Iron oxide nanoparticles as magnetic relaxation switching (MRSw) sensors: Current applications in nanomedicine.

Since pioneering work in the early 60s on the development of enzyme electrodes the field of sensors has evolved to different sophisticated technological platforms. Still, for biomedical applications, there are key requirements to meet in order to get fast, low-cost, real-time data acquisition, multiplexed and automatic biosensors. Nano-based sensors are one of the most promising healthcare applications of nanotechnology, and prone to be one of the first to become a reality. From all nanosensors strategies developed, Magnetic Relaxation Switches (MRSw) assays combine several features which are attractive for nanomedical applications such as safe biocompatibility of magnetic nanoparticles, increased sensitivity/specificity measurements, possibility to detect analytes in opaque samples (unresponsive to light-based interferences) and the use of homogeneous setting assay. This review aims at presenting the ongoing progress of MRSw technology and its most important applications in clinical medicine.

Fluorescent nanoparticle imaging allows noninvasive evaluation of immune cell modulation in esophageal dysplasia.

Esophageal tumors provide unique challenges and opportunities for developing and testing surveillance imaging technology for different tumor microenvironment components, including assessment of immune cell modulation, with the ultimate goal of promoting early detection and response evaluation. In this context, accessibility through the lumen using a minimally invasive approach provides a means for repetitive evaluation longitudinally by combining fluorescent endoscopic imaging technology with novel fluorescent nanoparticles that are phagocytized by immune cells in the microenvironment. The agent we developed for imaging is synthesized from Feraheme (ferumoxytol), a Food and Drug Administration-approved monocrystaline dextran-coated iron oxide nanoparticle, which we conjugated to a near-infrared fluorochrome, CyAL5.5. We demonstrate a high level of uptake of the fluorescent nanoparticles by myeloid-derived suppressor cells (MDSCs) in the esophagus and spleen of L2Cre;p120ctnflox/flox mice. These mice develop esophageal dysplasia leading to squamous cell carcinoma; we have previously demonstrated that dysplastic and neoplastic esophageal lesions in these mice have an immune cell infiltration that is dominated by MDSCs. In the L2Cre;p120ctnflox/flox mice, evaluation of the spleen reveals that nearly 80% of CD45+ leukocytes that phagocytized the nanoparticle were CD11b+Gr1+ MDSCs. After dexamethasone treatment, we observed concordant decreased fluorescent signal from esophageal lesions during fluorescent endoscopy and decreased CyAL5.5-fluorescent-positive immune cell infiltration in esophageal dysplastic lesions by fluorescence-activated cell sorting analysis. Our observations suggest that this translatable technology may be used for the early detection of dysplastic changes and the serial assessment of immunomodulatory therapy and to visualize changes in MDSCs in the esophageal tumor microenvironment.

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.

Fluorochrome-functionalized nanoparticles for imaging DNA in biological systems.

Attaching DNA binding fluorochromes to nanoparticles (NPs) provides a way of obtaining NPs that bind to DNA through fluorochrome mediated interactions. To obtain a nanoparticle (NP) that bound to the DNA in biological systems, we attached the DNA binding fluorochrome, TO-PRO 1 (TO), to the surface of the Feraheme (FH) NP, to obtain a fluorochrome-functionalized NP denoted TO-FH. When reacted with DNA in vitro, TO-FH formed microaggregates that were characterized by fluorescence, light scattering, and T2 changes. The formation of DNA/TO-FH microaggregates was also characterized by AFM, with microaggregates exhibiting a median size of 200 nm, and consisting of DNA and multiple TO-FH NPs whose individual diameters were only 25-35 nm. TO-FH failed to bind normal cells in culture, but treatment with chemotherapeutic agents or detergents yielded necrotic cells that bound TO-FH and vital fluorochromes similarly. The uptake of TO-FH by HT-29 xenografts (treated with 5-FU and oxaliplatin) was evident by surface fluorescence and MRI. Attaching multiple DNA binding fluorochromes to magnetic nanoparticles provides a way of generating DNA binding NPs that can be used to detect DNA detection by microaggregate formation in vitro, for imaging the DNA of necrotic cells in culture, and for imaging the DNA of a tumor treated with a chemotherapeutic agent. Fluorochrome functionalized NPs are a multimodal (magnetic and fluorescent), highly multivalent (n ≈ 10 fluorochromes/NP) nanomaterials useful for imaging the DNA of biological systems.

Fluorochrome-functionalized magnetic nanoparticles for high-sensitivity monitoring of the polymerase chain reaction by magnetic resonance.

Easy to find: magnetic nanoparticles bearing fluorochromes (red) that intercalate with DNA (green) form microaggregates with DNA generated by the polymerase chain reaction (PCR). These aggregates can be detected at low cycle numbers by magnetic resonance (MR).

A magnetofluorescent nanoparticle for ex-vivo cell labeling by covalently linking the drugs protamine and Feraheme.

We synthesized a nanoparticle (NP) for ex-vivo cell labeling and MRI tracking by covalently coupling the C-terminus of a rhodamine-labeled protamine (ProRho) to Feraheme (FH) in order to yield the nanoparticle denoted ProRho-FH. Since protamine can adsorb to certain charged surfaces, we confirmed a covalent interaction between ProRho and FH by heparin affinity chromatography. ProRho-FH lacks a net charge (zeta potential approximately 0) due to the combination of negative FH and positive ProRho charges. ProRho-FH was readily internalized by U87 cells and mouse mesenchymal stem cells as determined by FACS and MR relaxometry. Finally, some 4,000 stem cells were implanted in a mouse brain and imaged by MRI. Due to its lack of net surface charge, ProRho-FH relies on the internalizing properties of the surface guanidinium groups present in the arginine-rich protamine to induce NP uptake. ProRho-FH is a unique cell-labeling agent due to its synthesis using two approved drugs, magnetofluorescence, site-specific covalent attachment chemistry, and lack of surface charge.

Preventive oral treatment with resveratrol pro-prodrugs drastically reduce colon inflammation in rodents.

There is no pharmaceutical or definitive surgical cure for inflammatory bowel diseases (IBDs). The naturally occurring polyphenol resveratrol exerts anti-inflammatory properties. However, its rapid metabolism diminishes its effectiveness in the colon. The design of prodrugs to targeting active molecules to the colon provides an opportunity for therapy of IBDs. Herein we explore the efficacy of different resveratrol prodrugs and pro-prodrugs to ameliorate colon inflammation in the murine dextran sulfate sodium (DSS) model. Mice fed with a very low dose (equivalent to 10 mg for a 70 kg-person) of either resveratrol-3-O-(6'-O-butanoyl)-ß-D-glucopyranoside (6) or resveratrol-3-O-(6'-O-octanoyl)-ß-D-glucopyranoside (7) did not develop colitis symptoms and improved 6-fold the disease activity index (DAI) compared to resveratrol. Our results indicate that these pro-prodrugs exerted a dual effect: (1) they prevented the rapid metabolism of resveratrol and delivered higher quantities of resveratrol to the colon and (2) they reduced mucosal barrier imbalance and prevented diarrhea, which consequently facilitated the action of the delivered resveratrol in the colon mucosa.

Antioxidant activity of resveratrol in several fish lipid matrices: effect of acylation and glucosylation.

The antioxidant activity of resveratrol (1) and several acylated and glycosylated derivatives on fish oil enriched systems has been studied. Two long-chain acylated derivatives, 3-stearoylresveratrol (2) and 4'-stearoylresveratrol (3), and three glucosyl derivatives, resveratrol-3-beta-d-glucopyranoside (piceid, 4), resveratrol-3,5-di-beta-d-glucopyranoside (5), and resveratrol-3,4'-di-beta-d-glucopyranoside (6), have been prepared and tested. The results have shown a notable antioxidant capacity of resveratrol and piceid in fish oil-in-water emulsions, similar to that of the potent antioxidant hydroxytyrosol. Lipophilization of resveratrol did not improve its antioxidant activity, either in emulsions or in bulk fish oil. Further glucosylation of piceid yielding compounds 5 and 6 did not improve either resveratrol or piceid antioxidant efficiency in emulsions or in bulk oil. In all of the examples, the hydroxyl group at the 4'-position seems to be relevant for the antioxidant efficiency of resveratrol, and it should be maintained to keep the antiradical activity. Finally, resveratrol has shown to be a very good antioxidant for fish muscle, as good as the potent antioxidant hydroxytyrosol.

Surface-active properties of lipophilic antioxidants tyrosol and hydroxytyrosol fatty acid esters: a potential explanation for the nonlinear hypothesis of the antioxidant activity in oil-in-water emulsions.

Our group has recently observed a nonlinear tendency in antioxidant capacity of different hydroxytyrosol fatty acid esters in fish oil-in-water emulsions, where a maximum of antioxidant efficiency appeared for hydroxytyrosol octanoate. These results appear to disagree with the antioxidant polar paradox. Because the physical location of the antioxidants in an oil-water interface has been postulated as an important factor in explaining this behavior, we have prepared a series of tyrosol and hydroxytyrosol fatty acid esters with different chain length and studied their surface-active properties in water, because these physicochemical parameters could be directly related to the preferential placement at the interface. We have found that tyrosol and hydroxytyrosol fatty acid esters are relevant surfactants when the right hydrophilic-lipophilic balance (HLB) is attained and, in some cases, as efficient as emulsifiers commonly used in industry, such as Brij 30 or Tween 20. Moreover, a nonlinear dependency of surfactant effectiveness is observed with the increase in chain length of the lipophilic antioxidants. This tendency seems to fit quite well with the reported antioxidant activity in emulsions, and the best antioxidant of the series (hydroxytyrosol octanoate) is also a very effective surfactant. This potential explanation of the nonlinear hypothesis will help in the rational design of antioxidants used in oil-in-water emulsions.

Paramagnetic Gd-based gold glyconanoparticles as probes for MRI: tuning relaxivities with sugars.

Combining sugar conjugates and DO3A-Gd complexes, paramagnetic gold glyconanoparticles (GNPs) with different relaxivity values were obtained and tested in vivo as MRI probes.

Gold and gold-iron oxide magnetic glyconanoparticles: synthesis, characterization and magnetic properties.

The preparation, characterization and the magnetic properties of gold and gold-iron oxide glyconanoparticles (GNPs) are described. Glyconanoparticles were prepared in a single step procedure in the presence of aqueous solution of thiol functionalized neoglycoconjugates and either gold salts or both gold and iron salts. Neoglycoconjugates of lactose and maltose disaccharides with different linkers were used. Iron-free gold or gold-iron oxide GNPs with controlled gold-iron ratios were obtained. The average core-size diameters are in the range of 1.5-2.5 nm. The GNPs are fully characterized by (1)H NMR spectrometry, transmission electron microscopy (TEM), and UV-vis and X-ray absorption (XAS) spectroscopies. Inductive plasma-atomic emission spectrometry (ICP) and elemental analysis gave the average number of neoglycoconjugates per cluster. The magnetic properties were measured in a SQUID magnetometer. The most remarkable results was the observation of a permanent magnetism up to room temperature in the iron-free gold GNPs, that was not present in the corresponding gold-iron oxide GNPs.