Clickable iron oxide NPs based on catechol derived ligands: synthesis and characterization.

Clickable magnetic nanoparticles have attracted great attention as potential nanoplatforms for biomedical applications because of the high functionalization efficiency of their surfaces with biomolecules, which facilitates their bio-compatibilization. However, the design and synthesis of clickable NPs is still challenging because of the complexity of the chemistry on the magnetic NP surface, thus robust methods that improve the ligand synthesis and the transfer of magnetic NPs in physiological media being in high-demand. In this work, we developed a versatile and enhanced synthetic route to fabricate potentially clickable IONPs of interest in nanomedicine. Catechol anchor ligands with different stereo-electronic features were synthetized from a hetero bi-functional PEG spacer backbone. The resulting catechol ligands transferred in good yields and high stability to magnetic NPs by an improved energetic ligand exchange method that combines sonication and high temperature. The azido functionalized IONPs exhibited excellent characteristics as T2 MRI contrast agents with low cytotoxicity, making these clickable magnetic NPs promising precursors for nanomedicines.

Multifunctional Magnetic and Upconverting Nanobeads as Dual Modal Imaging Tools.

We report the fabrication of aqueous multimodal imaging nanocomposites based on superparamagnetic nanoparticles (MNPs) and two different sizes of photoluminescent upconverting nanoparticles (UCNPs). The controlled and simultaneous incorporation of both types of nanoparticles (NPs) was obtained by controlling the solvent composition and the addition rate of the destabilizing solvent. The magnetic properties of the MNPs remained unaltered after their encapsulation into the polymeric beads as shown by the T2 relaxivity measurements. The UCNPs maintain photoluminescent properties even when embedded with the MNPs into the polymer bead. Moreover, the light emitted by the magnetic and upconverting nanobeads (MUCNBs) under NIR excitation (λexc = 980 nm) was clearly observed through different thicknesses of agarose gel or through a mouse skin layer. The comparison with magnetic and luminescent nanobeads based on red-emitting quantum dots (QDs) demonstrated that while the QD-based beads show significant autofluorescence background from the skin, the signal obtained by the MUCNBs allows a decrease in this background. In summary, these results indicate that MUCNBs are good magnetic and optical probes for in vivo multimodal imaging sensors.

Manganese-Based Nanogels as pH Switches for Magnetic Resonance Imaging.

pH-responsive nanogels (NGs) were used to prepare high-efficiency magnetic resonance imaging dual T1/T2 contrast agents for pH imaging. The polymeric NG matrix acts as a strong polydentate ligand that chelates the Mn cations in its inner cavity generating a hybrid NG structure. The Mn chelate NG is sensitive to pH changes, such that protonation induces a change of the polymer hydration state and consequent swelling. The swollen nanogel allows water molecules to enter and interact with the Mn chelate, shortening the relaxation time (switch ON) and giving rise to positive or negative contrast on T1- or T2-weighted magnetic resonance images.

Optimization of iron oxide nanoparticles for MRI-guided magnetic hyperthermia tumor therapy: reassessing the role of shape in their magnetocaloric effect.

Superparamagnetic iron oxide nanoparticles have hogged the limelight in different fields of nanotechnology. Surprisingly, notwithstanding the prominent role played as agents in magnetic hyperthermia treatments, the effects of nanoparticle size and shape on the magnetic hyperthermia performance have not been entirely elucidated yet. Here, spherical or cubical magnetic nanoparticles synthesized by a thermal decomposition method with the same magnetic and hyperthermia properties are evaluated. Interestingly, spherical nanoparticles displayed significantly higher magnetic relaxivity than cubic nanoparticles; however, comparable differences were not observed in specific absorption rate (SAR), pointing out the need for additional research to better understand the connection between these two parameters. Additionally, the as-synthetized spherical nanoparticles showed negligible cytotoxicity and, therefore, were tested in vivo in tumor-bearing mice. Following intratumoral administration of these spherical nanoparticles and a single exposure to alternating magnetic fields (AMF) closely mimicking clinical conditions, a significant delay in tumor growth was observed. Although further in vivo experiments are warranted to optimize the magnetic hyperthermia conditions, our findings support the great potential of these nanoparticles as magnetic hyperthermia mediators for tumor therapy.

P/S ligands derived from carbohydrates in Rh-catalyzed hydrosilylation of ketones.

Reported is the synthesis of a number of diastereomerically pure cationic Rh(I)-complexes I starting from phosphinite thioglycosides. These complexes were used in the asymmetric hydrosilylation of prochiral ketones. The reactivity and enantioselectivity of the reaction was shown to be dependent on the pyranose ring, the substituent at the sulfur atom, the hydroxylic protective groups and most significantly on the alkene co-ligand.

"Nanohybrids" based on pH-responsive hydrogels and inorganic nanoparticles for drug delivery and sensor applications.

Allyl-PEG capped inorganic NPs, including magnetic iron oxide (IONPs), fluorescent CdSe/ZnS quantum dots (QDs), and metallic gold (AuNPs of 5 and 10 nm) both individually and in combination, were covalently attached to pH-responsive poly(2-vinylpyridine-co-divinylbenzene) nanogels via a facile and robust one-step surfactant-free emulsion polymerization procedure. Control of the NPs associated to the nanogels was achieved by the late injection of the NPs to the polymerization solution at a stage when just polymeric radicals were present. Remarkably, by varying the total amount of NPs injected, the swelling behavior could be affected. Furthermore, the magnetic response as well as the optical features of the nanogels containing either IONPs or QDs could be modified. In addition, a radical quenching in case of gold nanoparticles was observed, thus affecting the final nanogel geometry.

Biologically Relevant Micellar Nanocarrier Systems for Drug Encapsulation and Functionalization of Metallic Nanoparticles.

The preparation of new and functional nanostructures has received more attention in the scientific community in the past decade due to their wide application versatility. Among these nanostructures, micelles appear to be one of the most interesting supramolecular organizations for biomedical applications because of their ease of synthesis and reproducibility and their biocompatibility since they present an organization similar to the cell membrane. In this work, we developed micellar nanocarrier systems from surfactant molecules derived from oleic acid and tetraethylene glycol that were able to encapsulate and in vitro release the drug dexamethasone. In addition, the designed micelle precursors were able to functionalize metallic NPs, such as gold NPs and iron oxide NPs, resulting in monodispersed hybrid nanomaterials with high stability in aqueous media. Therefore, a new triazole-derived micelle precursor was developed as a versatile encapsulation system, opening the way for the preparation of new micellar nanocarrier platforms for drug delivery, magnetic resonance imaging, or computed tomography contrast agents for therapeutic and diagnostic applications.

Passive targeting of high-grade gliomas via the EPR effect: a closed path for metallic nanoparticles?

Passive tumor targeting via the enhanced permeability and retention (EPR) effect has long been considered the most effective mechanism for the accumulation of nanoparticles inside solid tumors. However, several studies have demonstrated that the EPR effect is largely dependent on the tumor type and location. Particularly complex is the situation in brain tumors, where the presence of the blood-brain tumor barrier (BBTB) adds an extra limiting factor in reaching the tumor interstitium. However, it remains unclear whether these restraints imposed by the BBTB prevent the EPR effect from acting as an efficient tumor targeting mechanism for metallic nanoparticles. In this work, we have studied the EPR effect of metallic magnetic nanoparticles (MMNPs) in a glioblastoma (GBM) model by parametric MRI. Our results showed that only MMNPs ≤50 nm could reach the tumor interstitium, whereas larger MMNPs were unable to cross the BBTB. Furthermore, even for MMNPs around 30-50 nm, the amount of them found within the tumor was scarce and restricted to the vicinity of large tumor vessels, indicating that the BBTB strongly limits the passive accumulation of metallic nanoparticles in brain tumors. Therefore, active targeting becomes the most reasonable strategy to target metallic nanoparticles to GBMs.

Carbohydrate-Based NK1R Antagonists with Broad-Spectrum Anticancer Activity.

NK1R antagonists, investigated for the treatment of several pathologies, have shown encouraging results in the treatment of several cancers. In the present study, we report on the synthesis of carbohydrate-based NK1R antagonists and their evaluation as anticancer agents against a wide range of cancer cells. All of the prepared compounds, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity, comparable to Cisplatin. This strategy has allowed us to identify the galactosyl derivative 14α, as an interesting hit exhibiting significant NK1R antagonist effect (kinact 0.209 ± 0.103 µM) and high binding affinity for NK1R (IC50 = 50.4 nM, Ki = 22.4 nM by measuring the displacement of [125I] SP from NK1R). Interestingly, this galactosyl derivative has shown marked selective cytotoxic activity against 12 different types of cancer cell lines.

Fe3O4-Au Core-Shell Nanoparticles as a Multimodal Platform for In Vivo Imaging and Focused Photothermal Therapy.

In this study, we report the synthesis of gold-coated iron oxide nanoparticles capped with polyvinylpyrrolidone (Fe@Au NPs). The as-synthesized nanoparticles (NPs) exhibited good stability in aqueous media and excellent features as contrast agents (CA) for both magnetic resonance imaging (MRI) and X-ray computed tomography (CT). Additionally, due to the presence of the local surface plasmon resonances of gold, the NPs showed exploitable "light-to-heat" conversion ability in the near-infrared (NIR) region, a key attribute for effective photothermal therapies (PTT). In vitro experiments revealed biocompatibility as well as excellent efficiency in killing glioblastoma cells via PTT. The in vivo nontoxicity of the NPs was demonstrated using zebrafish embryos as an intermediate step between cells and rodent models. To warrant that an effective therapeutic dose was achieved inside the tumor, both intratumoral and intravenous routes were screened in rodent models by MRI and CT. The pharmacokinetics and biodistribution confirmed the multimodal imaging CA capabilities of the Fe@AuNPs and revealed constraints of the intravenous route for tumor targeting, dictating intratumoral administration for therapeutic applications. Finally, Fe@Au NPs were successfully used for an in vivo proof of concept of imaging-guided focused PTT against glioblastoma multiforme in a mouse model.

Comprehensive Toxicity Assessment of PEGylated Magnetic Nanoparticles for in vivo applications.

Magnetic nanoparticles (MNPs) represent one of the greatest promises for the development of a new generation of diagnostic agents for magnetic resonance imaging, with improved specificity and safety. Indeed, during the last decade the number of studies published in this field has grown exponentially. However, the clinical translation achieved so far has been very limited. This situation is likely related to the fact that most studies are focused on the in vitro characterization of these new nanomaterials, and very few provide an exhaustive in vivo characterization, where key aspects, such as pharmacokinetics, bioavailability, and, most importantly, toxicity, are properly evaluated. In this work, we propose a protocol for the comprehensive assessment of the toxicity of MNPs, based on the use of zebrafish embryos as an intermediate screening step between cell culture assays and studies in rodents. MNPs with different cores, ferrite and manganese ferrite oxide, and sizes between 3 and 20 nm, were evaluated. Cell viability at a concentration of 50 µg/mL of PEGylated MNPs was above 90 % in all cases. However, the exposure of zebrafish embryos to manganese based MNPs at concentrations above 100 µg/mL showed a low survival rate (<50 %). In contrast, no mortality (survival rate ∼100 %) and normal hatching rate were obtained for the iron oxide MNPs. Based on these results, together with the physicochemical and magnetic properties (r2 = 153.6 mM-1·s-1), the PEGylated 20 nm cubic shape iron oxide MNPs were selected and tested in mice, showing very good MRI contrast and, as expected, absence of toxicity.

Synthesis and Characterization of Elongated-Shaped Silver Nanoparticles as a Biocompatible Anisotropic SERS Probe for Intracellular Imaging: Theoretical Modeling and Experimental Verification.

Progress in the field of biocompatible SERS nanoparticles has promising prospects for biomedical applications. In this work, we have developed a biocompatible Raman probe by combining anisotropic silver nanoparticles with the dye rhodamine 6G followed by subsequent coating with bovine serum albumin. This nanosystem presents strong SERS capabilities in the near infrared (NIR) with a very high (2.7 × 107) analytical enhancement factor. Theoretical calculations reveal the effects of the electromagnetic and chemical mechanisms in the observed SERS effect for this nanosystem. Finite element method (FEM) calculations showed a considerable near field enhancement in NIR. Using density functional quantum chemical calculations, the chemical enhancement mechanism of rhodamine 6G by interaction with the nanoparticles was probed, allowing us to calculate spectra that closely reproduce the experimental results. The nanosystem was tested in cell culture experiments, showing cell internalization and also proving to be completely biocompatible, as no cell death was observed. Using a NIR laser, SERS signals could be detected even from inside cells, proving the applicability of this nanosystem as a biocompatible SERS probe.

Shedding light on zwitterionic magnetic nanoparticles: limitations for in vivo applications.

Over the last few years several studies have dealt with the importance of the surface charge of nanoparticles in prolonging their blood circulation and minimizing their interaction with plasma proteins. These investigations claimed that zwitterionic nanoparticles exhibited a minimal macrophage response and long blood circulation times compared to nanoparticles with other surface charges. These differences in their in vivo behavior are mainly attributed to the interaction of nanoparticles with plasma proteins. Interestingly, most of these studies considered the total surface charge, instead of the outermost layer of the nanomaterial, as being mainly responsible for these undesirable interactions. However, the first contact with plasma proteins is most likely due to the outermost layer on the nanomaterials. Therefore, here we report a detailed study on the effect of the outermost surface charge of magnetic nanoparticles with regard to biodistribution, pharmacokinetics and bioavailability. Magnetic nanoparticles, coated with PEG chains functionalized with neutral, positive or zwitterionic groups, were intravenously injected into mice, followed in vivo by MRI and then quantified by ICP-MS in blood and the main organs. We found that neutral nanoparticles exhibited long blood circulation times, very good stealth properties and the highest bioavailability, whereas zwitterionic nanoparticles were readily recognized by the mononuclear phagocyte system and avidly taken up by the liver. Also, zwitterionic nanoparticles showed high non-specific cell internalization, whereas neutral nanoparticles showed the lowest cellular uptake, indicating that they require active transport to cross the plasma membrane, which is the desirable situation for therapeutic vehicles with low side effects. Thus, neutral nanoparticles exhibit very favorable characteristics for in vivo applications, whereas zwitterionic nanoparticles show important limitations.

Long-circulating PEGylated manganese ferrite nanoparticles for MRI-based molecular imaging.

Magnetic resonance based molecular imaging has emerged as a very promising technique for early detection and treatment of a wide variety of diseases, including cancer, neurodegenerative disorders, and vascular diseases. The limited sensitivity and specificity of conventional MRI are being overcome by the development of a new generation of contrast agents, using nanotechnology approaches, with improved magnetic and biological properties. In particular, for molecular imaging, high specificity, high sensitivity, and long blood circulation times are required. Furthermore, the lack of toxicity and immunogenicity together with low-cost scalable production are also necessary to get them into the clinics. In this work, we describe a facile, robust and cost-effective ligand-exchange method to synthesize dual T1 and T2 MRI contrast agents with long circulation times. These contrast agents are based on manganese ferrite nanoparticles (MNPs) between 6 and 14 nm in size covered by a 3 kDa polyethylene glycol (PEG) shell that leads to a great stability in aqueous media with high crystallinity and magnetization values, thus retaining the magnetic properties of the uncovered MNPs. Moreover, the PEGylated MNPs have shown different relaxivities depending on their size and the magnetic field applied. Thus, the 6 nm PEGylated MNPs are characterized by a low r2/r1 ratio of 4.9 at 1.5 T, hence resulting in good dual T1 and T2 contrast agents under low magnetic fields, whereas the 14 nm MNPs behave as excellent T2 contrast agents under high magnetic fields (r2 = 335.6 mM(-1) s(-1)). The polymer core shell of the PEGylated MNPs minimizes their cytotoxicity, and allows long blood circulation times. This combination of cellular compatibility and excellent T2 and r2/r1 values under low magnetic fields, together with long circulation times, make these nanomaterials very promising contrast agents for molecular imaging.

Ligand effect on the size, valence state and red/near infrared photoluminescence of bidentate thiol gold nanoclusters.

Synthesis and characterization of gold nanoclusters (Au NCs) stabilized by a zwitterion ligand (Zw) at different Au : Zw ratios are demonstrated. Au NCs exhibit photoluminescence (PL) emission which is tunable from the near infrared (805 nm) to the red spectral window (640 nm) and strongly influenced by the ligand shell size. Optical and chemical investigations suggest the presence of gold polymeric species and large nanoclusters for a molar ratio of Au : Zw = 1 : 1. For 1 : 5 < Au : Zw < 1 : 1, Zw induces etching of the large clusters and the formation of a monolayer of the bidentate ligands on the Au NCs (cluster size ∼7 to 10 kDa) accompanied by red PL emission at λ = 710 nm. A second organic layer starts to form for larger Zw fractions (Au : Zw < 1 : 5) as a result of electrostatic and covalent interactions of the zwitterion leading to an enhancement and a blue-shift of the PL emission. The effect of temperature and pH on the optical properties of gold clusters is strongly dependent on the ligand shell and demonstrates the importance of defining gold nanoclusters as supramolecular assemblies with a complex environment.

Glyconanosomes: disk-shaped nanomaterials for the water solubilization and delivery of hydrophobic molecules.

Herein, we describe the first report on a new class of disk-shaped and quite monodisperse water-soluble nanomaterials that we named glyconanosomes (GNS). GNSs were obtained by sliding out the cylindrical structures formed upon self-organization and photopolymerization of glycolipid 1 on single-walled carbon nanotube (SWCNT) sidewalls. GNSs present a sheltered hydrophobic inner cavity formed by the carbonated tails, surrounded by PEG and lactose moieties. The amphiphilic character of GNSs allows the water solubility of insoluble hydrophobic cargos such as a perylene-bisimide derivative, [60]fullerene, or the anti-carcinogenic drug camptothecin (CPT). GNS/C60 inclusion complexes are able to establish specific interactions between peanut agglutinin (PNA) lectin and the lactose moiety surrounding the complexes, while CPT solubilized by GNS shows higher cytotoxicity toward MCF7-type breast cancer cells than CPT alone. Thus, GNS represents an attractive extension of nanoparticle-based drug delivery systems.

Controlled release of doxorubicin loaded within magnetic thermo-responsive nanocarriers under magnetic and thermal actuation in a microfluidic channel.

We report a procedure to grow thermo-responsive polymer shells at the surface of magnetic nanocarriers made of multiple iron oxide superparamagnetic nanoparticles embedded in poly(maleic anhydride-alt-1-ocatadecene) polymer nanobeads. Depending on the comonomers and on their relative composition, tunable phase transition temperatures in the range between 26 and 47 °C under physiological conditions could be achieved. Using a suitable microfluidic platform combining magnetic nanostructures and channels mimicking capillaries of the circulatory system, we demonstrate that thermo-responsive nanobeads are suitable for localized drug delivery with combined thermal and magnetic activation. Below the critical temperature nanobeads are stable in suspension, retain their cargo, and cannot be easily trapped by magnetic fields. Increasing the temperature above the critical temperature causes the aggregation of nanobeads, forming clusters with a magnetic moment high enough to permit their capture by suitable magnetic gradients in close proximity to the targeted zone. At the same time the polymer swelling activates drug release, with characteristic times on the order of one hour for flow rates of the same order as those of blood in capillaries.