ABSTRACT
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.
Subject(s)
Antibodies/immunology , Complement System Proteins/immunology , Nanocapsules/chemistry , Phospholipids , Animals , Drug Design , Gadolinium/chemistry , Humans , Immunoglobulin M/immunology , Mice , Nanocapsules/adverse effects , Surface PropertiesABSTRACT
This article describes the solid-phase combinatorial methods developed for the synthesis of polyhydroxamate-based siderophores. This strategy was applied to generate several libraries of structural DFO (1a) analogues that include DFO variants, non-amide analogues, C-terminal modified analogues, reverse-amide analogues, and hybrid analogues. To assess the relative iron-binding affinities of these compounds, a high-throughput spectrophotometric screening method based on competition with 8-hydroxyquinoline-5-sulfonic acid was developed. Some of the promising candidates containing various terminal functional groups were identified and prepared on large scale to enable future studies in animal models for iron-overload diseases.
Subject(s)
Deferoxamine/analogs & derivatives , Deferoxamine/chemistry , Hydroxamic Acids/chemistry , Iron Chelating Agents/chemical synthesis , Oxyquinoline/analogs & derivatives , Alkylation , Chromatography, High Pressure Liquid , Ferric Compounds/chemistry , Models, Chemical , Oxyquinoline/chemistryABSTRACT
A solid-phase approach for the total synthesis of methyl carboxymycobactins 1a-d, with an on-resin cyclization leading to azopine 5 as the key step, was developed. The iron-affinity of these compounds was assessed by a competitive sulfoxine-binding assay, and antimycobacterial activity was tested against the growth of Mycobacterium avium.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Mycobacterium avium Complex/drug effects , Oxazoles/chemical synthesis , Chromatography, High Pressure Liquid , Cyclization , Indicators and Reagents , Iron/chemistry , Iron Chelating Agents/pharmacology , Microbial Sensitivity Tests , Mycobacterium avium Complex/growth & development , Oxazoles/pharmacology , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, UltravioletABSTRACT
4,13-Bis(benzotriazolylmethyl)-4,13-diaza-1,7,10,16-tetraoxacyclooctadecane (6) was synthesized as a versatile intermediate in the preparation of bis(lariats) of diaza-18-crown-6. N,N'-Bis(umbelliferon-8-ylmethyl) derivative 8, bis(lariats) with terminal unsaturated groups (11c,e), ester functionalities (11d), N,N'-di-beta-aralkyl derivatives (11a,b), and gamma-oxy-substituted (13, 14) and gamma-amino-substituted (17-19) propylene-side-armed derivatives were thus prepared in moderate to excellent yields. The X-ray structure of bis(lariat) 6 and stability constants for several of the complexes of bis(lariats), derivatives of 6, with metal cations are discussed.
ABSTRACT
A series of new 15- and 18-membered N-pivot lariat aza-crown ethers having a propylene linkage in the side arm was prepared starting from functionalized diethanolamines and functionalized lariat aza-crown ethers containing the easily modified benzotriazole moiety. Addition reactions of such derivatives to electron-rich vinyl ethers or vinylamides followed by displacement of the benzotriazolyl group in the addition products by hydrogen (by reduction with LiAlH(4)) gives a variety of N-(3-oxo-3-substituted)- and N-(3-aza-3-substituted)propylene side-armed derivatives of aza-crown ethers. Stability constants for the complexes of several synthesized lariats with metal cations are discussed.