Variable Antibody-dependent Activation of Complement by Functionalized Phospholipid Nanoparticle Surfaces
Divisions of Rheumatology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.Journal of Biological Chemistry (Impact Factor: 4.57). 11/2010; 286(1):123-30. DOI: 10.1074/jbc.M110.180760
A wide variety of nanomaterials are currently being developed for use in the detection and treatment of human diseases. However, there is no systematic way to measure and predict the action of such materials in biological contexts. Lipid-encapsulated nanoparticles (NPs) are a class of nanomaterials that includes the liposomes, the most widely used and clinically proven type of NPs. Liposomes can, however, activate the complement system, an important branch of innate immunity, resulting in undesirable consequences. Here, we describe the complement response to lipid-encapsulated NPs that are functionalized on the surface with various lipid-anchored gadolinium chelates. We developed a quantitative approach to examine the interaction of NPs with the complement system using in vitro assays and correlating these results with those obtained in an in vivo mouse model. Our results indicate that surface functionalization of NPs with certain chemical structures elicits swift complement activation that is initiated by a natural IgM antibody and propagated via the classical pathway. The intensity of the response is dependent on the chemical structures of the lipid-anchored chelates and not zeta potential effects alone. Moreover, the extent of complement activation may be tempered by complement inhibiting regulatory proteins that bind to the surface of NPs. These findings represent a step forward in the understanding of the interactions between nanomaterials and the host innate immune response and provide the basis for a systematic structure-activity relationship study to establish guidelines that are critical to the future development of biocompatible nanotherapeutics.
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- "We show an example of how to annotate a nanoparticle formulation and its material parts (chemical component, structural parts, and linkages) using the string nomenclature described in section 2. For our example, we consider the annotation of a nanoemulsion  composed of liquid perfluoro-octylbromide (PFOB) mixed with a surfactant comixture and glycerin in distilled, deionized water. The surfactant co-mixture is composed of lecithin, gadolinium DOTA-NH3-caproyl-phosphatidylethanolamine (Gd-DOTA- PE), and V 3 -peptidomimetic antagonist conjugated to PEG-2000-phosphatidylethanolamine. "
ABSTRACT: Nanoparticle formulations that are being developed and tested for various medical applications are typically multi-component systems that vary in their structure, chemical composition, and function. It is difficult to compare and understand the differences between the structural and chemical descriptions of hundreds and thousands of nanoparticle formulations found in text documents. We have developed a string nomenclature to create computable string expressions that identify and enumerate the different high-level types of material parts of a nanoparticle formulation and represent the spatial order of their connectivity to each other. The string expressions are intended to be used as IDs, along with terms that describe a nanoparticle formulation and its material parts, in data sharing documents and nanomaterial research databases. The strings can be parsed and represented as a directed acyclic graph. The nodes of the graph can be used to display the string ID, name and other text descriptions of the nanoparticle formulation or its material part, while the edges represent the connectivity between the material parts with respect to the whole nanoparticle formulation. The different patterns in the string expressions can be searched for and used to compare the structure and chemical components of different nanoparticle formulations. The proposed string nomenclature is extensible and can be applied along with ontology terms to annotate the complete description of nanoparticles formulations.12/2012; 2012:889-894. DOI:10.1109/BIBMW.2012.6470259
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ABSTRACT: Paramagnetic and superparamagnetic metals are used as contrast materials for magnetic resonance (MR) based techniques. Lanthanide metal gadolinium (Gd) has been the most widely explored, predominant paramagnetic contrast agent until the discovery and association of the metal with nephrogenic systemic fibrosis (NSF), a rare but serious side effects in patients with renal or kidney problems. Manganese was one of the earliest reported examples of paramagnetic contrast material for MRI because of its efficient positive contrast enhancement. In this review, manganese based contrast agent approaches are discussed with a particular emphasis on their synthetic approaches. Both small molecules based typical blood pool contrast agents and more recently developed novel nanometer sized materials are reviewed focusing on a number of successful molecular imaging examples.Tetrahedron 11/2011; 67(44):8431-8444. DOI:10.1016/j.tet.2011.07.076 · 2.64 Impact Factor
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ABSTRACT: A panel of in vitro tests intended for evaluation of the nano-sized drug delivery systems' compliance with human blood was applied to liposomal formulations of anticancer lipophilic prodrugs incorporated into the lipid bilayer. Liposomes on the basis of natural phosphatidylcholine (PC) and phosphatidylinositol (PI), 8:1 (mol) were loaded with 10 mol% of either methotrexate or melphalan 1,2-dioleoylglyceride esters (MTX-DOG and Mlph-DOG respectively) and either decorated with 2 mol% of sialyl Lewis X/A (SiaLe(X/A)) tetrasaccharide ligand or not. Hemolysis rate, red blood cells and platelets integrity and size distribution, complement (C) activation, and coagulation cascade functioning were analyzed upon the material incubation with whole blood. Both formulations were negatively charged with the zeta potential value being higher in the case of MTX-DOG liposomes, which also were larger than Mlph-DOG liposomes and more prone to aggregation. Accordingly, in hemocompatibility tests Mlph-DOG liposomes did not provoke any undesirable effects, while MTX-DOG liposomes induced significant C activation and abnormal coagulation times in a concentration-dependent manner. Reactivity of the liposome surface was not affected by the presence of SiaLe(X/A) or PI. Decrease in liposome loading with MTX-DOG from 10 to 2.5% resulted in lower surface charge density, smaller liposome size and considerably reduced impact on C activation and coagulation cascades.Journal of Controlled Release 12/2011; 160(2):394-400. DOI:10.1016/j.jconrel.2011.12.010 · 7.71 Impact Factor
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