In Situ Monitoring of Block Copolymer Self-Assembly via Solvent Exchange through Controlled Dialysis with Light and Neutron Scattering Detection.

Solution self-assembly of amphiphilic block copolymers (BCs) is typically performed by a solvent-to-water exchange. However, BC assemblies are often trapped in metastable states depending on the mixing conditions such as the magnitude and rate of water addition. BC self-assembly can be performed under near thermodynamic control by dialysis, which accounts for a slow and gradual water addition. In this Letter we report the use of a specifically designed dialysis cell to continuously monitor by dynamic light scattering and small-angle neutron scattering the morphological changes of PDMS-b-PEG BCs self-assemblies during THF-to-water exchange. The complete phase diagrams of near-equilibrium structures can then be established. Spherical micelles first form before evolving to rod-like micelles and vesicles, decreasing the total developed interfacial area of self-assembled structures in response to increasing interfacial energy as the water content increases. The dialysis kinetics can be tailored to the time scale of BC self-assembly by modifying the membrane pore size, which is of interest to study the interplay between thermodynamics and kinetics in self-assembly pathways.

Tear of lipid membranes by nanoparticles.

Health concerns associated with the advent of nanotechnologies have risen sharply when it was found that particles of nanoscopic dimensions reach the cell lumina. Plasma and organelle lipid membranes, which are exposed to both the incoming and the engulfed nanoparticles, are the primary targets of possible disruptions. However, reported adhesion, invagination and embedment of nanoparticles (NPs) do not compromise the membrane integrity, precluding direct bilayer damage as a mechanism for toxicity. Here it is shown that a lipid membrane can be torn by small enough nanoparticles, thus unveiling mechanisms for how lipid membrane can be compromised by tearing from nanoparticles. Surprisingly, visualization by cryo transmission electron microscopy (cryo-TEM) of liposomes exposed to nanoparticles revealed also that liposomal laceration is prevented by particle abundance. Membrane destruction results thus from a subtle particle-membrane interplay that is here elucidated. This brings into a firmer molecular basis the theorized mechanisms of nanoparticle effects on lipid bilayers and paves the way for a better assessment of nanoparticle toxicity.

Magnetic Ordering in Ultrasmall Potassium Ferrite Nanoparticles Grown on Graphene Nanoflakes.

Magnetic nanoparticles are central to the development of efficient hyperthermia treatments, magnetic drug carriers, and multimodal contrast agents. While the magnetic properties of small crystalline iron oxide nanoparticles are well understood, the superparamagnetic size limit constitutes a significant barrier for further size reduction. Iron (oxy)hydroxide phases, albeit very common in the natural world, are far less studied, generally due to their poor crystallinity. Templating ultrasmall nanoparticles on substrates such as graphene is a promising method to prevent aggregation, typically an issue for both material characterization and applications. We generate ultrasmall nanoparticles, directly on the carbon framework by the reaction of a graphenide potassium solution, charged graphene flakes, with iron(II) salts. After mild water oxidation, the obtained composite material consists of ultrasmall potassium ferrite nanoparticles bound to the graphene nanoflakes. Magnetic properties as evidenced by magnetometry and X-ray magnetic circular dichroism, with open magnetic hysteresis loops near room temperature, are widely different from classical ultrasmall superparamagnetic iron oxide nanoparticles. The large value obtained for the effective magnetic anisotropy energy density Keff accounts for the presence of magnetic ordering at rather high temperatures. The synthesis of ultrasmall potassium ferrite nanoparticles under such mild conditions is remarkable given the harsh conditions used for the classical syntheses of bulk potassium ferrites. Moreover, the potassium incorporation in the crystal lattice occurs in the presence of potassium cations under mild conditions. A transfer of this method to related reactions would be of great interest, which underlines the synthetic value of this study. These findings also give another view on the previously reported electrocatalytic properties of these nanocomposite materials, especially for the sought-after oxygen reduction/evolution reaction. Finally, their longitudinal and transverse proton NMR relaxivities when dispersed in water were assessed at 37 °C under a magnetic field of 1.41 T, allowing potential applications in biological imaging.

Mn2+ Complexes with Pyclen-Based Derivatives as Contrast Agents for Magnetic Resonance Imaging: Synthesis and Relaxometry Characterization.

Magnetic resonance imaging (MRI) has a leading place in medicine as an imaging tool of high resolution for anatomical studies and diagnosis of diseases, in particular for soft tissues that cannot be accessible by other modalities. Many research works are thus focused on improving the images obtained with MRI. This technique has indeed poor sensitivity, which can be compensated by using a contrast agent (CA). Today, the clinically approved CAs on market are solely based on gadolinium complexes that may induce nephrogenic systemic fibrosis for patients with kidney failure, whereas more recent studies on healthy rats also showed Gd retention in the brain. Consequently, researchers try to elaborate other types of safer MRI CAs like manganese-based complexes. In this context, the synthesis of Mn2+ complexes of four 12-membered pyridine-containing macrocyclic ligands based on the pyclen core was accomplished and described herein. Then, the properties of these Mn(II) complexes were studied by two relaxometric methods, 17O NMR spectroscopy and 1H NMR dispersion profiles. The time of residence (τM) and the number of water molecules (q) present in the inner sphere of coordination were determined by these two experiments. The efficacy of the pyclen-based Mn(II) complexes as MRI CAs was evaluated by proton relaxometry at a magnetic field intensity of 1.41 T near those of most medical MRI scanners (1.5 T). Both the 17O NMR and the nuclear magnetic relaxation dispersion profiles indicated that the four hexadentate ligands prepared herein left one vacant coordination site to accommodate one water molecule, rapidly exchanging, in around 6 ns. Furthermore, it has been shown that the presence of an additional amide bond formed when the paramagnetic complex is conjugated to a molecule of interest does not alter the inner sphere of coordination of Mn, which remains monohydrated. These complexes exhibit r1 relaxivities, large enough to be used as clinical MRI CAs (1.7-3.4 mM-1·s-1, at 1.41 T and 37 °C).

In vitro exploration of the synergistic effect of alternating magnetic field mediated thermo-chemotherapy with doxorubicin loaded dual pH- and thermo-responsive magnetic nanocomposite carriers.

Nanoparticle induced hyperthermia has been considered as a promising approach for cancer treatment for decades. The local heating ability and drug delivery potential highlight a diversified possibility in clinical application, therefore a variety of nanoparticles has been developed accordingly. However, currently, only a few of them are translated into the clinical stage indicating a 'medically underexplored nanoparticles' situation, which encourages their comprehensive biomedical exploration. This study presents a thorough biological evaluation of previous well-developed dual pH- and thermo-responsive magnetic doxorubicin-nanocarriers (MNC-DOX) in multiple cancer cell lines. The cytotoxicity of the nanocomposites has been determined by the MTT assay on primary cell lines. Histology and fluorescence microscopy imaging revealed the efficiency of cellular uptake of nanocarriers in different cell lines. The IC50 of MNC-DOX is significantly higher than that of free DOX without an alternating magnetic field (AMF), which implied the potential to lower the systemic cytotoxicity in clinical research. The concurrent thermo-chemotherapy generated by this platform has been successfully achieved under an AMF. Promising effective synergistic results have been demonstrated through in vitro study in multi-model cancer cell lines via both trypan blue exclusion and bioluminescence imaging methods. Furthermore, the two most used magnetic hyperthermia modalities, namely intracellular and extracellular treatments, have been compared on the same nanocarriers in all 3 cell lines, which showed that treatment after internalization is not required but preferable. These results lead to the conclusion that this dual responsive nanocarrier has extraordinary potential to serve as a novel broad-spectrum anticancer drug and worth pursuing for potential clinical applications.

Tuning Size and Morphology of mPEG-b-p(HPMA-Bz) Copolymer Self-Assemblies Using Microfluidics.

The careful design of nanoparticles, in terms of size and morphology, is of great importance to developing effective drug delivery systems. The ability to precisely tailor nanoparticles in size and morphology during polymer self-assembly was therefore investigated. Four poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) mPEG-b-p(HPMA-Bz) block copolymers with a fixed hydrophilic block of mPEG 5 kDa and a varying molecular weight of the hydrophobic p(HPMA-Bz) block (A: 17.1, B: 10.0, C: 5.2 and D: 2.7 kDa) were self-assembled into nanoparticles by nanoprecipitation under well-defined flow conditions, using microfluidics, at different concentrations. The nanoparticles from polymer A, increased in size from 55 to 90 nm using lower polymer concentrations and slower flow rates and even polymer vesicles were formed along with micelles. Similarly, nanoparticles from polymer D increased in size from 35 to 70 nm at slower flow rates and also formed vesicles along with micelles, regardless of the used concentration. Differently, polymers B and C mainly self-assembled into micelles at the different applied flow rates with negligible size difference. In conclusion, this study demonstrates that the self-assembly of mPEG-b-p(HPMA-Bz) block copolymers can be easily tailored in size and morphology using microfluidics and is therefore an attractive option for further scaled-up production activities.

Polyol-Made Luminescent and Superparamagnetic ß-NaY0.8Eu0.2F4@γ-Fe2O3 Core-Satellites Nanoparticles for Dual Magnetic Resonance and Optical Imaging.

Red luminescent and superparamagnetic ß-NaY0.8Eu0.2F4@γ-Fe2O3 nanoparticles, made of a 70 nm-sized ß-NaY0.8Eu0.2F4 single crystal core decorated by a 10 nm-thick polycrystalline and discontinuous γ-Fe2O3 shell, have been synthesized by the polyol process. Functionalized with citrate ligands they show a good colloidal stability in water making them valuable for dual magnetic resonance and optical imaging or image-guided therapy. They exhibit a relatively high transverse relaxivity r2 = 42.3 mM-1·s-1 in water at 37 °C, for an applied static magnetic field of 1.41 T, close to the field of 1.5 T applied in clinics, as they exhibit a red emission by two-photon excited fluorescence microscopy. Finally, when brought into contact with healthy human foreskin fibroblast cells (BJH), for doses as high as 50 µg·mL-1 and incubation time as long as 72 h, they do not show evidence of any accurate cytotoxicity, highlighting their biomedical applicative potential.

Auto-degradable and biocompatible superparamagnetic iron oxide nanoparticles/polypeptides colloidal polyion complexes with high density of magnetic material.

HYPOTHESIS: Superparamagnetic iron oxide nanoparticles (SPIONs) are extensively used as building block of colloidal nanocomposites for biomedical applications. Strategies employed to embed them in a biodegradable and biocompatible polymer matrix often fail to achieve a high density of loading which would greatly benefit to applications such as imaging and hyperthermia. In this study, poly(acrylic acid) coated SPION (γ-Fe2O3-PAA) are self-assembled with hydrolysable poly(serine ester) by electrostatic complexation, leading to perfectly defined spherical particles with ultra-high density of magnetic material and an ability to auto-degrade into individual SPION and biocompatible byproducts. EXPERIMENTS: Self-assembly and auto-degradation of γ-Fe2O3-PAA/poly(serine ester) and γ-Fe2O3-PAA/poly(serine ester)-b-PEG colloidal particles are studied by light scattering and microscopy. Colloidal stability in bio-fluids, hyperthermia under alternating magnetic field, cellular uptake, cytotoxicity and degradation of γ-Fe2O3-PAA/poly(serine ester)-b-PEG in living cells are investigated. FINDINGS: A remarkably slow electrostatic complexation leads to dense superparamagnetic γ-Fe2O3-PAA/poly(serine ester)-b-PEG polyion complexes (PICs) with controlled sizes (150-500 nm) and times of degradation in aqueous solvents (700-5000 h). The material shows good sustainability during hyperthermia, is well taken up by MC3T3 cells and non-cytotoxic. TEM images reveal a mechanism of degradation by "peeling" and fragmentation. In cells, PICs are reduced into individual SPIONs within 72 h.

Embedding of superparamagnetic iron oxide nanoparticles into membranes of well-defined poly(ethylene oxide)-block-poly(ε-caprolactone) nanoscale magnetovesicles as ultrasensitive MRI probes of membrane bio-degradation.

The present study reports the preparation of poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) polymer vesicles via a nanoprecipitation method and the loading of two different size hydrophobically coated ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles (a magnetic core size of 4.2 nm and 7.6 nm) into the membrane of these nanovesicles, whose thickness was measured precisely by small angle neutron scattering (SANS). Spherical nano-assemblies with a high USPIO payload and a diameter close to 150 nm were obtained as confirmed by dynamic light scattering (DLS), transmission electron microscopy (TEM) and cryo-TEM. The vesicular structure of these hybrid nano-assemblies was confirmed by multi-angle light scattering (MALS) measurements. Their magnetic properties were evaluated by T1 and T2 measurements (20 and 60 MHz) and by nuclear magnetic relaxation dispersion (NMRD) profiles. The size of USPIO entrapped in the membranes of PEO-b-PCL vesicles has a strong impact on their magnetic properties. It affects both their longitudinal and their transverse relaxivities and thus their magnetic resonance imaging (MRI) sensitivity. Acid-catalyzed hydrolysis of the PCL membrane also influences their relaxivities as shown by measurements carried out at pH 7 vs. pH 5. This property was used to monitor the membrane hydrolytic degradation in vitro, as a proof of concept of potential monitoring of drug delivery by nanomedicines in vivo and non-invasively, by MRI.

Effects of Chain Length of Chitosan Oligosaccharides on Solution Properties and Complexation with siRNA.

In the context of gene delivery, chitosan has been widely used as a safe and effective polycation to complex DNA, RNA and more recently, siRNA. However, much less attention has been paid to chitosan oligosaccharides (COS) despite their biological properties. This study proposed to carry out a physicochemical study of COS varying in degree of polymerization (DP) from 5 to 50, both from the point of view of the solution properties and the complexing behavior with siRNA. The main parameters studied as a function of DP were the apparent pKa, the solubility versus pH, the binding affinity with siRNA and the colloidal properties of complexes. Some parameters, like the pKa or the binding enthalpy with siRNA, showed a marked transition from DP 5 to DP 13, suggesting that electrostatic properties of COS vary considerably in this range of DP. The colloidal properties of siRNA/COS complexes were affected in a different way by the COS chain length. In particular, COS of relatively high DP (≥50) were required to form small complex particles with good stability.

Magnetic Polyion Complex Micelles for Cell Toxicity Induced by Radiofrequency Magnetic Field Hyperthermia.

Magnetic nanoparticles (MNPs) of magnetite (Fe3O4) were prepared using a polystyrene-graft-poly(2-vinylpyridine) copolymer (denoted G0PS-g-P2VP or G1) as template. These MNPs were subjected to self-assembly with a poly(acrylic acid)-block-poly(2-hydroxyethyl acrylate) double-hydrophilic block copolymer (DHBC), PAA-b-PHEA, to form water-dispersible magnetic polyion complex (MPIC) micelles. Large Fe3O4 crystallites were visualized by transmission electron microscopy (TEM) and magnetic suspensions of MPIC micelles exhibited improved colloidal stability in aqueous environments over a wide pH and ionic strength range. Biological cells incubated for 48 h with MPIC micelles at the highest concentration (1250 µg of Fe3O4 per mL) had a cell viability of 91%, as compared with 51% when incubated with bare (unprotected) MNPs. Cell internalization, visualized by confocal laser scanning microscopy (CLSM) and TEM, exhibited strong dependence on the MPIC micelle concentration and incubation time, as also evidenced by fluorescence-activated cell sorting (FACS). The usefulness of MPIC micelles for cellular radiofrequency magnetic field hyperthermia (MFH) was also confirmed, as the MPIC micelles showed a dual dose-dependent effect (concentration and duration of magnetic field exposure) on the viability of L929 mouse fibroblasts and U87 human glioblastoma epithelial cells.

Effect of Formulation and Processing Parameters on the Size of mPEG- b-p(HPMA-Bz) Polymeric Micelles.

Micelles composed of block copolymers of poly(ethylene glycol)- b-poly( N-2-benzoyloxypropyl methacrylamide) (mPEG- b-p(HPMA-Bz)) have shown great promise as drug-delivery carriers due to their excellent stability and high loading capacity. In the present study, parameters influencing micelle size were investigated to tailor sizes in the range of 25-100 nm. Micelles were prepared by a nanoprecipitation method, and their size was modulated by the block copolymer properties such as molecular weight, their hydrophilic-to-hydrophobic ratio, homopolymer content, as well as formulation and processing parameters. It was shown that the micelles have a core-shell structure using a combination of dynamic light scattering and transmission electron microscopy analysis. By varying the degree of polymerization of the hydrophobic block ( NB) between 68 and 10, at a fixed hydrophilic block mPEG5k ( NA = 114), it was shown that the hydrophobic core of the micelle was collapsed following the power law of ( NB × Nagg)1/3. Further, the calculated brush height was similar for all the micelles examined (10 nm), indicating that crew-cut micelles were made. Both addition of homopolymer and preparation of micelles at lower concentrations or lower rates of addition of the organic solvent to the aqueous phase increased the size of micelles due to partitioning of the hydrophobic homopolymer chains to the core of the micelles and lower nucleation rates, respectively. Furthermore, it was shown that by using different solvents, the size of the micelles substantially changed. The use of acetone, acetonitrile, ethanol, tetrahydrofuran, and dioxane resulted in micelles in the size range of 45-60 nm after removal of the organic solvents. The use of dimethylformamide and dimethylsulfoxide led to markedly larger sizes of 75 and 180 nm, respectively. In conclusion, the results show that by modulating polymer properties and processing conditions, micelles with tailorable sizes can be obtained.

Kinetics of Aggregation and Magnetic Separation of Multicore Iron Oxide Nanoparticles: Effect of the Grafted Layer Thickness.

In this work, we have studied field-induced aggregation and magnetic separation-realized in a microfluidic channel equipped with a single magnetizable micropillar-of multicore iron oxide nanoparticles (IONPs) also called "nanoflowers" of an average size of 27 ± 4 nm and covered by either a citrate or polyethylene (PEG) monolayer having a thickness of 0.2⁻1 nm and 3.4⁻7.8 nm, respectively. The thickness of the adsorbed molecular layer is shown to strongly affect the magnetic dipolar coupling parameter because thicker molecular layers result in larger separation distances between nanoparticle metal oxide multicores thus decreasing dipolar magnetic forces between them. This simple geometrical constraint effect leads to the following important features related to the aggregation and magnetic separation processes: (a) Thinner citrate layer on the IONP surface promotes faster and stronger field-induced aggregation resulting in longer and thicker bulk needle-like aggregates as compared to those obtained with a thicker PEG layer; (b) A stronger aggregation of citrated IONPs leads to an enhanced retention capacity of these IONPs by a magnetized micropillar during magnetic separation. However, the capture efficiency Λ at the beginning of the magnetic separation seems to be almost independent of the adsorbed layer thickness. This is explained by the fact that only a small portion of nanoparticles composes bulk aggregates, while the main part of nanoparticles forms chains whose capture efficiency is independent of the adsorbed layer thickness but depends solely on the Mason number Ma. More precisely, the capture efficiency shows a power law trend Λ âˆ M a−n, with n ≈ 1.4⁻1.7 at 300 < Ma < 104, in agreement with a new theoretical model. Besides these fundamental issues, the current work shows that the multicore IONPs with a size of about 30 nm have a good potential for use in biomedical sensor applications where an efficient low-field magnetic separation is required. In these applications, the nanoparticle surface design should be carried out in a close feedback with the magnetic separation study in order to find a compromise between biological functionalities of the adsorbed molecular layer and magnetic separation efficiency.

Thermo-responsive self-immolative nanoassemblies: direct and indirect triggering.

A thermo-responsive end-cap based on a retro-Diels-Alder and subsequent furan elimination reaction was developed. It was used to cap poly(ethyl glyoxylate), allowing end-to-end depolymerization upon thermal triggering. Using block copolymers, thermo-responsive micelles and vesicles were prepared and shown to disassemble upon heating. Thermal degradation could also be triggered indirectly by magnetic field hyperthermia after incorporation of iron oxide nanoparticles into the assemblies.

Controllable Microfluidic Production of Drug-Loaded PLGA Nanoparticles Using Partially Water-Miscible Mixed Solvent Microdroplets as a Precursor.

We present a versatile continuous microfluidic flow-focusing method for the production of Doxorubicin (DOX) or Tamoxifen (TAM)-loaded poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). We use a partially water-miscible solvent mixture (dimethyl sulfoxide DMSO+ dichloromethane DCM) as precursor drug/polymer solution for NPs nucleation. We extrude this partially water-miscible solution into an aqueous medium and synthesized uniform PLGA NPs with higher drug loading ability and longer sustained-release ability than conventional microfluidic or batch preparation methods. The size of NPs could be precisely tuned by changing the flow rate ratios, polymer concentration, and volume ratio of DCM to DMSO (VDCM/VDMSO) in the precursor emulsion. We investigated the mechanism of the formation of NPs and the effect of VDCM/VDMSO on drug release kinetics. Our work suggests that this original, rapid, facile, efficient and low-cost method is a promising technology for high throughput NP fabrication. For the two tested drugs, one hydrophilic (Doxorubicin) the other one hydrophobic (Tamoxifen), encapsulation efficiency (EE) as high as 88% and mass loading content (LC) higher than 25% were achieved. This new process could be extended as an efficient and large scale NP production method to benefit to fields like controlled drug release and nanomedicine.

Tuning Sizes, Morphologies, and Magnetic Properties of Monocore Versus Multicore Iron Oxide Nanoparticles through the Controlled Addition of Water in the Polyol Synthesis.

The polyol route is a versatile and up-scalable method to produce large batches of iron oxide nanoparticles with well-defined structures and magnetic properties. Importance of parameters such as temperature and reaction time, heating profile, nature of the polyol solvent or organometallic precursors on nanostructure and properties has already been described in the literature. Yet, the crucial role of water in the forced hydrolysis pathway has never been reported, despite its mandatory presence for nanoparticle production. This communication investigates the influence of the water amount and temperature at which it is injected in the reflux system for either a pure polyol solvent system or a mixture with poly(hydroxy)amine. Distinct morphologies of nanoparticles were thereby obtained, from ultra-ultra-small smooth spheres down to 4 nm in diameter to larger ones up to 37 nm. Well-defined multicore assemblies with narrow grain size dispersity termed nanoflowers were also synthesized. A diverse and large library of samples was obtained by manipulating the nature of solvents and the amount of added water while keeping all other parameters constant. The different morphologies lead to magnetic nanoparticles suitable for important biomedical applications such as magnetic hyperthermia, magnetic resonance imaging (MRI) contrast agent, or both.

Extensive characterization of magnetic microrods observed using optical microscopy.

The usage of micro or nanorods is steadily increasing in various applications from fundamental research to industry. Therefore their geometrical, mechanical and eventually magnetic properties need to be well determined. Here, using an optical microscope equipped with magnetic tweezers, we report an experimental procedure to obtain all those information on a single magnetic rod. In particular, we measure magnetic susceptibility χ by analyzing the deformation of a rod subjected to a uniform magnetic field. To do so, we refine a theoretical model which takes into account the variation of χ with the internal field. We prove experimentally that this model yields consistent measurements, at any value of the field strength and the incidence angle. From the combination of the different measurements, we also deduce the number of iron oxide nanoparticles which are embedded within the polymer matrix of the superparamagnetic rods under study.

In Vivo Imaging of Local Gene Expression Induced by Magnetic Hyperthermia.

The present work aims to demonstrate that colloidal dispersions of magnetic iron oxide nanoparticles stabilized with dextran macromolecules placed in an alternating magnetic field can not only produce heat, but also that these particles could be used in vivo for local and noninvasive deposition of a thermal dose sufficient to trigger thermo-induced gene expression. Iron oxide nanoparticles were first characterized in vitro on a bio-inspired setup, and then they were assayed in vivo using a transgenic mouse strain expressing the luciferase reporter gene under transcriptional control of a thermosensitive promoter. Iron oxide nanoparticles dispersions were applied topically on the mouse skin or injected subcutaneously with Matrigel™ to generate so-called pseudotumors. Temperature was monitored continuously with a feedback loop to control the power of the magnetic field generator and to avoid overheating. Thermo-induced luciferase expression was followed by bioluminescence imaging 6 h after heating. We showed that dextran-coated magnetic iron oxide nanoparticle dispersions were able to induce in vivo mild hyperthermia compatible with thermo-induced gene expression in surrounding tissues and without impairing cell viability. These data open new therapeutic perspectives for using mild magnetic hyperthermia as noninvasive modulation of tumor microenvironment by local thermo-induced gene expression or drug release.

Drug releasing nanoplatforms activated by alternating magnetic fields.

The use of an alternating magnetic field (AMF) to generate non-invasively and spatially a localized heating from a magnetic nano-mediator has become very popular these last years to develop magnetic hyperthermia (MH) as a promising therapeutic modality already used in the clinics. AMF has become highly attractive this last decade over others radiations, as AMF allows a deeper penetration in the body and a less harmful ionizing effect. In addition to pure MH which induces tumor cell death through local T elevation, this AMF-generated magneto-thermal effect can also be exploited as a relevant external stimulus to trigger a drug release from drug-loaded magnetic nanocarriers, temporally and spatially. This review article is focused especially on this concept of AMF induced drug release, possibly combined with MH. The design of such magnetically responsive drug delivery nanoplatforms requires two key and complementary components: a magnetic mediator which collects and turns the magnetic energy into local heat, and a thermoresponsive carrier ensuring thermo-induced drug release, as a consequence of magnetic stimulus. A wide panel of magnetic nanomaterials/chemistries and processes are currently developed to achieve such nanoplatforms. This review article presents a broad overview about the fundamental concepts of drug releasing nanoplatforms activated by AMF, their formulations, and their efficiency in vitro and in vivo. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader.

Modulation of phase separation at the micron scale and nanoscale in giant polymer/lipid hybrid unilamellar vesicles (GHUVs).

Phase separation in giant polymer/lipid hybrid unilamellar vesicles (GHUVs) has been described over the last few years. However there is still a lack of understanding on the physical and molecular factors governing the phase separation in such systems. Among these parameters it has been suggested that in analogy to multicomponent lipid vesicles hydrophobic mismatches as well as lipid fluidity play a role. In this work, we aim to map a global picture of phase separation and domain formation in the membrane of GHUVs by using various copolymers based on poly(dimethylsiloxane) (PDMS) and poly(ethylene glycol) (PEO) with different architectures (grafted, triblock) and molar masses, combined with phospholipids in the fluid (POPC) or gel state (DPPC) at room temperature. From confocal imaging and fluorescence lifetime imaging microscopy (FLIM) techniques, the phase separation into either micro- or nano-domains within GHUVs was studied. In particular, our systematic studies demonstrate that in addition to the lipid/polymer fraction or the lipid physical state, important factors such as line tension at lipid polymer/lipid boundaries can be finely modulated by the molar mass and the architecture of the copolymer and lead to the formation of stable lipid domains with different sizes and morphologies in such GHUVs.