Influence of SPION Surface Coating on Magnetic Properties and Theranostic Profile.

This study aimed to develop multifunctional nanoplatforms for both cancer imaging and therapy using superparamagnetic iron oxide nanoparticles (SPIONs). Two distinct synthetic methods, reduction-precipitation (MR/P) and co-precipitation at controlled pH (MpH), were explored, including the assessment of the coating's influence, namely dextran and gold, on their magnetic properties. These SPIONs were further functionalized with gadolinium to act as dual T1/T2 contrast agents for magnetic resonance imaging (MRI). Parameters such as size, stability, morphology, and magnetic behavior were evaluated by a detailed characterization analysis. To assess their efficacy in imaging and therapy, relaxivity and hyperthermia experiments were performed, respectively. The results revealed that both synthetic methods lead to SPIONs with similar average size, 9 nm. Mössbauer spectroscopy indicated that samples obtained from MR/P consist of approximately 11-13% of Fe present in magnetite, while samples obtained from MpH have higher contents of 33-45%. Despite coating and functionalization, all samples exhibited superparamagnetic behavior at room temperature. Hyperthermia experiments showed increased SAR values with higher magnetic field intensity and frequency. Moreover, the relaxivity studies suggested potential dual T1/T2 contrast agent capabilities for the coated SPpH-Dx-Au-Gd sample, thus demonstrating its potential in cancer diagnosis.

Multifunctional targeted solid lipid nanoparticles for combined photothermal therapy and chemotherapy of breast cancer.

Photothermal therapy has emerged as a new promising strategy for the management of cancer, either alone or combined with other therapeutics, such as chemotherapy. The use of nanoparticles for multimodal therapy can improve treatment performance and reduce drug doses and associated side effects. Here we propose the development of a novel multifunctional nanosystem based on solid lipid nanoparticles co-loaded with gold nanorods and mitoxantrone and functionalized with folic acid for dual photothermal therapy and chemotherapy of breast cancer. Nanoparticles were produced using an economically affordable method and presented suitable physicochemical properties for tumor passive accumulation. Upon Near-Infrared irradiation (808 nm, 1.7 W cm-2, 5 min), nanoparticles could effectively mediate a temperature increase of >20 °C. Moreover, exposure to light resulted in an enhanced release of Mitoxantrone. Furthermore, nanoparticles were non-hemolytic and well tolerated by healthy cells even at high concentrations. The active targeting strategy was found to be successful, as shown by the greater accumulation of the functionalized nanoparticles in MCF-7 cells. Finally, the combined effects of chemotherapy, light-induced drug release and photothermal therapy significantly enhanced breast cancer cell death. Overall, these results demonstrate that the developed lipid nanosystem is an efficient vehicle for breast cancer multimodal therapy.

Rational design of magnetoliposomes for enhanced interaction with bacterial membrane models.

There is a growing need for alternatives to target and treat bacterial infection. Thus, the present work aims to develop and optimize the production of PEGylated magnetoliposomes (MLPs@PEG), by encapsulating superparamagnetic iron oxide nanoparticles (SPIONs) within fusogenic liposomes. A Box-Behnken design was applied to modulate size distribution variables, using lipid concentration, SPIONs amount and ultrasonication time as independent variables. As a result of the optimization, it was possible to obtain MLPs@PEG with a mean size of 182 nm, with polydispersity index (PDI) of 0.19, and SPIONs encapsulation efficiency (%EE) around 76%. Cytocompatibility assays showed that no toxicity was observed in fibroblasts, for iron concentrations up to 400µg/ml. Also, for safe lipid and iron concentrations, no hemolytic effect was detected. The fusogenicity of the nanosystems was first evaluated through lipid mixing assays, based on Förster resonance energy transfer (FRET), using liposomal membrane models, mimicking bacterial cytoplasmic membrane and eukaryotic plasma membrane. It was shown that the hybrid nanosystems preferentially interact with the bacterial membrane model. Confocal microscopy and fluorescence lifetime measurements, using giant unilamellar vesicles (GUVs), validated these results. Overall, the developed hybrid nanosystem may represent an efficient drug delivery system with improved targetability for bacterial membrane.

Folate receptor-mediated delivery of mitoxantrone-loaded solid lipid nanoparticles to breast cancer cells.

The standard breast cancer therapy still faces major challenges due to non-specific tumor distribution and occurrence of dose-limiting adverse side-effects. Nanomedicine constitutes an appealing approach to improve the therapeutic index of different anti-cancer drugs. Given their biocompatibility, low-cost manufacture and easy surface modification, lipid nanoparticles, such as solid lipid nanoparticles (SLN), have a great potential for drug delivery in cancer therapy. In this work, SLN entrapping the antineoplastic drug Mitoxantrone (Mito) were developed and functionalized with Disteroylphosphatidylethanolamine-poly(ethylene glycol)-folic acid (DSPE-PEG-FA) ligand to improve blood circulation and tumor selectivity and limit the drug systemic side-effects. Nanoparticles presented adequate size and size distribution for intravenous injection and were stable for at least 6 months. Additionally, their hemocompatibility was demonstrated. Moreover, functionalized nanoparticles were able to improve the anti-cancer effect of the free drug, as assessed by the values of IC50 and the apoptotic effects in MCF-7 cells. Moreover, an enhanced cellular internalization of the functionalized SLN was demonstrated by confocal microscopy and flow cytometry studies. Finally, the cellular uptake of the SLN was found to occur via macropinocytosis and clathrin-mediated endocytosis, suggesting the involvement of (folate receptor) (FR)-mediated endocytosis. Overall these findings highlight that the developed SLN are efficient nanocarriers for the selective delivery of Mito to breast cancer cells.

The Magnetic Properties of Fe/Cu Multilayered Nanowires: The Role of the Number of Fe Layers and Their Thickness.

Multi-segmented bilayered Fe/Cu nanowires have been fabricated through the electrodeposition in porous anodic alumina membranes. We have assessed, with the support of micromagnetic simulations, the dependence of fabricated nanostructures' magnetic properties either on the number of Fe/Cu bilayers or on the length of the magnetic layers, by fixing both the nonmagnetic segment length and the wire diameter. The magnetic reversal, in the segmented Fe nanowires (NWs) with a 300 nm length, occurs through the nucleation and propagation of a vortex domain wall (V-DW) from the extremities of each segment. By increasing the number of bilayers, the coercive field progressively increases due to the small magnetostatic coupling between Fe segments, but the coercivity found in an Fe continuous nanowire is not reached, since the interactions between layers is limited by the Cu separation. On the other hand, Fe segments 30 nm in length have exhibited a vortex configuration, with around 60% of the magnetization pointing parallel to the wires' long axis, which is equivalent to an isolated Fe nanodisc. By increasing the Fe segment length, a magnetic reversal occurred through the nucleation and propagation of a V-DW from the extremities of each segment, similar to what happens in a long cylindrical Fe nanowire. The particular case of the Fe/Cu bilayered nanowires with Fe segments 20 nm in length revealed a magnetization oriented in opposite directions, forming a synthetic antiferromagnetic system with coercivity and remanence values close to zero.

Mitoxantrone-loaded lipid nanoparticles for breast cancer therapy - Quality-by-design approach and efficacy assessment in 2D and 3D in vitro cancer models.

Breast cancer is the leading cause of cancer-related deaths among women worldwide. The conventional chemotherapeutic regimens used in the treatment of this disease often lead to severe side-effects and reduced efficacy. In this study, a novel drug delivery system for the chemotherapeutic drug mitoxantrone (Mito) was developed using solid lipid nanoparticles (SLN). The production of the SLN was carried out using an organic-solvent-free, low-cost method and optimized using a Box-Behnken design. SLN presented adequate size for cancer-related applications, more than 90% of EE% and remained stable for at least 6 months. A much higher drug release was obtained at acidic pH (mimicking the endosomal compartment) than plasmatic pH, highlighting the potential of the nanosystem for tumor drug delivery. Additionally, SLN were non-hemolytic and cytocompatible, even at high concentrations of lipid. A significantly higher anti-cancer efficacy was obtained for Mito-loaded SLN comparing to the free drug at different concentrations in MCF-7 2D models. Finally, the nanoformulation was evaluated in heterotypic breast cancer spheroids showing capacity to penetrate the tridimensional structure and ability to induce a high anti-tumoral effect, similarly to the free drug. Overall, these results support that the developed SLN are effective Mito nanocarriers for the treatment of breast cancer.

Gold nanostructures as mediators of hyperthermia therapies in breast cancer.

Breast cancer is the leading cause of cancer-related deaths among women. Due to the limitations of the current therapeutics, new treatment options are needed. Hyperthermia is a promising approach to improve breast cancer therapy, particularly when combined with chemo and radiotherapy. This area has gained more attention following association with nanotechnology, with the emergence of modalities, such as photothermal therapy (PTT). PTT is a simple, minimally invasive technique that requires a near infrared (NIR) light source and a PTT agent. Gold nanostructures are excellent PTT agents as they offer biocompatibility, versatility, high photothermal conversion efficiency, imaging contrast and an easily-modified surface. In this review, we describe the molecular basis and the current clinical aspects of hyperthermia-based therapies. The emergent area of nanoparticle-induced hyperthermia will be explored, in particular gold nanostructure-mediated PTT, focusing on recent preclinical studies for breast cancer management.

Magnetic reversal modes in cylindrical nanostructures: from disks to wires.

Cylindrical magnetic nanowires are key elements of fast-recording and high-density 3D-storage devices. The accurate tuning of the magnetization processes at the nanoscale is crucial for the development of future nano-devices. Here, we analyzed the magnetization of Ni nanostructures with 15-100 nm in diameter and 12-230 nm in length and compared our results with experimental data for periodic arrays. Our modelling led to a phase diagram of the reversal modes where the presence of a critical diameter (d ≈ 30 nm) triggered the type of domain wall (DW) formed (transverse or vortex); while a critical length (L ≈ 100 nm) determined the number of DWs nucleated. Moreover, vortex-DWs originated from 3D skyrmion tubes, reported as one of the best configurations for storage devices. By increasing the diameter and aspect-ratio of nanowires with L > 100 nm, three reversal modes were observed: simultaneous propagation of two vortex-DWs; propagation of one vortex-DW; or spiral rotation of both DWs through "corkscrew" mechanism. Only for very low aspect-ratios (nanodisks), no skyrmion tubes were observed and reversal occurred by spiral rotation of one vortex-DW. The broad range of nanostructures studied allowed the creation of a complete phase diagram, highly important for future choice of nanoscaled dimensions in the development of novel nano-devices.

Tailoring the Anodic Hafnium Oxide Morphology Using Different Organic Solvent Electrolytes.

Highly ordered anodic hafnium oxide (AHO) nanoporous or nanotubes were synthesized by electrochemical anodization of Hf foils. The growth of self-ordered AHO was investigated by optimizing a key electrochemical anodization parameter, the solvent-based electrolyte using: Ethylene glycol, dimethyl sulfoxide, formamide and N-methylformamide organic solvents. The electrolyte solvent is here shown to highly affect the morphological properties of the AHO, namely the self-ordering, growth rate and length. As a result, AHO nanoporous and nanotubes arrays were obtained, as well as other different shapes and morphologies, such as nanoneedles, nanoflakes and nanowires-agglomerations. The intrinsic chemical-physical properties of the electrolyte solvents (solvent type, dielectric constant and viscosity) are at the base of the properties that mainly affect the AHO morphology shape, growth rate, final thickness and porosity, for the same anodization voltage and time. We found that the interplay between the dielectric and viscosity constants of the solvent electrolyte is able to tailor the anodic oxide growth from continuous-to-nanoporous-to-nanotubes.

Double-walled iron oxide nanotubes via selective chemical etching and Kirkendall process.

Double-walled oxide nanotube structures are interesting for a wide range of applications, from photocatalysis to drug delivery. In this work, a progressive oxidation method to fabricate double-walled nanotube structures is reported in detail. The approach is based on the electrodeposition of metallic iron nanowires, in porous alumina templates, followed by a selective chemical etching, nanoscale Kirkendall effect, a fast oxidation and out-diffusion of the metallic core structure during thermal annealing. To validate the formation mechanism of such core-shell structure, chemical composition and atomic structure were assessed. The resulting hematite nanotubes have a high degree of uniformity, along several microns, and a nanoscopic double-walled structure.

EGCG intestinal absorption and oral bioavailability enhancement using folic acid-functionalized nanostructured lipid carriers.

This work aimed to develop folic acid-functionalized nanostructured lipid carriers (NLC) loading epigallocatechin-3-gallate (EGCG) to increase its oral bioavailability. An active targeting strategy was used and these nanoparticles (NPs) were fully characterized. The NP's effect on Caco-2 cell viability was evaluated and the apparent permeability (Papp) on a Caco-2 cell monolayer was determined. The results demonstrated that the developed NPs exhibited adequate physicochemical characteristics for oral administration and were found to be biocompatible with epithelial Caco-2 cells. Further, folic acid-functionalized EGCG-loaded NLC significantly increased EGCG transport across the intestinal barrier, promoting a 1.8- fold increase in its apparent permeability (Papp). Taken together, these results support that the developed NLC can be used as a promising carrier for safer and efficient management of several diseases since the pharmacokinetic (PK) properties of EGCG were improved with this nanomedicine-based strategy.

The Role of Cu Length on the Magnetic Behaviour of Fe/Cu Multi-Segmented Nanowires.

A set of multi-segmented Fe/Cu nanowires were synthesized by a two-step anodization process of aluminum substrates and a pulsed electrodeposition technique using a single bath. While both Fe segment length and diameter were kept constant to (30 ± 7) and (45 ± 5) nm, respectively, Cu length was varied between (15 ± 5) and (120 ± 10) nm. The influence of the non-magnetic layer thickness variation on the nanowire magnetic properties was investigated through first-order reversal curve (FORC) measurements and micromagnetic simulations. Our analysis confirmed that, in the multi-segmented Fe/Cu nanowires with shorter Cu segments, the dipolar coupling between Fe segments controls the nanowire magnetic behavior, and its performance is like that of a homogenous Fe nanowire array of similar dimensions. On the other hand, multi-segmented Fe/Cu nanowires with larger Cu segments act like a collection of non-interacting magnetic entities (along the nanowire axis), and their global behavior is mainly controlled by the neighbor-to-neighbor nanodisc dipolar interactions.

Ferromagnetic sorbents based on nickel nanowires for efficient uptake of mercury from water.

This work reports the preparation of ferro-magnetic nickel nanowires (NiNW) coated with dithiocarbamate-functionalized siliceous shells and its application for the uptake of aqueous Hg(II) ions by magnetic separation. NiNW with an average diameter and length of 35 nm and 5 µm, respectively, were firstly prepared by Ni electrodeposition in an anodic aluminum oxide template. The NiNW surfaces were then coated with siliceous shells containing dithiocarbamate groups via a one-step procedure consisting in the alkaline hydrolytic co-condensation of tetraethoxysilane (TEOS) and a siloxydithiocarbamate precursor (SiDTC). A small amount of these new nanoadsorbents (2.5 mg·L(-1)) removed 99.8% of mercury ions from aqueous solutions with concentration 50 µg·L(-1) and in less than 24 h of contact time. This outstanding removal ability is attributed to the high affinity of the sulfur donor ligands to Hg(II) species combined with the high surface area-to-volume ratio of the NiNW.

Functionalization of nickel nanowires with a fluorophore aiming at new probes for multimodal bioanalysis.

This work reports research on the development of bimodal magnetic and fluorescent 1D nanoprobes. First, ferromagnetic nickel nanowires (NiNW) have been prepared by Ni electrodeposition in an anodic aluminum oxide (AAO) template. The highly ordered self-assembled AAO nanoporous templates were fabricated using a two-step anodization method of aluminum foil. The surface of the NiNW were then modified with polyethyleneimine (PEI) which was previously labeled with an organic dye (fluorescein isothiocyanate: FITC) via covalent bonding. The ensuing functionalized NiNW exhibited the characteristic green fluorescence of FITC and could be magnetically separated from aqueous solutions by using a NdFeB magnet. Finally, the interest of these bimodal NiNW as nanoprobes for in vitro cell separation and biolabeling was preliminary assessed in a proof of principle experiment that involved the attachment of biofunctionalized NiNW to blood cells.

Distinguishing nanowire and nanotube formation by the deposition current transients.

High aspect ratio Ni nanowires (NWs) and nanotubes (NTs) were electrodeposited inside ordered arrays of self-assembled pores (approximately 50 nm in diameter and approximately 50 µm in length) in anodic alumina templates by a potentiostatic method. The current transients monitored during each process allowed us to distinguish between NW and NT formation. The depositions were long enough for the deposited metal to reach the top of the template and form a continuous Ni film. The overfilling process was found to occur in two steps when depositing NWs and in a single step in the case of NTs. A comparative study of the morphological, structural, and magnetic properties of the Ni NWs and NTs was performed using scanning electron microscopy, X-ray diffraction, and vibrating sample magnetometry, respectively.

A versatile synthesis method of dendrites-free segmented nanowires with a precise size control.

We report an innovative strategy to obtain cylindrical nanowires combining well established and low-cost bottom-up methods such as template-assisted nanowires synthesis and electrodeposition process. This approach allows the growth of single-layer or multi-segmented nanowires with precise control over their length (from few nanometers to several micrometers). The employed techniques give rise to branched pores at the bottom of the templates and consequently dendrites at the end of the nanowires. With our method, these undesired features are easily removed from the nanowires by a selective chemical etching. This is crucial for magnetic characterizations where such non-homogeneous branches may introduce undesired features into the final magnetic response. The obtained structures show extremely narrow distributions in diameter and length, improved robustness and high-yield, making this versatile approach strongly compatible with large scale production at an industrial level. Finally, we show the possibility to tune accurately the size of the nanostructures and consequently provide an easy control over the magnetic properties of these nanostructures.

pH sensitive silica nanotubes as rationally designed vehicles for NSAIDs delivery.

A novel pH-sensitive drug delivery system based on functionalized silica nanotubes was developed for the incorporation of non-steroidal anti-inflammatory drugs (NSAIDs), aimed at a tailored drug release in acidic conditions characteristic of inflamed tissues. Silica nanotubes (SNTs) were synthesized by a nanoporous alumina template assisted sol-gel method. Inner surfaces were physically and chemically modified to improve both the functionalization and subsequent incorporation of the drug. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and transmission electron microscopy (TEM) were used to characterize the designed nanocarriers and their functionalization. To achieve the highest degree of functionalization, three types of aminosilanes were tested and calcination conditions were optimized. APTES was shown to be the most effective aminosilane regarding the functionalization of the SNTs' inner surface and an adequate calcination temperature (220°C) was found to attain mechanical stability without compromising functionalization efficiency. Finally, the incorporation of naproxen into the nanotubes was accessed by fluorescence measurements and drug release studies were performed, revealing that the electrostatic linkage ensures effective release of the drug in the acidic pH typical of inflamed cells, while maintaining the SNT-drug conjugates stable at the typical bloodstream pH.

Size and surface effects on the magnetic properties of NiO nanoparticles.

NiO nanoparticles (NPs) were prepared by a sol-gel process using the citrate route. The sol-gel parameters were tuned to obtain samples with different average particle sizes, ranging from 12 to 70 nm. Magnetic characterization revealed an increase in the blocking temperature with the diameter of the NPs and an increase in the effective magnetic anisotropy (K(eff)) with decreasing particle size. The magnetic moment per particle was calculated for all samples using the susceptibility value at T = 300 K. The number of uncompensated spins per NP was found to be proportional to n (n(S)≡ total number of spins), indicating that they are randomly distributed on the NP surface. For small diameters (<30 nm) the surface anisotropy constant was estimated, using, for NiO NPs, a recent model describing the evolution of K(eff) with particle size. Hysteretic loops performed at low temperatures after field cooling displayed loop shifts (∼6.5 kOe in the field axis and ∼0.18 emu g(-1) vertically), coercive field enhancement (H(C)≈ 4.8 kOe) and training effects for the smaller NPs. The sample with NPs of larger diameters presented magnetic properties close to those of bulk NiO.