Leisha M. Armijo

Intrathecal cannabilactone CB2R agonist, AM1710, controls pathological pain and restores basal cytokine levels

Summary Spinal AM1710 suppresses allodynia with corresponding anti‐inflammatory and anti‐MAGL (monoacylglycerol lipase) effects in the spinal cord and dorsal root ganglia. ABSTRACT Spinal glial and proinflammatory cytokine actions are strongly implicated in pathological pain. Spinal administration of the anti‐inflammatory cytokine interleukin (IL)‐10 abolishes pathological pain and suppresses proinflammatory IL‐1β and tumor necrosis factor alpha (TNF‐α). Drugs that bind the cannabinoid type‐2 receptor (CB2R) expressed on spinal glia reduce mechanical hypersensitivity. To better understand the CB2R‐related anti‐inflammatory profile of key anatomical nociceptive regions, we assessed mechanical hypersensitivity and protein profiles following intrathecal application of the cannabilactone CB2R agonist, AM1710, in 2 animal models; unilateral sciatic nerve chronic constriction injury (CCI), and spinal application of human immunodeficiency virus‐1 glycoprotein 120 (gp120), a model of peri‐spinal immune activation. In CCI animals, lumbar dorsal spinal cord and corresponding dorsal root ganglia (DRG) were evaluated by immunohistochemistry for expression of IL‐10, IL‐1β, phosphorylated p38‐mitogen‐activated‐kinase (p‐p38MAPK), a pathway associated with proinflammatory cytokine production, glial cell markers, and degradative endocannabinoid enzymes, including monoacylglycerol lipase (MAGL). AM1710 reversed bilateral mechanical hypersensitivity. CCI revealed decreased IL‐10 expression in dorsal spinal cord and DRG, while AM1710 resulted in increased IL‐10, comparable to controls. Adjacent DRG and spinal sections revealed increased IL‐1β, p‐p38MAPK, glial markers, and/or MAGL expression, while AM1710 suppressed all but spinal p‐p38MAPK and microglial activation. In spinal gp120 animals, AM1710 prevented bilateral mechanical hypersensitivity. For comparison to immunohistochemistry, IL‐1β and TNF‐α protein quantification from lumbar spinal and DRG homogenates was determined, and revealed increased DRG IL‐1β protein levels from gp120, that was robustly prevented by AM1710 pretreatment. Cannabilactone CB2R agonists are emerging as anti‐inflammatory agents with pain therapeutic implications.

Iron Oxide Nanocrystals for Magnetic Hyperthermia Applications

Magnetic nanocrystals have been investigated extensively in the past several years for several potential applications, such as information technology, MRI contrast agents, and for drug conjugation and delivery. A specific property of interest in biomedicine is magnetic hyperthermia—an increase in temperature resulting from the thermal energy released by magnetic nanocrystals in an external alternating magnetic field. Iron oxide nanocrystals of various sizes and morphologies were synthesized and tested for specific losses (heating power) using frequencies of 111.1 kHz and 629.2 kHz, and corresponding magnetic field strengths of 9 and 25 mT. Polymorphous nanocrystals as well as spherical nanocrystals and nanowires in paramagnetic to ferromagnetic size range exhibited good heating power. A remarkable 30 °C temperature increase was observed in a nanowire sample at 111 kHz and magnetic field of 25 mT (19.6 kA/m), which is very close to the typical values of 100 kHz and 20 mT used in medical treatments.

Rheological characterization of a magnetorheological ferrofluid using iron nitride nanoparticles

Magnetorheology of a magnetorheological ferrofluid (MRFF) was investigated to study the role of a ferromagnetic nanoparticle (NP) additive in magnetorheological fluids (MRFs). Iron nitride (Fe16N2) NPs, nominally within the diameter range of ∼16–45 nm (spherical NPs) and ∼30–66 nm (cubic NPs), were coated with carboxy-polyethylene glycol (carboxy-PEG) and dispersed in silicone oil in order to produce a magnetic carrier fluid or ferrofluid for two solids loadings: 2 vol. % and 5 vol. %. Conventional spherical carbonyl iron (CI) particles, varying in diameter from 6 to 10 μm, were suspended in the ferrofluid at 25 vol. % solids loading. Rheological properties of the MRFF synthesized with the carboxy-PEG-based ferromagnetic carrier fluid were compared to the MRF synthesized with silicone oil to determine how ferrofluid can influence dynamic viscosity and yield stress. Rheological measurements of both MRF and MRFF samples were carried out using a Paar Physica 300 rheometer to estimate the field-off viscosity ...

Delivery of tobramycin coupled to iron oxide nanoparticles across the biofilm of mucoidal Pseudonomas aeruginosa and investigation of its efficacy

Pseudomonas aeruginosa bacterium is a deadly pathogen, leading to respiratory failure in cystic fibrosis and nosocomial pneumonia, and responsible for high mortality rates in these diseases. P. aeruginosa has inherent as well as acquired resistance to many drug classes. In this paper, we investigate the effectiveness of two classes; aminoglycoside (tobramycin) and fluoroquinolone (ciprofloxacin) administered alone, as well as conjugated to iron oxide (magnetite) nanoparticles. P. aeruginosa possesses the ability to quickly alter its genetics to impart resistance to the presence of new, unrecognized treatments. As a response to this impending public health threat, we have synthesized and characterized magnetite nanoparticles capped with biodegradable short-chain carboxylic acid derivatives conjugated to common antibiotic drugs. The functionalized nanoparticles may carry the drug past the mucus and biofilm layers to target the bacterial colonies via magnetic gradient-guided transport. Additionally, the magnetic ferrofluid may be used under application of an oscillating magnetic field to raise the local temperature, causing biofilm disruption, slowed growth, and mechanical disruption. These abilities of the ferrofluid would also treat multi-drug resistant strains, which appear to be increasing in many nosocomial as well as acquired opportunistic infections. In this in vitro model, we show that the iron oxide alone can also inhibit bacterial growth and biofilm formation.

Effectiveness of tobramycin conjugated to iron oxide nanoparticles in treating infection in cystic fibrosis

Cystic fibrosis (CF) is an inherited childhood-onset life-shortening disease. It is characterized by increased respiratory production, leading to airway obstruction, chronic lung infection and inflammatory reactions. The most common bacteria causing persisting infections in people with CF is Pseudomonas aeruginosa. Superparamagnetic Fe3O4 iron oxide nanoparticles (NPs) conjugated to the antibiotic (tobramycin), guided by a gradient of the magnetic field or subjected to an oscillating magnetic field, show promise in improving the drug delivery across the mucus and P. aeruginosa biofilm to the bacteria. The question remains whether tobramycin needs to be released from the NPs after the penetration of the mucus barrier in order to act upon the pathogenic bacteria. We used a zero-length 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC) crosslinking agent to couple tobramycin, via its amine groups, to the carboxyl groups on Fe3O4 NPs capped with citric acid. The therapeutic efficiency of Fe3O4 NPs attached to the drug versus that of the free drug was investigated in P. aeruginosa culture.

Highly efficient multifunctional MnSe/ZnSeS quantum dots for biomedical applications

Colloidal quantum dots (QDs) are of interest for a variety of biomedical applications, including bioimaging, drug targeting, and photodynamic therapy. However, a significant limitation is that highly efficient photoluminescent QDs available commercially contain cadmium. Recent research has focused on cadmium-free QDs, which are anticipated to exhibit significantly lower cytotoxicity. Previous work has focused on InP and ZnO as alternative semiconductor materials for QDs. However, these nanoparticles have been shown to be cytotoxic. Recently, we have synthesized high quantum efficiency (exceeding 90%), color tunable MnSe/ZnSeS nanoparticles, as potentially attractive QDs for biomedical applications. Additionally, the manganese imparts magnetic properties on the QDs, which are important for magnetic field-guided transport, hyperthermia, and potentially magnetic resonance imaging (MRI). The QDs can be further biofunctionalized via conjugation to a ligand or a biomarker of disease, allowing combination of drug delivery with visual verification and colocalization due to the color tunability of the QDs.

Multifunctional superparamagnetic nanoparticles for enhanced drug transport in cystic fibrosis

Iron oxide colloidal nanoparticles (ferrofluids) are investigated for application in the treatment of cystic fibrosis lung infections, the leading cause of mortality in cystic fibrosis patients. We investigate the use of iron oxide nanoparticles to increase the effectiveness of administering antibiotics through aerosol inhalation using two mechanisms: directed particle movement in the presence of an inhomogeneous static external magnetic field and magnetic hyperthermia. Magnetic hyperthermia is an effective method for decreasing the viscosity of the mucus and biofilm, thereby enhancing drug, immune cell, and antibody penetration to the affected area. Iron oxide nanoparticles of various sizes and morphologies were synthesized and tested for specific losses (heating power). Nanoparticles in the superparamagnetic to ferromagnetic size range exhibited excellent heating power. Additionally, iron oxide / zinc selenide core/shell nanoparticles were prepared, in order to enable imaging of the iron oxide nanoparticles. We also report on synthesis and characterization of MnSe/ZnSeS alloyed quantum dots.

Characterisation of potassium bromide loaded with dysprosium fluoride nanocrystals for neutron detection

We explore a novel concept of passive optically-enabled detection of thermal neutrons that exploits transmutation of 164 Dy into 165 Ho. The concept relies on significant differences in optical properties of Dy and Ho and on our ability to find the most sensitive optical method of differentiating between Dy and Ho. While the concept applies equally well to bulk materials and to nanocrystals (NCs), the nanocrystalline approach is much more attractive due to its significantly lower cost, relative ease of colloidal synthesis of high quality NCs with controlled composition, and superior optical and mechanical properties of NCs compared to their bulk counterparts. One particular advantage of NCs for neutron detection is that in principle they can be integrated into a transparent host without causing optical scattering. Since Ho is known to have strong emission lines in mid-infrared, we considered potassium bromide (KBr), transparent in mid-IR spectral range, to be a suitable host for Dy-containing NCs. Here, we report on synthesis and characterisation of DyF 3 :10%Ce, HoF 3 :10%Ce, and DyF 3 :10%Ho,10%Ce NCs, their insertion into KBr matrix, and optical characterisation of the obtained nanocomposites, both non-irradiated and subjected to neutron irradiation.

Effects of La0.2Ce0.6Eu0.2F3 nanocrystals capped with polyethylene glycol on human pancreatic cancer cells in vitro

Lanthanide fluoride colloidal nanocrystals offer a way to improve the diagnosis and treatment of cancer through the enhanced absorption of ionizing radiation, in addition to providing visible luminescence. In order to explore this possibility, tests with a kilovoltage therapy unit manufactured by the Universal X-Ray Company were performed to estimate the energy sensitivity of this technique. La0.2Ce0.6Eu0.2F3 nanocrystals capped with polyethylene glycol of molecular weight 6000 were synthesized, suspended in deionized water, and made tolerant to biological ionic pressures by incubation with fetal bovine serum. These nanocrystals were characterized by dynamic light scattering, muffle furnace ashing, and photoluminescence spectroscopy. Clonogenic assays were performed on the cells to assay the cytotoxicity and radiotoxicity of the nanocrystals on the human pancreatic cancer cell line PANC-1, purchased from ATCC.

Thermal neutron detection with PMMA nanocomposites containing dysprosium fluoride nanocrystals

Naturally occurring dysprosium is attractive as a neutron detector because of its high thermal neutron capture cross section and high natural abundance. Neutron-induced transmutation of 164Dy results in production of stable isotopes of holmium and erbium (the latter only at sufficiently high neutron fluxes), due to beta decays caused by nucleus instability. This mechanism, unaffected by gamma radiation, can be used to unambiguously detect neutrons, without having to discriminate against an accompanying gamma flux. Optically-enabled thermal neutron detection can be based on significant differences in optical properties of Dy and Ho or Er, which allows to determine the relative fractions of Dy, and Ho, and E in an irradiated sample. In our search for the most sensitive method of differentiating between Dy and Ho residing in the same host material, we produced various Dy- and Ho-containing nanocrystals and uniformly dispersed them in a PMMA polymer matrix. Optical properties of the nanocomposites were analyzed by means of absorption and PL spectroscopy. We also report on neutron irradiation experiments with Dy-containing nanocrystals and our attempts to optically detect neutron-induced conversion of Dy into Ho.