67 amphiphilic copolymer chains, the amount and species of the

124 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

− capping groups on the surface of MNPs, solvent composition wire-79 81 and ring-like82 nanostructures are reported in other and immiscibility, as well as the temperature/pH of the literature studies. In addition to these 1D linear structures, solution in the polymer-assisted assembling process. On top of MNPs could also form 2D arrays83 and gels84 mainly based on that, through the fine-tuning of the interactions between the the species of polymer templates. Through optimizing the selected solvent with copolymer, or copolymer with nano- assembly parameters, such as nanoparticle size, concentration, particle, different assembly architectures can be obtained. For surface grafted ligands or the relative ratio between the instance, three distinct structures were achieved through hydrophobic block and the hydrophilic block of the polymer encapsulating MNPs with diblock copolymer poly(acrylic media, etc., MNPs could be localized in different domains of acid)-b-polystyrene (PAA-b-PS) (Figure 2), in which the assemblies, and the obtained nanocomposites exhibit rich − position of the MNPs is (1) locating between the interface of composition and structural diversity.29,85 87 the polymer core and shell (magneto-core-shell) (Figure 2a); Generally, such a variety of structures not only allows the (2) homogeneously distributing across the polymer matrix combination of properties from the individual nanoparticle but (magneto-micelles) (Figure 2b); (3) aggregating in the also takes advantage of the interactions between neighboring polymersome wall (magneto-polymersomes) (Figure 2c).29 nanoparticles, which can result in new properties and Among all the three assemblies, magneto-polymersomes applications ranging from photonics, separation and detection, to multimodal imaging, energy storage and transformation, and showed the highest transverse relaxivity rate (r2) due to high − MNPs loading density and water molecules accessibility. catalysis.73,88 90 Besides, the size, morphology, and structure of Besides, the magneto-core−shell assemblies also showed a the magnetic polymeric nanoassemblies are emerging as fi signi cantly higher r2 relaxivity rate than typical magneto- important modulators for their in vivo destiny, such as the micelles for the close MNPs packing density and water blood circulation time,91 the extent of cell internalization and metabolism,92,93 as well as drug delivery capability for accessibility. Therefore, precise control over a desired spatial − arrangement of MNPs within the polymers can not only subsequent therapeutic efficacy.94 96 improve the biological stability of MNPs, but also endow the assemblies with enhanced collective properties for further in 3. SYNTHETIC STRATEGIES OF POLYMER-ASSISTED vivo applications. Furthermore, they also confirmed that the MAGNETIC NANOPARTICLE ASSEMBLIES heterogeneous structures could be drastically changed as long Compared to the individual MNP, assembled MNPs produce a as the relative volume ratio between the hydrophobic and the collective behavior, especially the modified magnetic perform- hydrophilic block of the polymers be finely tuned during the ance induced by coupling the magnetic moments.97 Among the assembling process (Figure 2d). When a long hydrophobic various techniques reported for the construction of assembly block was used, the nanoparticles could self-assemble into structures, methods based on polymers assisted assembling vesicles, while tubular assemblies could be generated with have been well developed to pursue the enhancement and shorter hydrophobic blocks. Besides, the dissolution properties regulation of the performance and properties of MNP of block copolymers and nanoparticles in the solvents as well assemblies to meet the need for improved colloidal stability, as the nanoparticle size and concentrations also have impacts biocompatibility, and specific biological applications in the on their magnetic relaxation properties and could also be complicated biological environments.4,98,99 directed to optimize the MRI performance.72 Condensed In this section, we provide an introduction of the cluster is another main structure of the MNP assemblies fundamental techniques that can be used to construct assembly assisted by polymers via electrostatics and compensation,73,74 structures assisted by polymers, which include template-free or other chemical interactions.75 The monodispersed magnet- and template-based methods.100,101 ite colloidal clusters composed of small primary nanocrystals 3.1. Template-free Assembly. To date, several strategies can be tuned precisely from ∼30 to ∼180 nm and rendered have been demonstrated for the assembly of MNPs.5,102 The high magnetization and water-dispersion by the surface- relatively flexible way for controlled fabricating of stable MNP tethered PAA chains.76 The morphology and MNPs arrange- assemblies mainly mediated by the molecular interactions or ment of the condensed clusters are multiple, and the loading chemical bonds is called the template-free assembly, commonly quantity of MNPs may range from several to hundreds. including the hydrophobic interaction, hydrogen bonding, or Moreover, the MNPs interparticle spacing can be precisely electrostatic interaction.8 adjusted by varying the composition or length of grafted 3.1.1. Hydrophobic Reaction Directed Assembly. Hydro- polymers. phobic reaction directed assembly is a typical method to Apart from the spherical structure, there is a limited number construct the hierarchical nanostructures through the assem- of examples for the successful preparation of nonspherical bling of MNPs and amphiphilic copolymers. Since the ordered structures of MNP assemblies because controlled hydrophobic segments of an amphiphilic polymer could drive clustering of the nanoparticles and polymers during ex situ the assembly of MNPs via hydrophobic−hydrophobic coassembling or encapsulation process is exceptionally interactions with similar hydrophobic ligands on the surface challenging. Herein, the in situ method based on the polymer of MNPs and provide the nanocomposite structure with template provides opportunities for directing the formation of enhanced mechanical properties in the integrity, namely, not the nonspherical magnetic polymeric hybrid materials, where easily broken down, which in turn grant them better the architecture of the resulting magnetic assemblies primarily adaptability and biocompatibility in biological sys- − relies on the template structure. A typical example reported by tems.29,103 105 Lee et al.77 is the utilization of hyaluronic acid-graft-catechol as The coprecipitation method is a representative approach a 1D template to precisely control the preparation of metallic- that has been widely used to transfer the preformed NPs into nanoparticle assemblies. The length of the 1D nanochain is the copolymer matrix and form a typical core−shell tunable when adjusting the contour lengths. Except for the nanostructure in the selected solvent based on the hydro- nanochain structure, other architectures such as worm-,78 phobic−hydrophobic interactions. The resulting nanoassem-

125 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review blies could be obtained through dialysis with further CDDP)-encapsulated nanocapsule (CDDP-PAA-NC) was purification process. For example, Ling and co-workers9 prepared using a double emulsion method through ultra- reported the fabrication of magnetic nanoassemblies based sonication to form a core−shell structure with CDDP-PAA on this method. Briefly, amphiphilic copolymer ligands were core and PVA/SPION shell. The hydrogen bonds between dissolved in dimethylsulfoxide (DMSO) and slowly added into PAA and PVA facilitated the formation of a nanoshell and the chloroform solution containing oleic acid-coated extremely further incorporation of hydrophobic SPIONs into the small iron oxide nanoparticles (ESIONs) to form a hydrophobic organic layer. Moreover, the encapsulation of homogeneous mixture. Then the chloroform was evaporated CDDP was facilitated by the formation of coordination bonds from the system and the water was supplied. The DMSO between the platinum(II) atoms of cisplatin and the (good solvent) was completely removed and substituted with carboxylate groups of PAA. Both in vitro and in vivo results water (selective solvent) through the subsequent dialysis clearly showed that the magnetic CDDP-PAA-NCs signifi- process, leading to the aggregation of ESIONs into the cantly reduced toxicity and exhibited high anticancer hydrophobic regions in the nanoassemblies. Besides, Gao et activity.109 Another similar hydrogen bonding network al.50 added tetrahydrofuran (THF) solution which contained involving PVA was exploited by Huang and co-workers.110 poly(ε-caprolactone)-b-poly(ethylene glycol) (PCL-PEG) and Highly thermosensitive MNP assemblies composed of poly- hydrophobic MNPs into aqueous solution under sonication, (ethylene oxide)-b-poly(p-phenylene oxide)-b-poly(ethylene the resulting solution was stirred to allow the evaporation of oxide) (PEO-PPO-PEO) (F127) triblock-copolymer and THF to obtain the MNP assemblies dispersed in water. In this PVA was prepared using a mini-emulsion method (Figure 3). process, therapeutic drug doxorubicin could be loaded into the hydrophobic inner center of the micelle structure simulta- neously for further therapeutic applications. Emulsification is another typical method that is particularly advantageous for designing assembled structures utilizing amphiphilic block copolymers to accommodate MNPs within a complex nanostructure through the interfacial instability of emulsion droplets106 endowing the magnetic assemblies with ordered structures and high water-soluble characteristics. For instance, amphiphilic poly(isoprene)-b-poly(ethylene glycol) diblock copolymer (PI-b-PEG) and iron oxide nanoparticles (IONPs) were injected into water and formed micellar encapsulation of MNPs via hydrophobic interaction between the hydrophobic segments of polymers chains and oleic acids anchored on the surface of IONPs.7 Then the magnetic micelle was further stabilized by cross-linking polystyrene (PS) shell via emulsion polymerization process. The resulting MNP clusters ranging from the nano- to the microscale showed fl enhanced magnetic properties, and the r2 re exivity value increased along with the increasing of cluster size in a certain dimension range, neither obtainable from the singly encapsu- Figure 3. Using PVA and F127 to form a stable nanocarrier via H- lated nor from the bulk material. Moreover, MNP assemblies ff fi fi bonding e ect (a), nally obtained the drug-loaded MNP assemblies mediated by polymers upon physical emulsi cation have are obtained (b). Reproduced with permission from ref 110. structural flexibility and collectively functional adjustability, Copyright 2012 Royal Society of Chemistry. which shows great potential for fabricating multifunctional magnetic nanoparticle-based nanomedicine toward various applications.31 Besides, another advantage of the emulsifica- Within the nanoemulsion, amphiphilic polymer PVA was tion-based method is the ability to generate worm-like 1D employed as the H-bond provider to react with the PEO block hybrid micelle structures. For instance, Bae et al. dissolved of F127 to form an ultrathin nanoshell for the stabilization of PEO6.4K-PS19K with hydrophobic IONPs in chloroform, and the cargo and avoiding the undesired drug leakage before the mixture was then injected into water containing a reaching the targeting sites. surfactant of poly(vinyl alcohol) (PVOH) and stirred in an 3.1.3. Electrostatic Interactions Directed Assembly. open atmosphere for further emulsion and micelles-formation Electrostatic interactions also show their potential as a simple process. With the evaporation of chloroform, a worm-like 1-D and versatile route to assemble MNPs into well-defined hybrid micelle structure was exclusively formed, showing superstructures at room temperature and atmospheric promise for further biological applications.107 Moreover, pressure, and it displays a much higher yield as to allowing various structures ranging from spherical, cylindrical, to scaling up this process toward industry.111,112 For instance, Yan lamellar can be easily achieved through tuning the composition et al.113 presented a useful approach to control the electrostatic of the copolymer, which is rather difficult to obtain through the interaction during the self-assembly process, in which the aforementioned coprecipitation method.108 negatively charged poly(acrylic acid) coated maghemite NPs 3.1.2. Hydrogen-bonding Interaction Directed Assembly. and homopolyelectrolytes [poly(diallyldimethylammonium Apart from the hydrophobic interactions, the integration of the chloride) (PDADMAC) or PEI] were directly mixed at an MNPs with organic components could also be achieved appropriate ionic strength in an aqueous medium to address dependent on the formation of hydrogen bonds. For instance, the controllability over the shape and morphology. This amagneticcis-diamminedichloroplatinum(II) (cisplatin, aggregation process was slowed down to the time scale of

126 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review hours and indicated a clarity of the growth mechanism with nanoparticle subunits are acting through hydrophobic Phase I of clustering of individual NP with the assistance of interaction, hydrogen bond, orelectric/magneticdipole cationic polyelectrolytes and two different Phase II mecha- interactions; however, by virtue of the weakly interacting nisms, one is a random directional link and accretion of the forces, it is feasible to construct multifarious flexible dynamic precursor, and the other is subwires-liked aggregation with the nanostructures for “on-demand” signal amplification and presence of external magnetic field induced by the magnetic targeted drug delivery. dipolar interactions. Via the specific electrostatic absorption, 3.2. Template-Based Assembly. Template-based assem- MNPs could be selectively deposited at the desired site in the bly has become an attractive fabrication approach with polymeric matrix, providing another opportunity for the effective guidance for the formation of specific structures and precise arrangement of MNPs in the assemblies. morphologies. The templates can be divided into inorganic 3.1.4. Other Interactions Directed Assembly. In addition to rigid templates and organic soft templates according to their the interactions mentioned above, several other methods are physical properties, where the mesoporous silica nano- also studied for the controlled construction of MNP particles,117 block copolymers,9 biological materials such as assemblies. For example, Liu et al. reported the cross-linked DNA scaffolds,118 viruses,119 peptides,120 can all be applied for PEG-coated Fe3O4 NPs bearing surface reactive carbonyl the controlled assembly of MNPs. groups with poly-L-lysine (PLL) via molecular dipole reaction The catechol group is an adhesive molecule that can actively 121 between the carbonyl moieties and the amine group in PLL interact with a variety of organic/inorganic substrates. On repeated units to obtain the magnetic aggregates.114 On this the basis, a bioinspired polymeric template, hyaluronic acid- basis, further targeted modification created another oppor- catechol was reported and introduced into the fabrication tunity for the application of the MNP aggregates that could process of the MNP assemblies and showcased the abilities for result in the signal amplification effect in a lateral flow synthesizing 1D assembled nanochains, in which the immunochromatographic assay (LFIA) (Figure 4). morphology and properties of the assemblies were demon- strated to be determined by the nanoparticles solution concentration (Figure 6a).77 Another interesting study is to utilize the incompatible feature between polymers and inorganic nanoparticles to prepare monolayer- or multilayer- nanoparticles coated polymer beads. With the increased concentration of polymers during the evaporation process, nanoparticles were expelled and accumulated on the surfaces of the polymer beads (Figure 6b),122 where the number of nanoparticle layers is tunable by adjusting the polymer/ nanoparticle ratio in the oil droplet phase. Besides, Newland and co-workers adopted a photo-cross-linkable ethylene glycol dimethacrylate (EGDMA) homopolymer to make polymeric nanotubes within the pores of an anodized aluminum oxide template. Then the magnetically controllable nanotubes could fi be formed based on ferric oxide (Fe2O3) lled polymeric nanotubes, which could be directed by an external magnetic field for targeted drug delivery when loaded with anticancer Figure 4. Preparation of Fe O aggregates (upper panel) and LFIA 3 4 drugs.123 Yet another novel preparation method applied to principle based on Fe3O4 NPs and aggregates (lower panel). − Reproduced with permission from ref 114. Copyright 2011 American fabricate 3D porous Cu2O Fe3O4@carbon nanocomposites − Chemical Society. (Cu2O Fe3O4@CN) was using natural polymer-based hydro- gel as a template to immobilize cupric ion and ferrous ion by On top of that, Lee and co-workers115 introduced Dox and chemical complexation and adsorption, which showed distinct ff photocatalytic performance for organic contaminant degrada- four di erent molecular building blocks, including adamantane 124 (Ad)-grafted polyamidoamine dendrimers (Ad-PAMAM), β- tion under visible light irradiation. cyclodextrin-grafted branched polyethylenimine (CD-PEI), In the above-mentioned nanoassemblies, the polymers not Ad-functionalized polyethylene glycol (Ad-PEG), and Ad- only act as glue, matrix, or template for the assembling with NPs, but also provide fascinating opportunities and possibil- grafted Zn0.4Fe2.6O4 magnetic nanoparticles (Ad-MNP), to obtain multifunctional MNP assemblies as a unique on- ities for the accommodation of drugs or other functional demand drug delivery system (Figure 5). The self-assembly moieties. Recently, a variety of functional polymers have “ ” process initiated through a multivalent molecular recognition emerged and been used to construct smart MNP assemblies fi 125 between Ad and CD motifs in order to facilitate the control with responsiveness to speci c stimuli, such as pH, redox gradient,126 temperature,127 glutathione,128 and some en- over the size, surface chemistry, and payloads of MNP vectors 129 for a wide range of diagnostic and therapeutic applications.116 zymes, enabling promising biomedical applications such as precise diseases diagnosis, controlled and targeted drug Meanwhile, the incorporated Ad-MNPs served as a trans- 130,131 former that could convert radio frequency external alternating delivery, as well as therapeutics. magnetic field (AMF) into heat, triggering the burst release of DOX molecules from the magnetothermally responsive 4. BIOMEDICAL APPLICATIONS assemblies. Compared to the individually dispersed nanoparticles, the As compared to a stable integrity in which the individual assembly of MNPs assisted by polymers could have novel elemental constituents are strongly chemically bonded, these collective properties and multifunctionalities, simultaneously nanoparticle assemblies are usually weakly interacted since the maintaining stability in the physiological environment.

127 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Figure 5. Self-assembled synthetic strategy of Dox⊂MNPs and the magneto-thermally triggered release of Dox. The embedded Ad-MNP served as a built-in heat transformer that triggered the burst release of Dox molecules by the magneto-thermal stimuli under an alternating magnetic field (AMF). Reproduced with permission from ref 115. Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 6. Schematic illustration of the fabrication process of the 1D assembled nanochains on the bioinspired polymeric template (a) and polymer- template assisted clustering followed by phase segregation (b). (a) is reproduced with permission from ref 77. Copyright 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (b) is reproduced with permission from ref 122. Copyright 2009 American Chemical Society.

Furthermore, MNPs coassembling with stimuli-responsive decreased magnetization and can be used as T1 contrast agents ligands have also attracted considerable attention to targeted presumably through the spin-canting effect.5 On the contrary, drug delivery or signal amplification triggered by the specific larger-sized MNP assemblies display unconventionally en- ff endogenous or exogenous conditions, facilitating their hanced T2 contrast e ect due to the higher r2 value which potential applications in biomedical imaging, drug delivery, highly depends on the size of the particle. Moreover, the and diseases therapeutics, thus provide intriguing strategies and number and arrangement of MNPs in the assemblies also affect possibilities for further clinical uses. the biomedical imaging performance.132 On the basis of the 133 4.1. Biomedical Imaging Platform. It is well-known that above principles, Schmidtke et al. improved the T2 MR MNPs are excellent contrast agents for MRI. The enhanced contrast performance of amphiphilic PI-b-PEG diblock contrast properties are driven from the proton relaxation rate copolymer-based magnetic nanoclusters by elevating the affected by the MNPs local field and can be tuned through the SPIONs loading density and increasing the cluster size in the altering of particle size, shape, surface modification, and spatial assemblies. Similar effect was also observed in a triblock 7 arrangement. Normally, small-sized MNPs provide a higher copolymer PEI-b-PCL-b-PEG encapsulated FeOx-NPs and number of surface-exposed magnetic metal ions for water PLGA immobilized SPIONs systems, which can further be 134 proton coordination and chemical exchange, exhibiting a utilized for the construction of T2 MR contrast agents.

128 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Figure 7. Principle of triggered disassembly process and utilization of the self-assembly for MRI. (a) Schematic illustration of the triggered disassembly process of assembled MNPs; (b) T2-weighted MRI of the ischemic brain tissues via i.v. injection of (i) pH-responsive MRI probes; (ii) non-pH-responsive MRI agents, and (iii) polymer (control group). Reproduced with permission from ref 135. Copyright 2016 Royal Society of Chemistry.

Figure 8. Schematic fabrication, TEM image, relaxation rates (1/T1 and 1/T2) and T1-weighted MRI for aqueous Cat-MDBC/USNP (a) and Cat- MDRC/USNP (b) colloids respectively. Reproduced with permission from ref 75. Copyright 2015 American Chemical Society.

Especially, some smart MR contrast agents that possess amplification of S/N ratio in the specific lesion sites. For biological stimulus groups shed lights on the selective example, MNP assemblies were prepared and served as a novel

129 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Figure 9. Preparation and characterization of pH-responsive iron oxide nanocluster assemblies (RIAs) in vitro and in vivo. (a) Schematic illustration of the assembly/disassembly process of the RIAs; (b) schematic illustration of the working principle of the pH-responsive linker; (c) kinetic analysis of RIAs disassembly upon the pH changed from 7.4 to 6.5/5.5; (d) T1 weighted images (T1WI) of phantoms and (e) relaxivity data (r1 and r2) of RIAs in PBS (pH 7.4) and MES (pH 6.5 and 5.5); (f) T1WI of pH-responsive and the irresponsive iron oxide nanoclusters in orthotopic HCC mice. Reproduced with permission from ref 11. Copyright 2018 American Chemical Society.

MRI probe for cerebral ischemia detection (Figure 7a).135 A environment to trigger the release of SPIONs. The effective novel type of pH-responsive biodegradable copolymer was integration of SPIONs in the biological systems resulted in fi developed based on the methyloxy-poly(ethylene glycol)-b- ampli ed T2-magnetic resonance contrast signals at 24 h post- poly[dopamine-2-(dibutylamino) ethylamine-L-glutamate] injection (Figure 7b). (mPEG-b-P(DPA-DE)LG), which contains amine-terminated On the other hand, T1 contrast agents are usually preferred dopamine groups and pH-sensitive moieties. The assemblies for better clarity due to the bright signal presented at target ffi conferred with high loading e cacy of SPIONs and enhanced tissues especially in a clinical situation, such as NaGdF4-based 12,136 negative contrast revealed the ability as a T2 contrast agent and nanoparticles, rather than the dark signal produced by T2 could maintain stable status at physiological pH (∼7.4), while contrast agents. Additionally, the generated dark signals may quickly protonated under the targeted acidic pathological be confused with other internal conditions, such as blooding or

130 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Figure 10. Formation and in vivo behavior of the PMNs. (a) Design of PMNs for tumor pH activation based on the ligand-assisted self-assembly of ESIONs; (b) schematic representation of pH-dependent structural transformation and related magnetic/photoactivity change in PMNs; in vivo T1- weighted MR images (c) and fluorescent images (d) of tumor sites after injection of PMNs or InS-NPs into nude mice bearing HCT116 tumors; (e) Ce6 uptake by tumor cells in tumor tissue of nude mice after intravenous injection of PMNs. Reproduced with permission from ref 9. Copyright 2014 American Chemical Society. calcification. Recent studies have suggested that IONPs with the copolymer with the random distribution of pendant core size below 5 nm are optimal to form T1 or dual T1/T2 catechol groups, yielding a mixture of cluster-like structure 137,138 contrast agents. For instance, ultrasmall super-para- with a diameter of 42.6 nm and large aggregates (diameter > 1 magnetic iron oxide nanoparticles (USNPs) were anchored μm) in aqueous solution, presenting a transverse relaxivity rate by mussel-inspired multidentate block copolymers (MDBC) close to the typical values of negative MRI contrast agents. via pendant catechol groups, fabricating aqueous Cat-MDBC/ This result suggests that the Cat-MDRC/USNP colloids with USNP colloids with a diameter of ∼20 nm through a biphasic ligand exchange process (Figure 8a).75 They provided brighter aggregate-like structure are suitable for T2 contrast enhance- − ment, but not for T1 MR imaging (Figure 8b). Hence, not only T1-weighted imaging at the concentration of 0.38 0.57 mM Fe, which is significantly lower than that (0.9−1.9 mM Fe) for the particle size, but also the nanoparticle arrangement in the the corresponding MDBC with pendant carboxylates.139,140 At obtained assemblies based on the polymer design will the same time, the Cat-MDRC/USNP colloids fabricated by ultimately decide their imaging behaviors.

131 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

However, with the urgent requirement for accurate clinical accumulation of SPIONs at the target tissue, which was serving diagnosis, single-phase contrast enhancement of current results as an enhanced negative T2 contrast agent. The resulting are not that satisfying for the early detection and diagnosis of RMNs-HSA-Cy5.5 system not only showed MR imaging some debilitating diseases.13,141 As a consequence, an evolved capacity, but also simultaneously presented near-infrared versatile MRI platform based on the stimuli-responsive fluorescence imaging feature once reached the redox environ- assembly disassembly characteristic of the MNP assemblies ment in the tumor. The in vivo results revealed its excellent as a dual-phase images transformation agent from T2 to T1 function as a dual-modal imaging probe for early stage cancer pattern was investigated by Lu and co-workers (Figure 9).11 diagnosis.148 The ultrasmall iron oxide nanoclusters (USIONCs) with an 4.2. Drug Delivery. Conventional drug molecules without fi ff excellent ability for T1 MRI contrast enhancement were rst the delivery system often su er from the harsh internal synthesized through a typical thermal-deposition method and environment with metabolic instability, nonspecific toxicity, further covered with anchor DNAs. Then USIONCs were and poor treatment effects. As one of the most extensively cross-linked by the pH-responsive linkers composed of i-motif explored classes of nanosystems suitable for drug delivery, DNAs and their partially complementary strands (Figure 9a,b). MNPs can both enhance the drug delivery effect and also The obtained nanocluster assemblies based on the hybrid- monitor the treatment’sefficacy via imaging techniques ization of oligonucleotides took less than 40 s (t1/2 = 12.14 s) supplied by the magnetic cores or the polymers and loadings, to transform into individually dispersed USIONCs upon the with improved stability and structural integrity in the biological − pH value changing from 7.4 to 5.5 (Figure 9c). They also environment without significant detrimental effects.149 151 fi exhibited a signi cant drop in the r2 relaxivity and the decrease Normally, MNPs are widely used in the drug delivery system of the r2/r1 ratio when the pH value changed from neutral to based on the covalent and the noncovalent methods of drug acidic, consequently led to the transformation of the loading mediated by polymers. With the external stimuli or assemblies from a T2 contrast agent in the neutral environment changes in physiological conditions, MNPs display diverse to a T1 contrast agent in acidic conditions (Figure 9d,e). The drug release behaviors at the targeted locations. in vivo application of the pH-responsive assemblies on For example, Kim and co-workers152 reported a one-step orthotopic hepatocellular carcinomas (HCC) animal model fabrication of spontaneous self-assembly of the water-insoluble further verified the inverse contrast enhancement at the liver prodrug μ-oxo-bis(N,N′-ethylenebis (salicylideniminato)iron) region. The tumor region was significantly brightened by the [Fe(salen)] (magnetic core) and polypyrrole (PPy)-b-poly- pH-responsive disassembling behavior after a two-hour caprolactone (PCL) smart diblock copolymers, where PCL injection while the surrounding normal liver tissues were acted as a heat-responsive core scaffold, and PPy served as an darkened for significantly enhanced imaging contrast (Figure electronic core-size controller and pH-responsive shell. More- 9f). over, the as-synthesized core−shell magnetic nanocomposite Recently, an increasing amount of efforts have been had a high-loading capacity (∼90%) and also exhibited high dedicated to acquiring a more sensitive, accurate and clearer colloidal stability, biocompatibility, and thermo-stability for diagnoses imaging,142,143 thus combing different diagnoses effective drug delivery. Another multifunctional core−shell imaging techniques in one platform becomes a promising magnetic polymer nanocomposite consisting of a closely 144 “ ” prospect. The multimodal imaging system could substan- packed magnetic Fe3O4 nanocore , an acid hydrolysis PLGA tially enhance the versatility for the biomedical applications, “nanoshell”, a PVP stabilizer and a Herceptin targeting ligand, especially on the conditions where more than one stimulus- were rational designed to serve as a novel drug delivery system responsiveness can be easily achieved by using polymers in terms of the targeted delivery and sustained release of containing various functional groups. As in the early stage of therapeutic agent to the breast cancer cells. The as-synthesized disease diagnosis, MRI could be combined with other imaging nanocomposites exhibited pH-dependent feature that could patterns for a more accurate clinical diagnosis result, including switch between the intact and activated conditions in blood − optical, ultrasound, and X-ray-based CT imaging, etc.1,145 147 circulation (“Off” state) and tumors (“On” state) to release the Ling et al.9 utilized self-assembled IONPs with pH-responsive loading drugs at the desired sites.153 ligands to construct the pH-sensitive magnetic nanogrenades However, as delivery vehicles, not merely the loading and (PMNs) as an early stage tumor diagnosis probe, which would protection capability of various therapeutic agents, but also the switch the surface charge to a positive state for enhanced metabolic stability suffering from the harsh internal environ- tumor cell internalization once exposed to the acidic tumor ment and the targeting efficiency to the specific cell and tissue microenvironment. Then they disassembled into a highly should be emphasized. Therefore, another reported approach active state and turned on the unique T1 MR contrast and to increase the drug accumulation in the target tissue is to fluorescence signal when reached upon the more acidic utilize MNPs under the assistance of an external magnetic field lysosomes (Figure 10a,b). Compared to the pH-insensitive to provide direct guidance, in which MNPs could be appealed nanoparticle assemblies (InS-NPs), PMNs showed significant to the targeted site when the magnetic force exceeds the fl fl 154 T1 enhancement and high-resolution uorescent imaging of hydrodynamic drag forces exerted by the blood ow in vivo. ultrasmall HCT116 tumors after intravenous injection (Figure Nevertheless, heavy dependency on the external magnetic field 10c−e). Moreover, PMNs exhibited long blood half-life and of MNPs hinders their practically clinical applications for field- provided opportunities for enhanced tumor accumulation. directed targeting behavior. In another case, Yang et al. reported redox-responsive Recently, Zhang et al.155 reported a nonviral and magnetic magnetic nanovectors (RMNs) through self-assembling of field-independent gene transfection approach using magneto- SPIONs and polymeric ligands that contain disulfide bonds, some-like ferrimagnetic iron oxide nanochains (MFIONs) to while Cy5.5 labeled HSA was loaded into the magneto-core- genetically engineer mesenchymal stem cells (MSCs) for shell structures at the same time. The redox-sensitive highly efficient poststroke recovery. The compositions of disassembly behavior of the RMNs facilitated substantial MFIONs are cubic ferrimagnetic iron oxide nanocubes

132 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Figure 11. Design and fabrication of magnetosome-like ferrimagnetic iron oxide nanochains for efficient recovery postengineered MSCs therapy. (a) Schematic illustration of MFION-based engineering of MSCs for the recovery of postischemic stroke; (b) behavioral recovery of ischemic mice with the treatments of MSCs; (c) mean mNSS on the indicated days postischemic injury; (d) MRI examinations and (e) TTC staining showed the reduction in the infarct volume post the indicated treatments; (f) quantitative calculation of the infarct volume relative to the entire cerebrum by measuring the TTC extracted from the stained cerebral samples. Reproduced with permission from reference 155. Copyright 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

(FIONs) but not conventionally spherical SPIONs. In aqueous layers of densely packed SPIONs in membranes and solution, hydrophilic polymer and the permanent magnetic therapeutic agents encapsulated in the hollow cavity of MVs dipole interactions devoted to spontaneous self-assembly into were described by Yang and co-workers (Figure 12a).156 The 1D nanochains, which combined pDNA under the assistance release of payload doxorubicin could be tuned by varying the of the branch positive charge PEI through electrostatic membrane thickness of nanovesicles based on the poly- interactions. The facilitated cellular internalization and (styrene)-b-poly (acrylic acid) (PS-b-PAA). Besides, due to successfully overexpression of brain-derived neurotrophic the high packing density of SPIONs, the multilayered MVs factor (BDNF) were detectable, and the gene delivery (MuMVs) showed the highest magnetization and r2 in MRI capability of MFION was confirmed in the genetic engineering compared to the monolayered MVs, double-layered MVs and of MSCs. It is the first publication reported to dramatically individual SPIONs. Under the synergetic effect of magnetic enhance the therapeutic performance in ischemic stroke and active targeting, doxorubicin-loaded MuMVs conjugated recovery using MFION-engineered MSCs (Figure 11). with RGD peptides could be effectively enriched within tumor In order to cater for the needs in clinical applications, sites after intravenous injection (Figure 12b). The magnetic- multifunctional magnetic polymer nanocomposites with adjust- field enhanced accumulation of MuMVs was more significant able MNPs/drug loading capabilities and drug release rates are than individual SPIONs. Moreover, the group of RGD-Dox- gaining much more important status for the safety and practical MuMVs (magnet + ) exhibited the strongest fluorescence of use in the delivering systems. Thus, the fabrication of a Dox in tumors tissues among all the groups and a 1.6-, 1.3-, multifunctional magneto-vesicles (MVs) comprising tunable 11.8-fold increase for the groups of Dox-MuMVs (magnet + ),

133 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Figure 12. Utilization of the MuMVs for imaging-guided magnetic drug delivery. (a) Schematic illustration to show utilization of MuMVs for fl imaging-guided magnetic delivery of Dox into tumor-bearing mice; in vivo T2-weighted MRI (b) and uorescence imaging (c) of tumor sites at 1 h after injection of Dox-MuMVs (magnet ± ) and RGD-Dox-MuMVs (magnet ± ); (d) quantitative analysis of fluorescence intensity in corresponding tumor regions in (c). Reproduced with permission from ref 156. Copyright 2018 American Chemical Society.

RGD-Dox-MuMVs (magnet − ), and RGD-Dox-MuMVs direct intratumoral injection. Hence, the novel nanomaterials (magnet + ), respectively, indicating the enhanced delivery which could guarantee sufficient intratumoral temperatures efficacy thanks to a synergetic magnetic and active targeting and accumulation efficiency at tumor sites following systemic strategy (Figure 12c,d). administration under AMF are highly desirable. Recently, an 4.3. Therapeutic Platform. Another branch of applica- efficient magnetic nanocluster composed of cobalt- and tions concerning polymer-assisted MNP assemblies that being manganese-doped, hexagon-shaped IONPs (CoMn-IONP) ffi widely investigated is their inherent therapeutic e ciency. and poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG− Utilizing the intrinsic property of IONPs, which could generate PCL) was developed to fit the need of high heating efficiency heat when exposed to an alternating external magnetic field via systemically delivery.157 Encouragingly, compared to the (AMF), is referred to as magnetic hyperthermia. Consequently, ° fi 38.5 C caused by spherical IONPs, the intratumoral the calori c nanoparticles could increase the temperature of ° the surrounding tissues, which could be utilized to induce the temperature of the CoMn-IONP nanoclusters reached 44 C cell death of tumor tissues. The magnetic hyperthermia after 12 h postintravenous injection. Furthermore, magnetic fi therapy, namely noninvasive and selective for cancer treatment, hyperthermia mediated by CoMn-IONP nanoclusters signi - has been realized to be one of the most promising therapeutic cantly inhibited the growth of subcutaneous ovarian tumors tools. However, the conventional IONPs-mediated magnetic under a safe AMF frequency (Figure 13). The nanoclusters hyperthermia is currently limited to the treatment of localized and their capability to achieve therapeutically relevant and relatively accessible cancer tumors because the required temperatures provide a new possibility for tumor treatment therapeutic temperatures above 40 °C can only be achieved by by magnetic hyperthermia, either alone or in combination with

134 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Figure 13. Formation and utilization of the magnetic nanocluster for magnetic hyperthermia in tumor model. (a) The assembly process of the magnetic nanocluster composed of hexagon-shaped cobalt- and manganese-doped iron oxide nanoparticles (CoMn-IONP) and PEG−PCL polymer; (b) TEM image of CoMn-IONP nanoclusters; (c) intratumoral temperature upon exposure to an alternating magnetic field (AMF) (420 kHz, 26.9 kA/m); (d) tumor growth of mice with ES-2 xenografts after four cycles of treatment. Reproduced with permission from ref 157. Copyright 2019 American Chemical Society. other therapeutic modes including radiation, chemotherapy, or glycol)-b-poly(dopamine-ethylenediamine-2,3-dimethylmaleic immunotherapy. anhydride)-L-glutamate-Ce6 [mPEG-b-P(Dopa-Ethy-DMMA) In addition, the development of magnetic nanoclusters LG-Ce6] and SPIONs were incorporated into the HTAMN (MNCs) by encapsulating MnxZn1−xFe2O4 magnetic nano- via self-assembly. An improved tumor accumulation and particles into amphiphilic block copolymer matrix for magnetic enhanced tumor cellular internalization via pH-induced surface fluid hyperthermia (MFH) in vitro exhibited superparamag- charge switching were achieved, and then HTAMN was further netic characteristics, high specific absorption rate (SAR), large disassembled in more acidic intracellular compartments, which saturation magnetization (Ms), excellent stability, and good “turn on” the near-infrared fluorescence (NIRF) and initiated biocompatibility. It is clearly shown in these studies that the SOG generation triggered by the photosensitizer. In cancer cell death rate could be reached up to 90% within 15 comparison to pH-insensitive magnetic nanoparticles, min after the treatments of MnFe2O4/MNC and HTAMNs revealed more distinct clarity via a T2-weighted Mn0.6Zn0.4Fe2O4/MNC under optimized conditions of AMF. MR/NIRF imaging, enhanced tumor retention and superior in Moreover, the apoptosis mechanism of cell death was also vivo antitumor efficiency (Figure 14). investigated.158 Since the efficiency of magnetic hyperthermia fi ff Another interesting case exhibited the dual-mode heating is signi cantly a ected by the size, composition, and structures thermal treatment, including magnetothermal and photo- of the MNP assemblies, further optimized processes may need thermal therapy via polymer-assisted self-assembled super- to be taken into account to develop novel MNP assemblies for nanoparticles were consist of superparamagnetic Fe O more future applications.159 3 4 nanoparticles and photoluminescent PbS/CdS quantum dots From another perspective, as a critical component of MNP 164 assemblies, polymers present strong controllability and (Figure 15). The proposed self-assembled Fe3O4 and PbS/ diversity that could synergistically combine with other CdS (II-BW) supernanoparticles [SASNs (II-BW)] presented outstanding detectable photoluminescence through a 14 mm treatment modalities such as chemotherapy, radiation therapy, fi gene therapy and photodynamic therapy, etc.160 For instance, tissue, and signi cantly enhanced r2 relaxivity, which was 4 the treatment pattern of MNP assemblies can be turned into times higher than the individually dispersed Fe3O4 nano- photodynamic therapy (PDT), which is also a minimally particles. Besides, the dual-mode heating studies with SASNs ffi invasive therapeutic procedure for cancer treatment.9 The (II-BW) as heating agents showed an extremely e cient exerting of PDT relies on cytotoxic singlet oxygen generation heating output at the local site from the pork tissue, (SOG) produced by photosensitizers under irradiation, while demonstrating the potential use for deep-tissue dual-mode the indiscriminating damage to the normal tissues was seen as (magnetic resonance and photoluminescence) in vivo imaging, troubling to the treatment.161,162 Recent compelling evidence while could simultaneously provide the possibility of SASNs reported by Yang et al.163 was a hierarchical tumor acidity- (II-BW)-mediated amplified dual-mode heating treatment for responsive magnetic nanobomb (termed HTAMN) developed cancer therapy. Therefore, the combination of favorable MNP for PDT and diagnostic imaging. The chlorin e6 (Ce6), which assemblies-based thermal treatment, as well as other effective was employed as a photosensitizer, methoxy poly(ethylene therapeutic methods, may allow simultaneous tumor diagnosis

135 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Figure 14. Design and utilization of the hierarchical tumor acidity-responsive magnetic nanobomb for PDT and diagnostic imaging. (a) The formation and mechanism of pH-induced surface charge switch and pH-dependent disassembling process of HTAMN in the extracellular and intracellular of tumor cells; in vivo T2-weighted MRI (b) and NIRF (c) tumor images at 4 and 24 h after intravenous injection of HTAMN or non- HTAMN into tumor models; (d) tumor weights after the treatments of PBS (controlled), free Ce6, non-HTAMN, and HTAMN at the end of the in vivo PDT study. Reproduced with permission from ref 163. Copyright 2019 Elsevier B.V. and therapy toward personalized precise cancer treatment in size distribution, the location of NPs in the assemblies and the future. their stability, etc. The utilization of polymers has been demonstrated to be a 5. CONCLUSIONS AND FUTURE PERSPECTIVES powerful tool to assist assembly of MNPs with improved The assembly of MNPs opens up new avenues to achieve the precision of control, biocompatibility, and multifunctionality, desired and favorable physicochemical properties for various in which the delicate interaction forces between MNPs with biomedical applications. In contrast to individually dispersed polymers, polymers with solvent, as well as MNPs with MNPs MNPs, assembling of MNPs offers distinct constructions, direct the assembling process offering facile control over self- physicochemical characteristics, as well as different in vivo assembly to achieve various sizes and shapes. This review circulation, distribution, and elimination pathways. Manipu- provides an overview of recent progress in MNP assemblies lation of MNP assemblies can enable target-amplified imaging mediated by polymers, we briefly introduce the interactions and responsive drug release for local, on-demand applications between the blocking units, assembly methods as well as their with reduced side effects and enhanced treatment efficacy. biomedical applications. The state-of-the-art assembly strat- Although some progress in the design and synthesis of MNP egies including template-free and template-based approaches assemblies has been achieved, the precise control of the have been highlighted. Important intrinsic characteristics, such assemblies is still in the initial stage, such as the architecture, as magnetic properties and magnetothermal effect, which

136 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review

Figure 15. Schematic illustration of the formation (a) and utilization (b) of self-assembled Fe3O4 and PbS/CdS (II-BW) supernanoparticles; (c) ff Ex vivo NIR images of SASNs (I-BW) and SASNs (II-BW) through di erent thicknesses of pork tissue; (d) relaxation rate (r2) of SASNs (II-BW) and free Fe3O4 NPs; (e) in vivo T2-weighted MRI of a tumor position taken at preinjection and 12 h intravenous postinjection of SASNs (II-BW); (f) time-dependent temperature curves of different concentrations SASNs (II-BW) under three types of modulation; (g) optical image of pork tissue used for ex vivo dual-modal heating and their thermal images at 3 min postinjection of SASNs (II-BW) under three types of modulations. Reproduced with permission from ref 164. Copyright 2019 American Chemical Society. present deep insight into the collective functions of the Besides, despite the clinical trials with early generations of assembled structures have been discussed. Furthermore, we MNPs, e.g., SPION and USPION, the clinical translation of have highlighted the recent cutting-edge research of MNP updated MNP assemblies is still hindered by the variations assemblies based biomedical applications such as biomedical between different batches, the lack of information in their in imaging, drug delivery, therapy, and theranostics. vivo toxicological and pharmacokinetic profiles, as well as host To date, various polymer-assisted MNP assemblies have immune responses. Moreover, understanding the interactions been continuously developed and applied in the biomedical field, which has achieved great progress in multifunctional and between the MNP assemblies and diverse biomolecules in the intellectual nanostructures such as stimuli-responsive MNP living system is currently limited, and the in vivo behaviors of assemblies. However, it should be noted that the development the assemblies still need further in-depth investigation. In this of these assemblies always demands knowledge from both consideration, polymers and MNPs may need to be evaluated inorganic chemistry and polymer science. The complexity of separately in order to provide a full picture of the toxicity the assembling/disassembling process is a challenge, both for profile of MNP assemblies, which is especially a concern for most of the up-to-date synthetic and analysis techniques, and MNP assemblies encompassing both organic and inorganic for the control of the interactions between two phases to materials. obtain precisely designed materials with attractive and desired In summary, polymer-assisted MNP assemblies are witness- functions. Given that the synthesis methods of MNPs are ing more applications in precision medicines because of their relatively mature, well-defined polymer construction especially improved imaging performance with enhanced S/N ratio at for the synthesis or purification of stimuli-responsive lesions and effective disease treatments. Although challenges copolymers or other functional triblock/multiblock polymeric fi ligands for MNPs surface coating, as well as the synergic still remain to be addressed, advances in this eld provide a combination of two phases remains challenging for the control new opportunity for developing novel nanomaterials with over the polymer/MNP interfaces. On top of that, the controlled responsive behaviors and tunable functionalities, reproducibility of as-synthesized assemblies from different opening a new frontier for biomedical imaging/or drug batches should not be ignored. delivery applications.

137 DOI: 10.1021/acsabm.9b00896 ACS Appl. Bio Mater. 2020, 3, 121−142 ACS Applied Bio Materials Review ■ AUTHOR INFORMATION (10) Yang, H. Y.; Li, Y.; Lee, D. S. Multifunctional and Stimuli- Responsive Magnetic Nanoparticle-Based Delivery Systems for Corresponding Authors Biomedical Applications. Adv. Ther. 2018, 1, 1800011. *(D.L.) E-mail: [email protected]. (11) Lu, J.; Sun, J.; Li, F.; Wang, J.; Liu, J.; Kim, D.; Fan, C.; Hyeon, *(R.Q.) E-mail: [email protected]. T.; Ling, D. Highly Sensitive Diagnosis of Small Hepatocellular ORCID Carcinoma Using pH-Responsive Iron Oxide Nanocluster Assemblies. J. Am. Chem. Soc. 2018, 140, 10071−10074. Thomas P. Davis: 0000-0003-2581-4986 (12) Lu, Y.; Xu, Y. J.; Zhang, G. B.; Ling, D.; Wang, M. Q.; Zhou, Y.; Ruirui Qiao: 0000-0002-8351-7093 Wu, Y. D.; Wu, T.; Hackett, M. J.; Hyo Kim, B.; Chang, H.; Kim, J.; Daishun Ling: 0000-0002-9977-0237 Hu, X. T.; Dong, L.; Lee, N.; Li, F.; He, J. C.; Zhang, L.; Wen, H. Q.; Yang, B.; Hong Choi, S.; Hyeon, T.; Zou, D. H. Iron Oxide Author Contributions # Nanoclusters for T1Magnetic Resonance Imaging of Non-Human Y.L. and N.W. contributed equally to this work. Primates. Nat. Biomed. Eng. 2017, 1, 637−643. Notes (13) Zhou, H.; Tang, J.; Li, J.; Li, W.; Liu, Y.; Chen, C. In vivo The authors declare no competing financial interest. Aggregation-Induced Transition between T1 and T2 Relaxations of Magnetic Ultra-Small Iron Oxide Nanoparticles in Tumor Micro- environment. Nanoscale 2017, 9, 3040−3050. ■ ACKNOWLEDGMENTS (14) Liu, Q.; Song, L.; Chen, S.; Gao, J.; Zhao, P.; Du, J. A This work was supported by National Key Research and Superparamagnetic Polymersome with Extremely High T2 Relaxivity for MRI and Cancer-Targeted Drug Delivery. Biomaterials 2017, 114, Development Program of China (2016YFA0203600), the − Natural Science Foundation of China (NSFC) project 23 33. (15) Crucho, C. I. 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