Fabrication of Magnetic Polymeric Micelles: History
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Contributor:
Margarida S. Miranda
,
Ana F. Almeida
,
Manuela E. Gomes
,
Márcia T. Rodrigues

Hybrid nanoarchitectures such as magnetic polymeric micelles (MPMs) are among the most promising nanotechnology-enabled materials for biomedical applications combining the benefits of polymeric micelles and magnetic nanoparticles within a single bioinstructive system. MPMs are formed by the self-assembly of polymer amphiphiles above the critical micelle concentration, generating a colloidal structure with a hydrophobic core and a hydrophilic shell incorporating magnetic particles (MNPs) in one of the segments. MPMs have been investigated most prominently as contrast agents for magnetic resonance imaging (MRI), as heat generators in hyperthermia treatments, and as magnetic-susceptible nanocarriers for the delivery and release of therapeutic agents. The versatility of MPMs constitutes a powerful route to ultrasensitive, precise, and multifunctional diagnostic and therapeutic vehicles for the treatment of a wide range of pathologies. 

  • hybrid nanosystems
  • magnetic polymeric micelles
  • polymeric micelles

1. Introduction

There is a worldwide growing demand for advanced medical nanotechnologies able to provide complementary functionalities mimicking complex biological processes while enabling biorecognition and bioresponsiveness to bring clinical benefits to patients. To meet these daunting challenges, hybrid nanoarchitectures such as magnetic polymer micelles (MPMs) offer unprecedented solutions at a cellular scale in fostering interactions with living entities and integrating extracellular environment dynamics. MPMs share de advantages of polymer micelles (PMs) and magnetic nanoparticles (MNPs) in a single nanoplatform with flexible capabilities.
Polymeric micelles (PMs) are nanosized colloidal particles built from amphiphilic copolymers that self-assemble in an aqueous solution above the critical micelle concentration (CMC). PMs are formed of a hydrophobic core and a hydrophilic outer shell and are characterized by a high loading efficiency of different cargos. As most conventional medicines share a hydrophobic nature, they can be accommodated in the hydrophobic core, whereas the hydrophilic shell may house complementary hydrophilic drugs and bioactive molecules in addition to providing colloidal stability and intrinsic stealth effect [1][2]. The shell is also responsible for environmental protection, limiting opsonin adsorption towards a longer circulation time or better blood stability and for active targeting through conjugation with ligands or antibodies against molecules and protein complexes at the cell membrane. This structural duality gives PMs high versatility and efficacy over other nanocarriers, packing multiple cargos with different properties into one system. Despite the multimodal potential, the impact of PMs in biomedicine can be greatly incremented by the inclusion of magnetic nanoparticles (MNPs) in the core or in the shell to produce magnetically responsive micellar structures enabling precision and noninvasive control over the spatiotemporal distribution of physical and chemical factors in cells, tissues, and living organisms.

2. Types of Polymers Used in the Shell of Magnetic Polymeric Micelles

2.1. Synthetic Polymers

Synthetic polymers have been widely studied in bioengineering due to their well-defined chemical structure, batch-to-batch uniformity, and biocompatibility [3][4]. They are also recognized for their high purity, suitable mechanical properties, and nontoxicity.
The most investigated polymer for the MPM shell is poly(ethylene glycol) (PEG). PEG is a highly versatile polymer with excellent solubility in aqueous media and chemical labiality for chemical modification with different functional groups [5]. PEG provides both the stealth effect and immune protection by reducing the adhesion of opsonins present in the blood as well as MPM uptake by phagocytic cells [6]. A potential alternative to PEG is polysarcosine (PSar), a nonionic polypeptoid based on the amino acid sarcosine, i.e., N-methylated glycine, found in muscles and other tissues [7]. PSar presents PEG-like properties including high water solubility and protein resistance, low cellular toxicity, and a nonimmunogenic character. A less conventional block is triethylene glycol monomethyl ether (TEGME). TEGME is a hydroxypolyether that has been used to bind to the poly(phenyl isocyanide (PPI) block to afford a water-soluble amphiphilic copolymer [8].
Smart polymers can undergo physical or chemical modifications in response to a change in environment or a precise stimulus such as pH or temperature (revised from [9]). Poly amino acids and esters (e.g., poly(glutamic acid) (PGA), poly(2-azidoethyl-L-glutamate) (PAELG), poly(β-amino ester) (PAE) as well as polyolefines (e.g. poly(acrylic acid) (PAA)) have been investigated to increase the hydrophilicity of the shell to control MPM responsiveness to pH variation. For gene delivery, the micelle corona is typically constituted by poly(ethylenimine) (PEI). The amino groups available in PEI are responsible for their highly positive charge density and the binding to negatively charged molecules comprising short DNA or RNA polymers. PEI has been considered one of the most efficient nonviral gene delivery vectors [10][11] despite its reported nonbiodegradability and cellular toxicity. To circumvent PEI limitations, cationic spermine (Spm) and poly(aspartic acid)-dimethylethanediamine (PAsp(DMA)) were proposed for delivering nucleotides [12]. Spm is an aliphatic polyamine bearing multiple amino groups holding important roles in the metabolism of eukaryotic cells [13]. Considering its endogenous function, it is expected that Spm will render improved biocompatibility over that of other synthetic molecules. Polymers sensitive to temperature, for instance poly(N-isopropylacrylamide) (PNIPAM), have been used for thermal-controlled drug release. PNIPAM presents a reversible hydration/dehydration state across the lower critical solution temperature (LCST, 32 °C), whose behavior is associated with conformational changes of the polymer chains induced by temperature variation [14][15]. Other polymers, for instance poly(2-hydroxymethyl) methacrylate (PHEMA), have been combined with platinum to generate a polymeric prodrug that can be further assembled into a micellar nanocomplex for enhanced accumulation and efficacy of tumor-oriented drugs [16].

2.2. Natural-Origin Polymers

Natural-based polymers are biomaterials obtained from sustainable and renewable sources, namely plants, animals, or fungi. Most natural-origin polymers are cost-effective, easily available, biodegradable, and nontoxic with vast applications in pharmaceutics and biotechnology. Natural polymers have been widely investigated in different nanoarchitectures (revised from [17]). Among these, polysaccharides such as hyaluronic acid (HA) [18][19][20], chitosan (CHI) [21][22], and dextran (DEX) [23] and proteins such as lactoferrin (LF) [24] have been proposed for the development of MPM due to the presence of specific moieties that promote cell recognition and interactions with cells [25].
HA is naturally found in tissue matrices having a crucial role in tissue structure, cell motility and adhesion, and proliferation processes. HA is already applied in clinics for diagnosis, in ophthalmological and ontological surgeries, in the treatment of arthritic patients, and also in the cosmetic regeneration and reconstruction of soft tissue [26][27]. Furthermore, HA is chemically versatile and can be modified in a myriad of forms to ameliorate its physico-chemical properties and biological functionality.
CHI is a polysaccharide produced by the deacetylation of chitin obtainable from marine biological structures. CHI is one of the few cationic polymers available for electrostatically binding with anionic bioactive compounds. CHI contains amino and hydroxyl groups on its backbone, permitting its conjugation with bioactive molecules under physiological conditions. Like HA, CHI can be easily modified to improve the targeting efficiency, respond to environmental stimuli, and obtain value-added delivery systems by increasing the solubility and embedding efficiency of hydrophobic therapeutic agents. Based on such findings, amphipathic CHI derivatives have been developed by modifying CHI with hydrophobic octyl, hydrophilic quaternary ammonium, and PEG groups to fabricate a drug delivery carrier with enhanced solubility and controlled payload release [22].
MPM shells have also been fabricated with DEX, which can be obtained from the lactic acid bacteria Leuconostoc mesenteroides and commercially produced from sucrose [28]. Because DEX possesses abundant hydroxyl groups, it is a water-soluble polymer with chemical modification potential for the transportation of drugs, proteins, and other bioactive agents. Hydrophobic chains, stimuli-sensitive chains/groups, and drugs have been conjugated to DEX to obtain self-assembling derivatives. DEX is resistant to protein adsorption and is clinically applied as a plasma expander and as an antithrombotic agent to reduce blood viscosity [28][29].
Along with polysaccharides, proteins have served as micellar shells. LF is a non-heme iron-binding glycoprotein derived from milk and other mammalian fluids with antimicrobial activity [30]. LF has an unusually high isoelectric point (pI > 8) and therefore tends to be cationic at neutral pH. LF has been described as minimizing the possible interaction of MPMs with serum proteins, extending their systemic circulation [24].

3. Types of Copolymers Used in the Core of Magnetic Polymeric Micelles

3.1. Synthetic Polymers

Poly(ε-caprolactone) (PCL) is a commonly used polymer for the MPM core, together with polylactic acid (PLA) and poly(lactide-co-glycolic acid) (PLGA). These polyester-based polymers are approved by the United States Food and Drug Administration (FDA) for several biomedical applications and share the characteristics of hydrophilic synthetic polymers (Section 2.1.1), comprising well-defined chemical structure, biocompatibility, and nontoxicity. Since most molecules with therapeutic value have hydrophobic behavior, other hydrophobic blocks like poly(L-aspartic acid) (PAsp) derivatives, poly(4-vinylpyridine) (P4VP), and poly(styrene) (PS) have been proposed to transport MNPs and drugs inside MPMs. In particular, poly(2-methoxy-2-oxo-1,3,2-dioxaphospholane) (PHEP) and poly(acrylamide-co-acrylonitrile) (P(AAm-co-AN)) transit from a hydrophobic state to a water-soluble disassembled state upon heating, enabling temperature-responsive payload release which is of special interest in drug delivery during hyperthermia treatment [31][32].

3.2. Small Molecules

Palmitic acid (PA), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), cholic acid (CA), and aminoethyl 5β-cholanomide (CAM) are small hydrophobic molecules utilized as lipid moieties in the assembly of MPMs. The balance of phospholipids in cells is maintained by PA, the most common saturated fatty acid found in the cell membrane of animals, plants, and microorganisms. Likewise, phosphatidylethanolamines are available in cell membranes and may contribute to improved magnetic micelle-cell communication. With different biological roles, CA and 5β-cholanic acid are bile acids responsible for facilitating the digestion of dietary fats serving as micelle-forming surfactants. CA is FDA approved for the treatment of bile acid synthesis disorders. CAM is derived from 5β-cholanic acid that has been chemically changed with a terminal amino group to be conjugated with polymers containing carboxylic acids such as HA [33].

3.3. Proteins

Despite the potential for MPM assemblies, protein reports are scarce. The only exception is Zein, a prolamine that occurs specifically in cereals [34]. Zein is the major storage protein in corn and has been considered a waste protein until recently. Its unique solubility in aqueous alcohol solutions and deficit in basic and acidic amino acids, especially tryptophan and lysine, have been recently appreciated for drugs and bioactive molecules delivery and tissue engineering [35][36][37].

4. Intrinsically Amphiphilic Natural Polysaccharides

Up to the present time, levan was the only intrinsically amphiphilic natural polysaccharide described with obvious potential for MPM assembly [38]. Levan is a fructose homopolymer derived from microorganisms and some plants with anti-tumor and anti-infection activities [39]. Levan presents a hydrophobic moiety and the methylene group in the furanoside moieties, and its amphiphilic character has shown prospects for water-forming nanoparticles and the delivery of proteins and peptides [39][40].

5. Magnetic Nanoparticles

5.1. The Impact of Magnetic Compliance

MNPs are a class of nanomaterials characterized by their magnetic responsiveness to external magnetic fields. MPMs typically incorporate iron oxide-based MNPs, namely, superparamagnetic iron oxide nanoparticles (SPIONs) such as magnetite (Fe3O4) [8]. In contrast with other MNPs, the superparamagnetic behavior allows SPIONs to lose magnetism and re-disperse when the magnetic field is removed, which is an appealing feature for the manipulation and navigation to specific sites under an external magnetic field.
The basic principle of magnetic field-based manipulation relies on magnetic field strength, a magnetic field gradient, and a susceptible difference between the magnetically responsive material and the cells or tissues [41]. The magnetic field applied can be constant, also referred to as static or stationary magnetic field and provided by permanent magnets, or alternating, induced by charge movements in solenoids or electromagnets. Unlike static magnetic fields, alternating magnetic fields (AMFs) vary in time and can be divided into low or high frequency depending on how slow (low) or fast (high) the magnetic field varies in time. Depending on the imaging devices, the magnetic fields in magnetic resonance imaging (MRI) go up to 7 T for several minutes while musculoskeletal treatment modalities with magnetotherapy equipment (e.g., Globus XL) vary between 1.5 mT to 10 mT applied for up to 3 h per session.
Magnetic fields demonstrate excellent tissue penetration and have a low interference with the biological environment due to the not inherently magnetic nature of cells and tissues, which are powerful arguments for taking advantage of magnetic field-based technologies in the development of multifunctional hybrid systems. The contactless actuation of the magnetic field minimizes possible harmful effects that could reduce cell integrity and viability. Moreover, the magnetic field is poorly influenced by internal and external features such as ionic strength, surface charges, pH, and temperature, which can be advantageous for human-driven applications. Finally, magnetic fields can be generated from simple use and inexpensive instrumentation (e.g., permanent magnets) that can support and facilitate the exploitation and commercialization pathways of magnetic targeting into clinical modalities.
The strong magnetic moment of MNPs has been explored for visualization, tracking, and monitoring in imaging techniques such as MRI and magnetic particle imaging for assisting with diagnosis modalities. This unique feature of MNP-based probes could transform disease detection and imaging-guided therapies into precision delivery and targeted theranostic platforms with promising interventions in the management and treatment of pathological conditions.

5.2. Magnetic Nanoparticles Synthesis

MNPs can be synthesized by wet chemistry, microfluidic reactors, or biogenic synthesis (revised from [42][43][44]) to produce nanoparticles with well-controlled size, distribution, and shape. The synthesis route also determines the hydrophilic/hydrophobic nature of the MNP coating, and thus the MNP integration within one of the MPM segments.
In MPM assemblies, thermal decomposition and co-precipitation are the most commonly used methods of producing MNPs. Thermal decomposition produces hydrophobic MNP with tunable sizes (5–22 nm), narrow size distribution, and high crystallinity, holding scalability potential [45][46]. On the other hand, co-precipitation, which is a simple and rapid procedure, results in the synthesis of MNPs with high polydispersity and poor crystallinity [2][47][48]. Typically, MNPs are synthesized first and then co-assembled with amphiphilic copolymers into MPMs. Nevertheless, a study by Bastakoti et al. reported the in situ synthesis of SPIONs by co-precipitation after micelle assembly with poly(styrene-block-acrylic acid-block-ethylene oxide) (PS-b-PAA-b-PEG) [2]. The chelating behavior of the carboxylic acid groups from the PAA segment provides the reaction sites for iron ions and controls the crystal overgrowth during the co-precipitation reaction. This unconventional approach resulted in an increase in the hydrodynamic diameter of the MPMs in comparison with nonmagnetic micelles and a higher polydispersity index (PDI of 0.3) due to the formation of secondary nano and micro aggregates [2]. Even though the in-situ synthesis of MPMs has been scarcely reported, the control of the properties such as dimension, shape, and magnetic responsiveness are likely more pertinent to improving MPM functionalities and effectiveness as cutting-edge nanovehicles.

5.3. Shape and the Core Composition of MNPs

The shape and the core composition of MNPs have been explored in MPM production anticipating efficiency improvements for diagnostic and therapeutic actions. Although the MNPs used in the MPM fabrication are often spherical, other shapes have been prepared by playing with synthesis parameters [49][50]. Cube-shaped SPIONs evidenced higher heating efficiency and enhanced MRI contrast in comparison with sphered SPIONs due to their value-added magnetic properties [51][52][53]. Accordingly, cubic MnFe2O4-based MPMs exhibited a higher negative contrast enhancement of MRI signals (r2 = 373 mM−1 s−1) in comparison with spherical MnFe2O4-based MPMs (r2 = 321 mM−1 s−1) highlighting the morphology and shape of SPIONs as critical aspects for the development of diagnostic imaging agents [49]. MPMs have also been produced using SPIONs doped with Zn and/or Mn known as ferrite nanoparticles, where iron is partially substituted by other metallic elements (e.g., MFe2O4, M = Zn; Mn) [49][54][55]. These elements have been shown to increase the magneto-thermal capability and the performance of MRI contrast agents relative to commercially available contrast agents based on pure SPIONs (Fe3O4) [56]. MnFe2O4-, Zn1.15Fe1.85O4-, and Mn0.6Zn0.4Fe2O4-based micelles have been constructed for imaging purposes [49][54][55]. Interestingly, Zn1.15Fe1.85O4 micelles have also shown value for magnetic delivery and Mn0.6Zn0.4Fe2O4 micelles for hyperthermia treatments, supporting the multifunctional identity of magnetic-based nanosystems. Nonetheless, comparative studies are still missing for hierarchically classifying the important features influencing contrast imaging properties, heating capability, and half-life in circulation.

5.4. Biocompatibility of MNPs

The low tendency of SPIONs to form particle aggregates after magnetic field removal, rendered by their superparamagnetic nature, is highly relevant to biomedicine approaches and contributes to a significant decrease in toxicity in living environments [57]. Similar to other metallic nanoparticles, the toxicity of SPIONs is dependent on various factors including size, surface chemistry, concentration, the method of administration, and biodegradability [58][59][60][61][62][63][64], and may be related to oxidative stress and iron-mediated radical formation [65]. Nonetheless, the potential toxicity effects of SPIONs below 100 µg mL−1 have been considered neglectable on several cell lines [58][60].
Although the interactions between MNPs and cells or tissues are not comprehensively elucidated, and nor are the long-term biological impacts in humans, studies have demonstrated that MNPs are engulfed in cell endosomes that later fuse with lysosomes, where an acid-induced degradation occurs [66]. The iron ions released from the SPION degradation join the intracellular iron pool and the innate iron metabolic pathway. Ultimately, these ions are recycled and used for hemoglobin synthesis after uptake by erythroid precursor cells [67].
In response to foreign nanoparticles, cells can also orchestrate autophagy, with crucial signaling in processes like infection, inflammation, polarization, and tumor cytotoxicity, to assist in important functions including antigen presentation, lymphocyte homeostasis, and the secretion of immune factors. Disputable outcomes of MNP-induced autophagy suggest that the autophagic response of macrophages may correlate with cytokine cascades and inflammatory response, while others indicate a protective autophagy response of SPIONs in monocytes and macrophages [68][69].
Immune cells are sensitive to the presence of MNPs and respond by either releasing inflammatory mediators or stimulating anti-inflammatory functions. Immune activation can be useful, for instance for enhancing antitumor immunity by reversing the M2-like phenotype of tumor-associated macrophages, which serve roles in inhibiting inflammation and promoting tumor development. Macrophages exposed to ferumoxytol (Feraheme®) displayed increased mRNA associated with pro-inflammatory responses, suggesting that ferumoxytol could be applied “off label” to potentiate macrophage-modulating cancer immunotherapies [70]. Additionally, iron oxide@chlorophyll clustered nanoparticles modified with 4-carboxyphenylboronic acid were reported to reprogram tumor microenvironment in combination with photo and chemodynamic therapies by the inactivation of programmed death-ligand 1 and suppression of M2-like macrophages accumulation [71].
On the other hand, the interaction of human macrophages with dextran-coated [72][73] and silica-coated [72] SPIONs did not trigger the release of pro-inflammatory molecules as IL-12, IL-6, TNF-α, and IL1-β, suggesting that the immunomodulatory capacities of MNPs can be also utilized to potentiate new imaging scenarios, regulate the phenotype transition of immune cells, or to create an environment conducive for tissue regeneration preventing persistent inflammatory triggers. In a work by Wu et al., a fibroblast growth factor (bFGF)-loaded Fe3O4 nanoparticle accelerated wound healing through M2 macrophage polarization and increased cell proliferation in a full-thickness wound murine model [74].
Thus, controlling the design of MPMs, in particular, the surface functionalities of SPIONs to meet a particular application could tackle the biosafety concerns. Furthermore, the small dimension of MPMs enables optimal in vivo delivery, avoids rapid renal clearance, and improves MPM’s safety and effectiveness [75][76]. These features together with a high loading capacity and magnetic navigation foresee MPMs as compelling smart structures for state-of-the-art medical diagnosis and therapeutic purposes [47][48], capitalizing on MPM’s translational success.

6. Self-Assembly Architectures of Amphiphilic Copolymers

Amphiphilic copolymers were designed to self-assemble into MPMs with di-block, tri-block, multi-block, star-like, and graft copolymer architectures.
The hydrophobic moieties can be introduced by grafting them as side groups along the polymer chains or via coupling to end groups (end-to-end coupling strategies), using chemical tools (e.g., amidation, esterification, click chemistry) or polymer synthesis (e.g., ring-opening or living radical polymerization).
The nanocarriers based on traditional di-block copolymers are characterized by poor structural tunability. The combination of different block types into mixed micelles enables the design of nanostructured materials with increased architectural complexity, improved control over micellization, and enhanced functionality. An example is the use of a star-like block copolymer with PLGA and PEG arms for the fabrication of MPM aiming at quercetin (QCT) drug delivery [77]. Star polymers contain more end-groups than linear polymers, thus presenting higher hydrophilicity, and when used as drug nanocarriers, they also show higher drug loading efficiency [78]. Moreover, the demand for multifunctionally competent MPMs has led to the arrangement of linear polymers with different generations of dendrimers referred to as telodendrimers. The MPM assemblies with telodendrimers found applicability in MRI and fluorescent dual imaging joining telodendrimer dendritic oligo-cholic acid-block-poly(ethyleneglycol) ((CA)4-Lys3-PEG) with SPIONs and Nile Red, a model hydrophobic dye. (CA)4-Lys3-PEG was designed by linking the end of PEG with the second generation of dendritic polylysine (PEG-Lys3) to which CA molecules were coupled [79].
The self-assembly of copolymers and the integration of MNPs into MPM involves the optimization of the hydrophilic/hydrophobic balance of the block copolymer, MNP surface ligands, and the type of organic solvent used to dissolve copolymers and MNPs [80]. The colloidal stability of MPM is of critical importance for preventing the premature release of drugs and prolonging the blood circulation time. Cross-linking methods have been used to fix the core or the shell of MPM with organic molecules. Although covalent cross-linking can be employed in both the hydrophobic and hydrophilic segments, cross-linking of the shell can lead to inter-micellar cross-linking, loss of shell fluidity, and polar affinity causing a decreased stealth effect.
Traditional organic cross-linking strategies involve toxic and expensive organic molecules as well as complicated and time-consuming procedures. Alternatively, organosilica cross-linking is performed under mild conditions and involves easier processing. This strategy was performed by Yang et al. to lock the PCL core using a 3-mercaptopropyltrimethoxysilane cross-linking agent under alkaline conditions [81]. The resultant MPM exhibited excellent stability in biological fluids.
Using a double cross-linking approach, Bauer et al. [82] developed MPM from SPIONs and PCys(SO2Et)-b-PSar copolymer. These MPMs were cross-linked with dihydrolipoic acid enabling both disulfide bond formation in the core and direct grafting onto the SPIONs surface through the carboxylic group of dihydrolipoic acid. This approach was successful to improve the stability of the SPIONs in the MPM.
MPMs generally exhibit a spherical morphology ranging from 20 to 500 nm [21][49][79][83][84] but, rod bacterium-like MPMs have been developed [85] with a diameter of 20 nm and length of 600 nm combining PCL-PEG, SPIONs, and doxorubicin (DOX). Interestingly, rod MPMs were shown to present a higher loading content of DOX together with a higher saturation magnetization (23.15 emu g−1) than spherical MPM (17.36 emu g−1). Moreover, rod-shaped MPMs have an extensive blood circulation time (>24 h) and are more easily internalized by HepG2 and A549 cells than their spherical counterparts [85].
Micelle size is influenced both by the size [21][49][83][84] and the clustering [86] of loaded SPIONs. For a given SPION-loaded amount, increasing SPIONs size leads to an enlargement of MPMs. The amount of loaded SPIONs also influences the micelle diameter, as elegantly investigated by Jiang et al. [86]. The SPION-free micelles presented a diameter of 24 ± 3 nm, and the diameters increased to 80 ± 13, 100 ± 9 and 108 ± 8 nm, respectively, when SPIONs were loaded into the micelles by weight ratio of 15, 30, and 50% [86].

7. Techniques for the Preparation of Magnetic Polymeric Micelles

The shape-controlled and highly stable MPMs with narrow size distribution were successfully achieved through five distinct routes: (i) emulsion–solvent evaporation, (ii) thin film rehydration, (iii) nanoprecipitation, (iv) dialysis, and (v) ultrasonication. The selection of one of these routes depends on the solubility of the copolymer considering that the MNPs are commonly hydrophobic and thus are dissolved in an organic solvent. Likewise, the hydrophobic/hydrophilic nature of drugs to be incorporated in the core or shell of the MPM, respectively, dictates that hydrophobic drugs be included in the organic phase while the hydrophilic drugs are dissolved in the aqueous solution.
In the emulsion–solvent evaporation method, the co-polymer and MNPs are dissolved in an organic solvent. The resulting mixture is added to an aqueous solution under stirring or sonication to which surfactants may be added to increase the stability of the emulsion. The organic solvent is then evaporated to form the MPMs. In a study by Karami et al. [76], naproxen (NPX)-loaded MPMs were successfully prepared using this method. The organic phase containing the dissolved PCL-b-PEG copolymer, naproxen, and SPIONs was injected into the aqueous phase (polyvinyl acetate 0.5% w/v) under homogenization to obtain an emulsion followed by the chloroform evaporation.
In the case of copolymers with phospholipids in the hydrophobic block, thin-film hydration was used. Polymeric micelles of DSPE-b-PEG have been produced with MNPs and paclitaxel (PTX) loads by dissolving the copolymer and MNPs in a volatile organic solvent that was then evaporated by rotary evaporation to produce a thin film [87][88]. The film is rehydrated and vortexed vigorously to produce MPMs.
The nanoprecipitation and dialysis methods have a similar procedure. The copolymer and MNPs are first dissolved in a water-miscible organic solvent and added to the aqueous phase under stirring. With the nanoprecipitation method, the MPMs are readily formed, and the organic solvent is removed by evaporation or dialysis. In the dialysis method, the mixture is placed into a dialysis bag and immersed in water for several hours, inducing the MPM assembly through solvent exchange [83]. Unlike the nanoprecipitation method in which the MPMs are produced in a simple and fast manner, the dialysis method can be time-consuming and requires a great amount of water, resulting in the formation of a large volume of waste liquid.
Ultrasonication is normally used for water-soluble copolymers. MNPs are added to the copolymer, and an ultrasonication procedure allows the formation of MPM after removing the organic solvent. In a study by Park et al. [38], SPIONs in hexane were added to levan, and the mixture was moved to an ultrasonic water bath. The organic solvent was then removed by heating.

This entry is adapted from the peer-reviewed paper 10.3390/ijms231911793

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