Nanocarrier-Mediated Inhibition of Macrophage Migration Inhibitory Factor Attenuates Secondary Injury after Spinal Cord Injury

Abstract

Spinal cord injury (SCI) can lead to permanent motor and sensory deficits. Following the initial traumatic insult, secondary injury mechanisms characterized by persistent heightened inflammation are initiated and lead to continued and pervasive cell death and tissue damage. Anti-inflammatory drugs such as methylprednisolone (MP) used clinically have ambiguous benefits with debilitating side effects. Typically, these drugs are administered systemically at high doses, resulting in toxicity and paradoxically increased inflammation. Furthermore, these drugs have a small time window postinjury (few hours) during which they need to be infused to be effective. As an alternative to MP, we investigated the effect of a small molecule inhibitor (Chicago sky blue, CSB) of macrophage migration inhibitory factor (MIF) for treating SCI. The pleiotropic cytokine MIF is known to contribute to upregulation of several pro-inflammatory cytokines in various disease and injury states. In vitro, CSB administration alleviated endotoxin-mediated inflammation in primary microglia and macrophages. Nanocarriers such as liposomes can potentially alleviate systemic side effects of high-dose therapy by enabling site-specific drug delivery to the spinal cord. However, the therapeutic window of 100 nm scale nanoparticle localization to the spinal cord after contusion injury is not fully known. Thus, we first investigated the ability of nanocarriers of different sizes to localize to the injured spinal cord up to 2 weeks postinjury. Results from the study showed that nanocarriers as large as 200 nm in diameter could extravasate into the injured spinal cord up to 96 h postinjury. We then formulated nanocarriers (liposomes) encapsulating CSB and administered them intravenously 48 h postinjury, within the previously determined 96 h therapeutic window. In vivo, in this clinically relevant contusion injury model in rats, CSB administration led to preservation of vascular and white matter integrity, improved wound healing, and an increase in levels of arginase and other transcripts indicative of a resolution phase of wound healing. This study demonstrates the potential of MIF inhibition in SCI and the utility of nanocarrier-mediated drug delivery selectively to the injured cord.

Controlled release strategies for modulating immune responses to promote tissue regeneration

“…Administration of factors that inhibit inflammatory cytokines, such as macrophage migration inhibitory factor (MIF) and IL-6, have been implemented to reduce inflammation after injury. MIF inhibitors, such as gremlin-1 and liposome encapsulated Chicago sky blue can alleviate inflammation by limiting monocyte recruitment from the bone marrow/spleen through the vasculature to sites of inflammation and by promoting M2 macrophages [136, 162]. Intravenously administrated nanoparticles can also target monocytes responsible for acute inflammation.…”

Drug delivery, cell-based therapies, and tissue engineering approaches for spinal cord injury

“…Systemic administration of ferulic acid (FA)- glycol chitosan (GC) (FA-GC) NPs was reported to cause improvements in locomotion, axonal and myelin protection, attributed to the neuroprotective properties of FA and GC which extend anti-oxidative effects to prevent inflammation and excitotoxicity (86). Administration of small molecule inhibitors such as Chicago sky blue, a macrophage migration inhibitory factor, encapsulated in NPs increased white matter and blood vessel integrity post-SCI (87), but demonstrated activation of both pro- and anti-inflammatory signals which could be ascribed to dynamic changes in macrophage phenotypes while still being reparative in nature (88). Another pharmacological approach modulated the activated microglia/macrophage response in the subacute phase of inflammation by using minocycline loaded polymeric polycaprolactone NPs (89).…”

Nanoparticle Technologies in the Spinal Cord

“…Lipid nanoparticles are also able to cross the BBB Wang et al, 2010]. Liposomes (with diameters around 100-200 nm) were able to deliver Chicago Sky Blue to inhibit macrophage migration inhibitory factor following SCI [Saxena et al, 2015]. This treatment reduced secondary injury following spinal cord contusion injury in rats.…”

“…The inflammation can also trigger the synthesis and deposition of chondroitin sulfate proteoglycans (CSPGs), molecules which are well known for inhibiting axonal sprouting. Nanoparticles have been utilized to deliver anti-inflammatory agents such as methylprednisolone [Kim et al, 2009;Cerqueira et al, 2013], flavopiridol [Ren et al, 2014], estrogen [Cox et al, 2015] and macrophage migration inhibitory factor [Saxena et al, 2015] at early times following injury. These have been tested in various SCI paradigms, including hemisection and contusion models in rodents.…”

“…Nanoparticles can be fab-ricated from a wide variety of materials, including polymers, liposomes, inorganics, and metals [Gurny, 1981;Park et al, 2009;Papastefanaki et al, 2015;Saxena et al, 2015]. Due to the vast differences among these materials, there is a broad range of functions and applications for nanoparticles; they are utilized for imaging, cell identification, cell targeting, and drug delivery [Sun et al, 2008;Ruoslahti et al, 2010;Chan et al, 2013;Joo et al, 2015;Accomasso et al, 2016].…”