Role of carbohydrate receptors in the macrophage uptake of dextran-coated iron oxide nanoparticles.
ABSTRACT 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: Tumor-associated macrophages (TAMs) form approximately 50% of tumor mass. TAMs were shown to promote tumor growth by suppressing immunocompetent cells, inducing neovascularization and supporting cancer stem cells. TAMs retain mobility in tumor mass, which can potentially be employed for better intratumoral biodistribution of nanocarriers and effective tumor growth inhibition. Due to the importance of TAMs, they are increasingly becoming principal targets of novel therapeutic approaches. In this review, we compare features of macrophages and TAMs that are essential for TAM-directed therapies, and illustrate the advantages of nanomedicine that are related to the preferential capture of nanocarriers by Mϕ in the process of drug delivery. We discuss recent efforts in reprogramming or inhibiting tumor-protecting properties of TAMs, and potential strategies to increase efficacy of conventional chemotherapy by combining with macrophage-associated delivery of nanodrugs.Nanomedicine 04/2014; 9(5):695-707. · 5.26 Impact Factor
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ABSTRACT: Inflammation is an immune response that marks several pathophysiological conditions in our body. Though adaptive immune cells play a major role in the progression of the disease, components of innate immune system, mainly monocytes and macrophages play the central role in onset of inflammation. Tissue-associated macrophages are widely distributed in the body showing tremendous anatomical and functional diversity and are actively involved in maintaining the homeostasis. They exhibit different phenotypes depending on their residing tissue microenvironment and the two major functional phenotypes are classically activated M1 phenotype showing pro-inflammatory characteristics and alternatively activated M2 phenotype demonstrating anti-inflammatory nature. Several cytokines, chemokines and other regulatory mediators delicately govern the balance of the two phenotypes in a tissue. This balance, however, is subverted during infection, injury or autoimmune response leading to increased population of M1 phenotype and subsequent chronic inflammatory disease states. This review underlines the role of macrophages in inflammatory diseases with an insight on potential molecular targets for nucleic acid therapy. Finally, some recent nanotechnology-based approaches to devise macrophage-specific targeted therapy have been highlighted.Journal of Controlled Release 04/2014; · 7.63 Impact Factor
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ABSTRACT: Production of minute concentrations of superoxide (O2(-)) and nitrogen monoxide (nitric oxide, NO) plays important roles for several aspects of cellular signaling and metabolic regulation. However, in an inflammatory environment, the concentrations of these radicals can drastically increase and the antioxidant defenses may become overwhelmed. Thus, biological damage may occur due to redox imbalance - a condition called oxidative and/or nitrosative stress. A complex interplay exists between iron metabolism, O2(-), hydrogen peroxide (H2O2), and NO. Iron is involved in both, the formation and the scavenging of these species. Iron deficiency (anemia) [ID(A)] is associated with oxidative stress, but its role in the induction of nitrosative stress is largely unclear. Moreover, oral as well as intravenous (i.v.) iron preparations used for the treatment of ID(A) may also induce oxidative and/or nitrosative stress. Oral administration of ferrous salts may lead to high transferrin saturation (TSAT) levels and thus, formation of non-transferrin bound iron (NTBI), a potentially toxic form of iron with a propensity to induce oxidative stress. One of the factors that determine the likelihood of oxidative and nitrosative stress induced upon administration of an i.v. iron complex is the amount of labile (or weakly-bound) iron present in the complex. Stable dextran-based iron complexes used for i.v. therapy, although they contain only negligible amounts of labile iron, can induce oxidative and/or nitrosative stress through so far unknown mechanisms. In this review, after summarizing the main features of iron metabolism and its complex interplay with O2(-), H2O2, NO, and other more reactive compounds derived from these species, the potential of different iron therapies to induce oxidative and nitrosative stress will be discussed and possible underlying mechanisms will be proposed. Understanding the mechanisms, by which different iron formulations may induce oxidative and nitrosative stress, will help to develop better tolerated and more efficient therapies for different dysfunctions of iron metabolism.Free Radical Biology & Medicine 09/2013; · 5.27 Impact Factor