Efficient Strategy to Synthesize Tunable pH-Responsive Hybrid Micelles Based on Iron Oxide and Gold Nanoparticles.

The preparation of multifunctional nanomaterials based on inorganic nanoparticles with organic materials has emerged as a promising strategy for the development of new nanomedicines for in vitro and in vivo biomedical applications. Here, we synthesized pH-responsive hybrid inorganic micelles by combining a novel pH-responsive amphiphilic molecule with hydrophobic payloads. This amphiphile was synthesized in a one-pot reaction and self-assembled readily into micelles under acidic pH conditions. In the presence of hydrophobic NP payloads such as AuNPs or IONPs, the amphiphile self-organized around them through hydrophobic interactions, resulting in the formation of colloidally stable hybrid micelles. The size of the hydrophobic NPs determined the pH-response of the inorganic hybrid micelles, which is tuned from pH 7 to 11 for our pH-responsive amphiphilic molecule. This achievement represents a novel approach for the synthesis of tunable pH-responsive hybrid micelles based on inorganic NPs for biomedical imaging, hyperthermia treatment, and also drug delivery nanosystems.

Biological evaluation of carbohydrate-based aprepitant analogs for neuroblastoma treatment.

Different studies using Aprepitant, a NK1R antagonist currently used as a clinical drug for treating chemotherapy-related nausea and vomiting, have demonstrated that pharmacological inhibition of NK1R effectively reduces the growth of several tumor types such as neuroblastoma (NB). In a previous work, we demonstrated that a series of carbohydrate-based Aprepitant analogs, 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. In this new study, we explore the selective cytotoxic effects of these derivatives for the treatment of NB. Furthermore, we describe the design and stereoselective synthesis of a new generation of d-glucose derivatives as Aprepitant analogs, supported by docking studies. This approach showed that most of our carbohydrate-based analogs are significantly more selective than Aprepitant. The galactosyl derivative 2α, has demonstrated a marked in vitro selective cytotoxic activity against NB, with IC50 values in the same range as those of Aprepitant and its prodrug Fosaprepitant. Interestingly, the derivative 2α has shown similar apoptotic effect to that of Aprepitant. Moreover, we can select the glucosyl amino derivative 10α as an interesting hit exhibiting higher in vitro cytotoxic activity against NB than Aprepitant, being 1.2 times more selective.

Scaling Up Magnetic Nanobead Synthesis with Improved Stability for Biomedical Applications.

The growing interest in multifunctional nano-objects based on polymers and magnetic nanoparticles for biomedical applications motivated us to develop a scale-up protocol to increase the yield of polymeric magnetic nanobeads while aiming at keeping the structural features at optimal conditions. The protocol was applied to two different types of magnetic ferrite nanoparticles: the Mn-ferrite selected for their properties as contrast agents in magnetic resonance imaging and iron oxide nanostar shaped nanoparticles chosen for their heat performance in magnetic hyperthermia. At the same time, some experiments on surface functionalization of nanobeads with amino modified polyethyelene glycol (PEG) molecules have provided further insight into the formation mechanism of magnetic nanobeads and the need to cross-link the polymer shell to improve the stability of the beads, making them more suitable for further manipulation and use. The present work summarizes the most important parameters required to be controlled for the upscaling of nanobead synthesis in a bench protocol and proposes an alternative cross-linking strategy based on prefunctionalization of the polymer prior to the nanobead formation as a key parameter to improve the nanobead structural stability in solutions at different pHs and during surface functionalization.

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

Correction for 'Clickable iron oxide NPs based on catechol derived ligands: synthesis and characterization' by Esther Pozo-Torres et al., Soft Matter, 2020, 16, 3257-3266, DOI: 10.1039/C9SM02512J.

Magnetic Nanoparticles as MRI Contrast Agents.

Iron oxide nanoparticles (IONPs) have emerged as a promising alternative to conventional contrast agents (CAs) for magnetic resonance imaging (MRI). They have been extensively investigated as CAs due to their high biocompatibility and excellent magnetic properties. Furthermore, the ease of functionalization of their surfaces with different types of ligands (antibodies, peptides, sugars, etc.) opens up the possibility of carrying out molecular MRI. Thus, IONPs functionalized with epithelial growth factor receptor antibodies, short peptides, like RGD, or aptamers, among others, have been proposed for the diagnosis of various types of cancer, including breast, stomach, colon, kidney, liver or brain cancer. In addition to cancer diagnosis, different types of IONPs have been developed for other applications, such as the detection of brain inflammation or the early diagnosis of thrombosis. This review addresses key aspects in the development of IONPs for MRI applications, namely, synthesis of the inorganic core, functionalization processes to make IONPs biocompatible and also to target them to specific tissues or cells, and finally in vivo studies in animal models, with special emphasis on tumor models.

Bi-Magnetic Core-Shell CoFe2O4@MnFe2O4 Nanoparticles for In Vivo Theranostics.

In this work, we report the synthesis and characterization of three magnetic nanosystems, CoFe2O4, CoFe2O4@ZnFe2O4, and CoFe2O4@MnFe2O4, which were developed as potential theranostic agents for magnetic hyperthermia and magnetic resonance imaging (MRI). These nanosystems have been thoroughly characterized by X-ray Diffraction (XRD), Transmission Electron Miscroscopy (TEM), Dark Field-TEM (DF-TEM), Vibrating Sample Magnetometry (VSM), and inductive heating, in order to elucidate their structure, morphology, and magnetic properties. The bi-magnetic CoFe2O4@ZnFe2O4 and CoFe2O4@MnFe2O4 nanoparticles (NPs) exhibited a core-shell structure with a mean average particle size of 11.2 ± 1.4 nm and 14.4 ± 2.4 nm, respectively. The CoFe2O4@MnFe2O4 NPs showed the highest specific absorption rate (SAR) values (210-320 W/g) upon exposure to an external magnetic field, along with the highest saturation magnetization (Ms). Therefore, they were selected for functionalization with the PEGylated ligand to make them stable in aqueous media. After the functionalization process, the NPs showed high magnetic relaxivity values and very low cytotoxicity, demonstrating that CoFe2O4@MnFe2O4 is a good candidate for in vivo applications. Finally, in vivo MRI experiments showed that PEGylated CoFe2O4@MnFe2O4 NPs produce high T2 contrast and exhibit very good stealth properties, leading to the efficient evasion of the mononuclear phagocyte system. Thus, these bi-magnetic core-shell NPs show great potential as theranostic agents for in vivo applications, combining magnetic hyperthermia capabilities with high MRI contrast.

In Vivo Pharmacokinetics of Magnetic Nanoparticles.

Over the past few years, many papers have been published on the nanomedical applications of magnetic nanoparticles. However, most studies lack important information about the in vivo behavior of these nanoparticles, which is a critical aspect for their rational design. In this chapter we describe a simple protocol for the in vivo characterization of the pharmacokinetics of magnetic nanoparticles intravenously injected in mice, using basic MRI sequences.

Highly water-stable rare ternary Ag-Au-Se nanocomposites as long blood circulation time X-ray computed tomography contrast agents.

X-ray computed tomography (CT) is a powerful and widely used medical non-invasive technique that often requires intravenous administration of contrast agents (CAs) to better visualize soft tissues. In this work, we have developed a novel CT contrast agent based on ternary Ag-Au-Se chalcogenide nanoparticles (NP). A facile ligand exchange by using a 3 kDa PEGylated ligand with a dithiol dihydrolipoic acid as an anchor group resulted in highly water-soluble and monodisperse nanoparticles. These PEGylated ternary NPs were tested in vivo in mice, showing slow uptake by the mononuclear phagocyte system, long blood circulation times, low toxicity, and very good X-ray contrast, thus being promising candidates as CT contrast agents for clinical applications.

Instructable Nanoparticles Using Dynamic Combinatorial Chemistry.

The application of nanoparticles to the multivalent recognition of biomacromolecules or programmed self-assembly requires control over the relative placement of chemical groups on their surface. We have developed a method to direct the functionalization of surfaces of aldehyde-equipped gold nanoparticles using a DNA template. An error-correction mechanism is built into the functionalization process thanks to the thermodynamic control enabled by the hydrazone exchange reaction. This reversible reaction can be conveniently switched off by removing the catalyst, preserving the functionalization.

Functionalization of strongly interacting magnetic nanocubes with (thermo)responsive coating and their application in hyperthermia and heat-triggered drug delivery.

Herein, we prepare nanohybrids by incorporating iron oxide nanocubes (cubic-IONPs) within a thermoresponsive polymer shell that can act as drug carriers for doxorubicin(doxo). The cubic-shaped nanoparticles employed are at the interface between superparamagnetic and ferromagnetic behavior and have an exceptionally high specific absorption rate (SAR), but their functionalization is extremely challenging compared to bare superparamagnetic iron oxide nanoparticles as they strongly interact with each other. By conducting the polymer grafting reaction using reversible addition-fragmentation chain transfer (RAFT) polymerization in a viscous solvent medium, we have here developed a facile approach to decorate the nanocubes with stimuli-responsive polymers. When the thermoresponsive shell is composed of poly(N-isopropylacrylamide-co-polyethylene glycolmethyl ether acrylate), nanohybrids have a phase transition temperature, the lower critical solution temperature (LCST), above 37 °C in physiological conditions. Doxo loaded nanohybrids exhibited a negligible drug release below 37 °C but showed a consistent release of their cargo on demand by exploiting the capability of the nanocubes to generate heat under an alternating magnetic field (AMF). Moreover, the drug free nanocarrier does not exhibit cytotoxicity even when administered at high concentration of nanocubes (1g/L of iron) and internalized at high extent (260 pg of iron per cell). We have also implemented the synthesis protocol to decorate the surface of nanocubes with poly(vinylpyridine) polymer and thus prepare pH-responsive shell coated nanocubes.

Mesoscale assemblies of iron oxide nanocubes as heat mediators and image contrast agents.

Iron oxide nanocubes (IONCs) represent one of the most promising iron-based nanoparticles for both magnetic resonance image (MRI) and magnetically mediated hyperthermia (MMH). Here, we have set a protocol to control the aggregation of magnetically interacting IONCs within a polymeric matrix in a so-called magnetic nanobead (MNB) having mesoscale size (200 nm). By the comparison with individual coated nanocubes, we elucidate the effect of the aggregation on the specific adsorption rates (SAR) and on the T1 and T2 relaxation times. We found that while SAR values decrease as IONCs are aggregated into MNBs but still keeping significant SAR values (200 W/g at 300 kHz), relaxation times show very interesting properties with outstanding values of r2/r1 ratio for the MNBs with respect to single IONCs.

Intracellular accumulation and immunological properties of fluorescent gold nanoclusters in human dendritic cells.

We have studied the effect of highly fluorescent gold nanoclusters (Au NCs) (∅ < 3 nm) stabilized by different ligands on the intracellular accumulation and immune response of human derived-monocyte dendritic cells (DCs). Results indicate that the high uptake efficiency of Au NCs is strongly related to their small size and to the nature of the ligand, with zwitterionic ligands being more effective than PEGylated ones. Evidence from flow cytometry and microscopy demonstrate time and concentration-dependent Au NCs internalization by endocytic pathway(s) involving amorphous and laminar organelles, while maintaining their discrete size and photoluminescence properties. The uptake of zwitterionic ligand-stabilized Au NCs induced very low cytotoxicity and a strong immunosuppressive response (Th1/Treg pattern), associated with a DC maturation state. This behavior contrasts to the effect of bigger particles (∼12 nm size) which induced a cytotoxic response involving Natural Killer (CD56) cells. Overall, this study stresses the critical importance of particle size and ligand type on the immunostimulation of DCs and highlights the remarkable potential of this new class of nanomaterial as a novel vaccine platform.

Molecular imaging of breast cancer: present and future directions.

Medical imaging technologies have undergone explosive growth over the past few decades and now play a central role in clinical oncology. But the truly transformative power of imaging in the clinical management of cancer patients lies ahead. Today, imaging is at a crossroads, with molecularly targeted imaging agents expected to broadly expand the capabilities of conventional anatomical imaging methods. Molecular imaging will allow clinicians to not only see where a tumor is located in the body, but also to visualize the expression and activity of specific molecules (e.g., proteases and protein kinases) and biological processes (e.g., apoptosis, angiogenesis, and metastasis) that influence tumor behavior and/or response to therapy. Breast cancer, the most common cancer among women and a research area where our group is actively involved, is a very heterogeneous disease with diverse patterns of development and response to treatment. Hence, molecular imaging is expected to have a major impact on this type of cancer, leading to important improvements in diagnosis, individualized treatment, and drug development, as well as our understanding of how breast cancer arises.

Synthesis and non-covalent functionalization of carbon nanotubes rings: new nanomaterials with lectin affinity.

We present a mild and practical carbon nanotubes rings (CNRs) synthesis from non-covalent functionalized and water-soluble linear single-wall carbon nanotubes. The hemi-micellar-supramolecular self-organization of lactose-based glycolipid 1 on the ring surface, followed by photo-polymerization of the diacetylenic function triggered by UV light afforded the first water-soluble and biocompatible CNRs. The obtained donut-like nanoconstructs expose a high density of lactose moieties on their surface, and are able to engage specific interactions with Arachis hypogea lectin similar to glycoconjugates on the cell membrane.

Magnetic nanocarriers with tunable pH dependence for controlled loading and release of cationic and anionic payloads.

Superparamagnetic nanocarriers with tunable pH dependence of the surface charge are designed by a simple co-precipitation method. By exploiting electrostatic interactions, cationic or anionic payloads can be adsorbed and desorbed depending on the pH. On three different resulting nanocarrier systems, experiments of loading and release of gold nanoparticles as well as effective siRNA loading and in vitro delivery on human cells are performed.

Copper-catalyzed azide-alkyne cycloaddition in the synthesis of polydiacetylene: "click glycoliposome" as biosensors for the specific detection of lectins.

Supramolecular self-assembly of conjugated diacetylenic amphiphile-tethered ligands photopolymerize to afford polydiacetylene (PDA) functional liposomes. Upon specific interaction with a variety of biological analytes in aqueous solution, PDA exhibits rapid colorimetric transitions. The PDA nanoassemblies, which are excellent membrane mimics, include an ene-yne polymeric reporter responsible for the chromatic transitions and the molecular recognition elements that are responsible for selective and specific binding to the biological target. A bottleneck in the fabrication of these colorimetric biosensors is the preparation of the diacetylenic monomer embedded with the recognition element of choice. In the present work, we make use of copper-catalyzed azide-alkyne cycloaddition (CuAAC) as key step in the preparation of sugar-coated liposome biosensors. The regioselective click ligation of the triacetylenic N-(2-propynyl)pentacosa-10,12-diynamide (NPPCDAM) with a variety of mannose- and lactose-tethered azides afforded chemo- and regioselectively the corresponding 1,2,3-triazole. The obtained diacetylenic monomers were incorporated efficiently into vesicles to afford functional mannose- and lactose-coated glycoliposomes. The obtained PDA-based click glycoliposomes have been characterized by using transmission electronic microscopy (TEM), dynamic light scattering (DLS), and UV/Vis spectroscopy. The efficiency of the reported approach was demonstrated by the rapid optimization of the hydrophilic spacer between the lipidic matrix and the mannose head group for the colorimetric detection of Concavalin A.

Tailoring carbon nanotube surfaces with glyconanorings: new bionanomaterials with specific lectin affinity.

Remarkably stable, water-soluble glyconanoring-coated SWCNTs were prepared by self organization and photopolymerization of neutral diacetylene-based glycolipids on the nanotube surface; the nanoconstructs are able to engage in specific ligand-lectin interactions in a similar way to glycoconjugates on cell membranes.

C2-symmetric bissulfoxides as organocatalysts in the allylation of benzoyl hydrazones: spacer and concentration effects.

A comparative study on the allylation of a benzoyl hydrazone with allyl trichlorosilane using monosulfoxides, methylene-bridged C2-symmetric bissulfoxides, and ethylene-bridged C2-symmetric bissulfoxides shows that the enantioselectivity of the process is highly dependent on the spacer between the two sulfinyl sulfurs and the concentration of the reaction.