Role of Carbohydrate Receptors in the Macrophage Uptake of Dextran-Coated Iron Oxide Nanoparticles
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.Advances in Experimental Medicine and Biology (Impact Factor: 1.96). 01/2012; 733:115-23. DOI: 10.1007/978-94-007-2555-3_11
Superparamagnetic iron oxide (SPIO, Ferumoxides, Feridex), an important MRI intravenous contrast reagent, is efficiently recognized and eliminated by macrophages in the liver, spleen, lymph nodes and atherosclerotic lesions. The receptors that recognize nanoparticles are poorly defined and understood. Since SPIO is coated with bacterial polysaccharide dextran, it is important to know whether carbohydrate recognition plays a role in nanoparticle uptake by macrophages. Lectin-like receptors CD206 (macrophage mannose receptor) and SIGNR1 were previously shown to mediate uptake of bacterial polysaccharides. We transiently expressed receptors MGL-1, SIGNR-1 and msDectin-1 in non-macrophage 293T cells using lipofection. The expression was confirmed by reverse transcription PCR. Following incubation with the nanoparticles, the uptake in receptor-expressing cells was not statistically different compared to control cells (GFP-transfected). At the same time, expression of scavenger receptor SR-A1 increased the uptake of nanoparticles three-fold compared to GFP-transfected and control vector-transfected cells. Blocking CD206 with anti-CD206 antibody or with the ligand mannan did not affect SPIO uptake by J774.A1 macrophages. Similarly, there was no inhibition of the uptake by anti-CD11b (Mac-1 integrin) antibody. Polyanionic scavenger receptor ligands heparin, polyinosinic acid, fucoidan and dextran sulfate decreased the uptake of SPIO by J774A.1 macrophages and Kupffer cells by 60-75%. These data unambiguously show that SPIO is taken up via interaction by scavenger receptors, but not via dextran recognition by carbohydrate receptors. Understanding of nanoparticle-receptor interaction can provide guidance for the design of long circulating, non-toxic nanomedicines.
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ABSTRACT: Lipid-based nanoparticles (LNPs) hold great promise as delivery vectors in the treatment of cancer, inflammation, and infections and are already used in clinical practice. Numerous strategies based on LNPs are being developed to carry drugs into specific target sites. The common denominator for all of these LNPs-based platforms is to improve the payloads' pharmacokinetics, biodistribution, stability and therapeutic benefit, and to reduce to minimal adverse effects. In addition, the delivery system must be biocompatible and non-toxic and avoid undesirable interactions with the immune system. In order to achieve optimal benefits from these delivery strategies, interactions with the immune system must be thoroughly investigated. This report will center on the interactions of LNPs with different subsets of leukocytes and will detail representative examples of suppression or activation of the immune system by these carriers. By understanding the interactions of LNPs with the innate and the adaptive arms of the immune system it might be possible to attain improved therapeutic benefits and to avoid immune toxicity.Journal of Controlled Release 12/2011; 161(2):600-8. DOI:10.1016/j.jconrel.2011.12.034 · 7.71 Impact Factor
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ABSTRACT: Lipid-based nanoparticles (LNPs) such as liposomes, micelles, and hybrid systems (e.g. lipid-polymer) are prominent delivery vehicles that already made an impact on the lives of millions around the globe. A common denominator of all these LNP-based platforms is to deliver drugs into specific tissues or cells in a pathological setting with minimal adverse effects on bystander cells. All these platforms must be compatible to the physiological environment and prevent undesirable interactions with the immune system. Avoiding immune stimulation or suppression is an important consideration when developing new strategies in drug and gene delivery, whereas in adjuvants for vaccine therapies, immune activation is desired. Therefore, profound understanding of how LNPs elicit immune responses is essential for the optimization of these systems for various biomedical applications. Herein, I describe general concepts of the immune system and the interaction of subsets of leukocytes with LNPs. Finally, I detail the different immune toxicities reported and propose ways to manipulate leukocytes' functions using LNPs.Advanced drug delivery reviews 07/2012; 64(15). DOI:10.1016/j.addr.2012.06.013 · 15.04 Impact Factor
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ABSTRACT: The pathogenic hallmark of systemic lupus erythematosus is the autoimmune response against self nuclear Ags, including dsDNA. The increased expression of the proinflammatory cytokine IL-1β has been found in the cutaneous lesion and PBMCs from lupus patients, suggesting a potential involvement of this cytokine in the pathogenesis of lupus. IL-1β is produced primarily by innate immune cells such as monocytes and can promote a Th17 cell response, which is increased in lupus. IL-1β production requires cleaving pro-IL-β into IL-1β by the caspase-1-associated multiprotein complex called inflammasomes. In this study we show that self dsDNA induces IL-1β production from human monocytes dependent on serum or purified IgG containing anti-dsDNA Abs by activating the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Reactive oxygen species (ROS) and K(+) efflux were involved in this activation. Knocking down the NLRP3 or inhibiting caspase-1, ROS, and K(+) efflux decreased IL-1β production. Supernatants from monocytes treated with a combination of self dsDNA and anti-dsDNA Ab(+) serum promoted IL-17 production from CD4(+) T cells in an IL-1β-dependent manner. These findings provide new insights in lupus pathogenesis by demonstrating that self dsDNA together with its autoantibodies induces IL-1β production from human monocytes by activating the NLRP3 inflammasome through inducing ROS synthesis and K(+) efflux, leading to the increased Th17 cell response.The Journal of Immunology 01/2013; 190(4). DOI:10.4049/jimmunol.1201195 · 4.92 Impact Factor
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