Core-Shell Nanohydrogels with Programmable Swelling for Conformance Control in Porous Media.

Conformance control during waterflooding in an oil reservoir is utilized to redistribute water and increase the sweep efficiency and hence oil production. Using preformed gel particles can effectively redirect the flow by blocking the high-permeability zones and forcing water into low-permeability zones where the oil is trapped. However, the size of such gel particles can limit their applications deeper within the reservoir and can result in shear-induced degradation near the well bore. Here, we fabricate core-shell nanohydrogels with delayed swelling behavior; their volume increases by a factor of 200 after about 30 days in brine under reservoir conditions. We study their effect on the flow behavior in a three-dimensional porous medium micromodel consisting of randomly packed glass beads. Using confocal microscopy, we directly visualize the spatial variations of flow in the micromodel before and after nanohydrogel injection and swelling. The swollen nanohydrogels block some pores reducing the permeability of the micromodel and diverting the water into low-permeability regions. A core flood experiment further confirms that the nanohydrogels can significantly reduce the permeability of a reservoir sample and divert the fluid flow. Our results demonstrate that these core-shell nanohydrogels might be useful for flow control in porous media and can be used as a conformance control agent.

Coarse-Grained Simulations of Polymer-Grafted Nanoparticles: Structural Stability and Interfacial Behavior.

In the tertiary oil recovery method known as "polymer flooding", the viscosity of the injected water is increased by dissolving partially hydrolyzed polyacrylamide so as to lower the mobility ratio and raise the vertical and areal sweep efficiencies. However, its drawbacks include the degradation of the polymer in the reservoir due to (1) shear while passing through chokes, perforations, and pore throats, (2) morphological changes induced by divalent ions, and (3) complete hydrolysis of the polymer at high temperatures. These factors adversely affect the viscosity of the polymer flood. Past experimental research showed that polymer-grafted nanoparticles (PNPs) could achieve the same viscosity enhancement at lower quantities than traditional linear polymers. The PNPs have the putative advantage of greater stability when confronted with the aforementioned reservoir conditions. In this work, we use dissipative particle dynamics (DPD) to simulate the oil-PNP-water system at the mesoscale and estimate its sensitivity to brine in ways that could serve as guidelines to experiments. We study the effect of salinity on the structure of linear and branched polyelectrolytes before extending the DPD model to PNPs at the oil-water interface. To this end, we parameterize the interactions of the polymer with the oil and water phases, and broadly map out solvent conditions that change the graft's morphology and affect the interfacial behavior of the grafted particle. We find that the equilibrium location of the grafted nanoparticle in an oil-brine system depends on its grafting density and the salinity.

Cellular mechanism of oral absorption of solidified polymer micelles.

Oral delivery of poorly soluble and permeable drugs represents a significant challenge in drug development. The oral delivery of drugs remains to be the ultimate route of any drugs. However, in many cases, drugs are not absorbed well in the gastrointestinal tract, or they lose their activity. Polymer micelles were recognized as an effective carrier system for drug encapsulation, and are now studied as a vehicle for oral delivery of insoluble compounds. We characterized the properties of monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles, and visualized their internalization in mouse small intestine. Using Caco-2 cells as a cellular model, we studied the kinetics of particle uptake, their transport, and the molecular mechanism of their intestinal absorption. Moreover, by inhibiting specific endocytosis pathways, pharmacologically and genetically, we found that mPEG-PLA nanoparticle endocytosis is mediated by clathrin in an energy-dependent manner, and that the low-density lipoprotein receptor is involved. FROM THE CLINICAL EDITOR: Many current drugs used are non-water soluble and indeed, the ability to deliver these drugs via the gastrointestinal tract remains the holy grail for many researchers. The authors in this paper developed monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles as a drug nanocarrier, and studied the mechanism of uptake across intestinal cells. The findings should improve our current understanding and point to the development of more nanocarriers.

Inhibition of neuroblastoma cell proliferation with omega-3 fatty acids and treatment of a murine model of human neuroblastoma using a diet enriched with omega-3 fatty acids in combination with sunitinib.

INTRODUCTION: We investigated the use of dietary omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) in the treatment of neuroblastoma both as a sole agent and in combination with sunitinib, a broad-spectrum tyrosine kinase receptor inhibitor. RESULTS: Substitution of all dietary fat with menhaden oil (ω-3 PUFA rich) resulted in a 40-70% inhibition of tumor growth and a statistically significant difference in the levels of several PUFAs (18:2 ω-6, 20:4 ω-6, 22:4 ω-6, 20:5 ω-3) as compared with a control diet. Furthermore, tumors from animals on the ω-3 fatty acid (FA)-enriched diet had an elevated triene/tetraene ratio suggestive of a change in local eicosanoid metabolism in these tissues similar to that seen with essential fatty acid deficiency. The ω-3 FA-enriched diet also decreased tumor-associated inflammatory cells and induced mitochondrial changes suggestive of mitochondrial damage. Combination treatment with sunitinib resulted in further reduction in tumor proliferation and microvessel density. DISCUSSION: These findings suggest a potential role for ω-3 PUFAs in the combination treatment of neuroblastoma. METHODS: We used a murine model of orthotopic and subcutaneous human neuroblastoma and diets that differ in the FA content to define the optimal dietary ω-3/omega-6 (ω-6) FA ratio required for the inhibition of these tumors.

Effect of a calcium-channel blocker (verapamil) on the morphology, cytoskeleton and collagenase activity of human skin fibroblasts.

The effects of verapamil modulating collagen biosynthesis have prompted us to study the role of this drug in cultured fibroblasts. In this article, we describe the effects of verapamil on fibroblast behaviour, with special emphasis to phenotypic modifications, reorganisation of actin filaments and secretion of MMP1. Human dermal fibroblasts treated with 50-µM verapamil changed their normal spindle-shaped morphology to stellate. Treated cells showed discrete reorganisation of actin filaments, as revealed by fluorescein isothiocyanate (FITC)-phalloidin staining and confocal microscopy. We hypothesised that these effects would be associated to lower levels of cytosolic Ca(2+). Indeed, short time loading with calcium green confirmed that verapamil-treated fibroblasts exhibited lower intracellular calcium levels compared to controls. We also observed that verapamil increases the secretion of MMP1 in cultured fibroblasts, as demonstrated by zymography, specific substrate assays and immunoblot. The morphological alterations induced by verapamil are neither cytotoxic nor associated with other dramatic cytoskeleton alterations. Thus we may conclude that this drug enhances collagenase secretion and does not disrupt the major tracks necessary to deliver these enzymes in the extracellular space. The present results suggested that verapamil could be used at physiological levels to enhance collagen I breakdown, and may be considered a potential candidate for intralesional therapy of wound healing and fibrocontractive diseases.

Platelets actively sequester angiogenesis regulators.

Clinical trials with antiangiogenic agents have not been able to validate plasma or serum levels of angiogenesis regulators as reliable markers of cancer presence or therapeutic response. We recently reported that platelets contain numerous proteins that regulate angiogenesis. We now show that accumulation of angiogenesis regulators in platelets of animals bearing malignant tumors exceeds significantly their concentration in plasma or serum, as well as their levels in platelets from non-tumor-bearing animals. This process is selective, as platelets do not take up a proportional amount of other plasma proteins (eg, albumin), even though these may be present at higher concentrations. We also find that VEGF-enriched Matrigel pellets implanted subcutaneously into mice or the minute quantities of VEGF secreted by microscopic subcutaneous tumors (0.5-1 mm(3)) result in an elevation of VEGF levels in platelets, without any changes in its plasma levels. The profile of other angiogenesis regulatory proteins (eg, platelet-derived growth factor, basic fibroblast growth factor) sequestered by platelets also reflects the presence of tumors in vivo before they can be macroscopically evident. The ability of platelets to selectively take up angiogenesis regulators in cancer-bearing hosts may have implications for the diagnosis and management of many angiogenesis-related diseases and provide a guide for antiangiogenic therapies.

Nanomagnetic actuation of receptor-mediated signal transduction.

Complex cell behaviours are triggered by chemical ligands that bind to membrane receptors and alter intracellular signal transduction. However, future biosensors, medical devices and other microtechnologies that incorporate living cells as system components will require actuation mechanisms that are much more rapid, robust, non-invasive and easily integrated with solid-state interfaces. Here we describe a magnetic nanotechnology that activates a biochemical signalling mechanism normally switched on by binding of multivalent chemical ligands. Superparamagnetic 30-nm beads, coated with monovalent ligands and bound to transmembrane receptors, magnetize when exposed to magnetic fields, and aggregate owing to bead-bead attraction in the plane of the membrane. Associated clustering of the bound receptors acts as a nanomagnetic cellular switch that directly transduces magnetic inputs into physiological cellular outputs, with rapid system responsiveness and non-invasive dynamic control. This technique may represent a new actuator mechanism for cell-based microtechnologies and man-machine interfaces.

An orally delivered small-molecule formulation with antiangiogenic and anticancer activity.

Targeting angiogenesis, the formation of blood vessels, is an important modality for cancer therapy. TNP-470, a fumagillin analog, is among the most potent and broad-spectrum angiogenesis inhibitors. However, a major clinical limitation is its poor oral availability and short half-life, necessitating frequent, continuous parenteral administration. We have addressed these issues and report an oral formulation of TNP-470, named Lodamin. TNP-470 was conjugated to monomethoxy-polyethylene glycol-polylactic acid to form nanopolymeric micelles. This conjugate can be absorbed by the intestine and selectively accumulates in tumors. Lodamin significantly inhibits tumor growth, without causing neurological impairment in tumor-bearing mice. Using the oral route of administration, it first reaches the liver, making it especially efficient in preventing the development of liver metastasis in mice. We show that Lodamin is an oral nontoxic antiangiogenic drug that can be chronically administered for cancer therapy or metastasis prevention.

Integrin binding angiopoietin-1 monomers reduce cardiac hypertrophy.

Angiopoietins were thought to be endothelial cell-specific via the tie2 receptor. We showed that angiopoietin-1 (ang1) also interacts with integrins on cardiac myocytes (CMs) to increase survival. Because ang1 monomers bind and activate integrins (not tie2), we determined their function in vivo. We examined monomer and multimer expressions during physiological and pathological cardiac remodeling and overexpressed ang1 monomers in phenylephrine-induced cardiac hypertrophy. Cardiac ang1 levels (mRNA, protein) increased during postnatal development and decreased with phenylephrine-induced cardiac hypertrophy, whereas tie2 phosphorylations were unchanged. We found that most or all of the changes during cardiac remodeling were in monomers, offering an explanation for unchanged tie2 activity. Heart tissue contains abundant ang1 monomers and few multimers (Western blotting). We generated plasmids that produce ang1 monomers (ang1-256), injected them into mice, and confirmed cardiac expression (immunohistochemistry, RT-PCR). Ang1 monomers localize to CMs, smooth muscle cells, and endothelial cells. In phenylephrine-induced cardiac hypertrophy, ang1-256 reduced left ventricle (LV)/tibia ratios, fetal gene expressions (atrial and brain natriuretic peptides, skeletal actin, beta-myosin heavy chain), and fibrosis (collagen III), and increased LV prosurvival signaling (akt, MAPK(p42/44)), and AMPK(T172). However, tie2 phosphorylations were unchanged. Ang1-256 increased integrin-linked kinase, a key regulator of integrin signaling and cardiac health. Collectively, these results suggest a role for ang1 monomers in cardiac remodeling.

Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib.

BACKGROUND: Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours. METHODS: We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice. FINDINGS: Eight of 75 (11%) patients given repeating cycles of sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes. INTERPRETATION: Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.