91 research outputs found
Anomalous solubility behavior of mixed monolayer protected metal nanoparticles
Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2005.Includes bibliographical references (leaves 30-32).The solubility of mixed monolayer protected gold nanoparticles was studied. Monolayer protected metal nanoparticles are attractive materials because of the optical and electronic properties of their metal cores and because of the surface properties of their ligand coating. Recently, it was discovered that a mixture of ligands phase separate into ordered domains of single nanometer or subnanometer width on the surface of metal nanoparticles. The morphology and length of the ligand domains (which take the form of ripples on the particle surface) has given these nanoparticles novel properties. Because monolayer protected nanoparticles can be dissolved and dried many times, they can be handled and processed in ways not available to other nanomaterials. Understanding the solubility of mixed monolayer protected metal nanoparticles could help in implementing their unique new properties. This study demonstrates that the solubility of these particles in organic solvents cannot be explained only in terms of the composition of the ligand shell. Instead, solubility is also closely linked to morphology of the ligand shell via relationships between the size of the solvent molecule and the size of the features in the morphology.by Jacob W. Myerson.S.B
Thrombin-Inhibiting Perfluorocarbon Nanoparticles: A New Class of Therapeutic for Acute Thrombosis Treatment and Diagnosis
Optimization of the mediation of acute thrombi remains a significant research challenge in the treatment of emergency conditions including heart attack and ischemic stroke. We have demonstrated that a nanoparticle carrying potent direct thrombin inhibitors can advance the treatment of acute thrombosis arising from various cardiovascular pathologies. The thrombin-inhibiting nanoparticles presented herein are designed to focus the antithrombotic impact of direct thrombin inhibitors at the site of thrombus formation and to provide imaging contrast to highlight the formation or the abatement and eventual disintegration of the thrombus.
Perfluorocarbon nanoparticles were functionalized by covalent addition of PPACK or bivalirudin to carboxy-PEG capped lipid components to the stabilizing lipids. Over 10000 inhibitors were added per particle. In vitro experiments evaluated inhibition of thrombin cleavage of the chromogenic substrate Chromozym TH and defined the kinetics of the particle-thrombin interaction. Thrombin-inhibiting activity of the component inhibitors was undiminished on the nanoparticles and, as explored in appended work, the nanoparticles had a significant kinetic advantage over the lone inhibitors.
To demonstrate efficacy of the particles as inhibitors of clot-bound thrombin, fibrinopeptide A ELISAs assayed the production of fibrin in plasma exposed to the surface of forming clots treated with PPACK, bivalirudin, PPACK nanoparticles, or bivalirudin nanoparticles. Similarly treated clots were monitored for growth in plasma via magnetic resonance imaging. Nanoparticles exceeded the activity of the component inhibitors in blocking FPA production by bound thrombin and formed an inhibitory layer that stopped further growth of clots in plasma.
In vivo testing of thrombosis inhibition was performed in C57BL/6 mice and NZW rabbits using the Rose Bengal laser-induced thrombosis model (with ultrasonic flow probes tracking progress to occlusive thrombus). Thrombin-inhibiting particles were compared to Heparin, PPACK, bivalirudin, saline, and analogous non-functionalized particles as inhibitors of acute thrombosis in mice. Thrombin-inhibiting nanoparticles significantly delayed occlusion time in mice, outperforming heparin and the component inhibitors. Ultrasound and magnetic resonance imaging were employed to evaluate deposition of nanoparticles in mouse or rabbit thrombi. Thrombi were analyzed following in vivo experiments, using imaging and histochemical methods. Magnetic resonance imaging and spectroscopy revealed the specific deposition of thrombin-inhibiting nanoparticles in thrombi. For evaluation of fine clot morphology, mouse thrombi were examined with transmission electron microscopy. For evaluation of fibrin and platelet content in the thrombus Carstair\u27s staining was employed. Clots formed following nanoparticle administration exhibited lesser platelet content.
In additional experiments, bleeding times and APTT measurements determined the systemic effects of the nanoparticles. Though the thrombin-inhibiting nanoparticles delayed thrombotic occlusion at a site of arterial injury to 1.5-2 hours, significant effects on blood pool coagulation parameters were observed for less than 20 minutes.
We have demonstrated that the thrombin-inhibiting nanoparticle is kinetically superior to conventional direct inhibitors. In vivo, the potent inhibition kinetics, combined with the pharmacokinetic and pharmacodynamic properties of perfluorocarbon nanoparticles enabled superior inhibition of thrombosis while maintaining an excellent safety profile with short-lived systemic effects. Imaging data indicated the formation of layers of nanoparticles at sites of arterial injury. Thrombin-inhibiting nanoparticles are thus derived here as a new tool for treatment of acute thrombosis. The particles open a new avenue in this field of medical research as the first therapeutic to form a detectable, site-specific, and quantifiable anticoagulant layer that seals against the progress of acute thrombosis
Impurity incorporation in solution crystallization: diagnosis, prevention, and control
Despite their widespread use for purification, our current methods for the development of solution crystallization processes lack a sufficient understanding on how impurities incorporate in growing crystals. This is, in part, due to the large number of mechanisms often encountered for impurity incorporation, and due to limitations in our methods for diagnosis of those mechanisms. These limitations propagate into largely empirical process development strategies, which are still based on trial and error and centered on solvent selection. This manuscript highlights recent developments in the diagnosis, prevention, and control of impurity incorporation during batch and continuous crystallization. The goal is to provide process development scientists with an updated toolkit for understanding how specific impurities are retained in the solid product, and to review recent prevention and control strategies that may be used to improve crystal purity in industrial crystallization processes
PPACK and Bivalirudin nanoparticles enable simultaneous imaging and potent inhibition of acute clotting
Quantifying the Evolution of Vascular Barrier Disruption in Advanced Atherosclerosis with Semipermeant Nanoparticle Contrast Agents
Acute atherothrombotic occlusion in heart attack and stroke implies disruption of the vascular endothelial barrier that exposes a highly procoagulant intimal milieu. However, the evolution, severity, and pathophysiological consequences of vascular barrier damage in atherosclerotic plaque remain unknown, in part because quantifiable methods and experimental models are lacking for its in vivo assessment.To develop quantitative nondestructive methodologies and models for detecting vascular barrier disruption in advanced plaques.Sustained hypercholesterolemia in New Zealand White (NZW) rabbits for >7-14 months engendered endothelial barrier disruption that was evident from massive and rapid passive penetration and intimal trapping of perfluorocarbon-core nanoparticles (PFC-NP: ∼250 nm diameter) after in vivo circulation for as little as 1 hour. Only older plaques (>7 mo), but not younger plaques (<3 mo) demonstrated the marked enhancement of endothelial permeability to these particles. Electron microscopy revealed a complex of subintimal spongiform channels associated with endothelial apoptosis, superficial erosions, and surface-penetrating cholesterol crystals. Fluorine ((19)F) magnetic resonance imaging and spectroscopy (MRI/MRS) enabled absolute quantification (in nanoMolar) of the passive permeation of PFC-NP into the disrupted vascular lesions by sensing the unique spectral signatures from the fluorine core of plaque-bound PFC-NP.The application of semipermeant nanoparticles reveals the presence of profound barrier disruption in later stage plaques and focuses attention on the disrupted endothelium as a potential contributor to plaque vulnerability. The response to sustained high cholesterol levels yields a progressive deterioration of the vascular barrier that can be quantified with fluorine MRI/MRS of passively permeable nanostructures. The possibility of plaque classification based on the metric of endothelial permeability to nanoparticles is suggested
A network approach to public goods
Abstract We study settings where each agent can exert costly effort that creates nonrival, heterogeneous benefits for some of the others. For example, municipalities can forgo consumption to reduce pollution. How do the prospects for efficient cooperation depend on asymmetries in the effects of players' actions? We approach this question by analyzing a network that describes the marginal benefits agents can confer on one another. The first set of results explains how the largest eigenvalue of this network measures the marginal gains available from cooperating; as an application, we describe the players whose participation is essential to achieving any Pareto improvement on an inefficient status quo. Next, we examine mechanisms all of whose equilibria are Pareto efficient and individually rational; an outcome is called robust if it is an equilibrium outcome in every such mechanism. Robust outcomes exist and correspond to the Lindahl public goods solutions. The main result is a characterization of effort levels at these outcomes in terms of players' centralities in the benefits network. It entails that an outcome is robust if and only if agents contribute in proportion to how much they value the efforts of those who help them
- …