Therapeutic siRNA silencing in inflammatory monocytes in mice

Abstract

Inflammatory monocytes -- but not the non-inflammatory subset -- depend on the chemokine receptor CCR2 for distribution to injured tissue and stimulate disease progression. Precise therapeutic targeting of this inflammatory monocyte subset could spare innate immunity's essential functions for maintenance of homeostasis and thus limit unwanted effects. Here we developed siRNA nanoparticles targeting CCR2 expression in inflammatory monocytes. We identified an optimized lipid nanoparticle and silencing siRNA sequence that when administered systemically, had rapid blood clearance, accumulated in spleen and bone marrow and showed high cellular localization of fluorescently tagged siRNA inside monocytes. Efficient degradation of CCR2 mRNA in monocytes prevented their accumulation in sites of inflammation. Specifically, the treatment attenuated their number in atherosclerotic plaques, reduced infarct size following coronary artery occlusion, prolonged normoglycemia in diabetic mice after pancreatic islet transplantation and resulted in reduced tumor volumes and lower numbers of tumor-associated macrophages. Taken together, siRNA nanoparticle-mediated CCR2 gene silencing in leukocytes selectively modulates functions of innate immune cell subtypes and may allow for the development of specific anti-inflammatory therapy.

Monocytes and Macrophages in Cancer: Development and Functions

“…In addition, Leuschner and colleagues targeted monocyte recruitment to tumors using siRNA-mediated silencing of the chemokine receptor CCR2 in EL4 lymphoma and CT26 colon carcinoma models in mice, which resulted in decreased TAM accumulation and tumor growth [94].…”

Erratum: Inflammatory processes in cardiovascular disease: a route to targeted therapies

“…For example, in experimental myocardial infarction, the targeting of inflammatory 'classical' monocytes to reduce the total number of monocytes recruited to infarcted, inflamed myocardium by splenectomy or by the administration of angiotensinconverting-enzyme inhibitors has been shown to result in a reduction in infarct size and improved left ventricular function 61 . Similarly, targeting their recruitment with the administration of CCR2-siRNA delivered by nanoparticles also resulted in a reduction in the number of recruited monocytes, with a consequent reduction in infarction size and improved left ventricular function 8,62 . On the basis of these (and other) promising experimental data, a number of agents have been or are currently being investigated in clinical trials (TABLE 1).…”

“…Author Manuscript in experimental models can variously attenuate disease progression and injury, and promote healing [7][8][9][10] .…”

Targeted therapeutics in inflammatory atherosclerosis

“…Nanoparticle delivery of anti-inflammatory drugs (e.g. corticosteroids) [156] or CCR-2 siRNA [135] can modulate the bone marrow response to circulating proinflammatory cytokines. The enhanced permeability of bone marrow blood vessels and the increased nanoparticle uptake by activated macrophages can facilitate their accumulation and retention [157][158][159].…”

“…The use of bone marrow-targeted nanomedicines can improve the therapeutic efficacy of small molecules, such as bortezomib in myeloma [162]. Tackling the hyper-proliferative state and/or the egression of HSCs and inflammatory monocytes has been shown to be an upstream approach for managing inflammatory diseases [135]. In addition, combining bone marrowtargeted nanomedicines with molecular imaging can be used to assess the effect of this therapeutic approach on bone marrow activation.…”