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Intravenous immune-modifying nanoparticles as a therapy for spinal cord injury in mice.

ABSTRACT: Intravenously infused synthetic 500nm nanoparticles composed of poly(lactide-co-glycolide) are taken up by blood-borne inflammatory monocytes via a macrophage scavenger receptor (macrophage receptor with collagenous structure), and the monocytes no longer traffic to sites of inflammation. Intravenous administration of the nanoparticles after experimental spinal cord injury in mice safely and selectively limited infiltration of hematogenous monocytes into the injury site. The nanoparticles did not bind to resident microglia, and did not change the number of microglia in the injured spinal cord. Nanoparticle administration reduced M1 macrophage polarization and microglia activation, reduced levels of inflammatory cytokines, and markedly reduced fibrotic scar formation without altering glial scarring. These findings thus implicate early-infiltrating hematogenous monocytes as highly selective contributors to fibrosis that do not play an indispensable role in gliosis after SCI. Further, the nanoparticle treatment reduced accumulation of chondroitin sulfate proteoglycans, increased axon density inside and caudal to the lesion site, and significantly improved functional recovery after both moderate and severe injuries to the spinal cord. These data provide further evidence that hematogenous monocytes contribute to inflammatory damage and fibrotic scar formation after spinal cord injury in mice. Further, since the nanoparticles are simple to administer intravenously, immunologically inert, stable at room temperature, composed of an FDA-approved material, and have no known toxicity, these findings suggest that the nanoparticles potentially offer a practical treatment for human spinal cord injury.

SUBMITTER: Jeong SJ

PROVIDER: S-EPMC5675775 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Intravenous immune-modifying nanoparticles as a therapy for spinal cord injury in mice.

Jeong Su Ji SJ Cooper John G JG Ifergan Igal I McGuire Tammy L TL Xu Dan D Hunter Zoe Z Sharma Sripadh S McCarthy Derrick D Miller Stephen D SD Kessler John A JA

Neurobiology of disease 20170818

Intravenously infused synthetic 500nm nanoparticles composed of poly(lactide-co-glycolide) are taken up by blood-borne inflammatory monocytes via a macrophage scavenger receptor (macrophage receptor with collagenous structure), and the monocytes no longer traffic to sites of inflammation. Intravenous administration of the nanoparticles after experimental spinal cord injury in mice safely and selectively limited infiltration of hematogenous monocytes into the injury site. The nanoparticles did no ...[more]

PMID: 28823935

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Project description:BackgroundSpinal cord injury (SCI) is damage to the central nervous system (CNS) that causes devastating complications from chronic pain to breathing problems. Unfortunately, few effective and safe treatments are known to relieve the damages of SCI. Nanomedicines are used for the treatment of SCI with relatively few side effects, but only depending on the delivery of additional drugs, which increase complexity to the treatment. Considering the urgent need for saving SCI patients, it is important to develop promising nanobiotechnology for relieving their pains.MethodsThe clinical survey was used to investigate SCI patients, thereafter the therapy plan was designed. The receiver-operating characteristics (ROC) curves of the prediction model were built to find symptoms after SCI. The treatment plan (i.e. immunosuppressive strategy) was designed by manufacturing therapies based on gold nanoclusters (AuNCs). The response of the immune cells (macrophages) was studied accordingly. The western blot, reactive oxygen species (ROS) activity assay, enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR (RT-qPCR), and immunochemical staining were used for evaluation of the in vivo and in vitro therapeutic effects.ResultsWe found increased monocytes/macrophages (M/Ms) levels in 114 SCI subjects (44.7% with severe SCI complications) by the clinical survey. Additionally, the enhanced macrophage level was found to be closely related to the walking disorder after SCI. Since macrophages were central effector cells of the immune system, we assumed that the immune-suppressing strategies could be used for SCI therapy. Thereafter, AuNCs were stabilized by dihydrolipoic acid (DHLA) enantiomers (including DL-DHLA, R-DHLA; A racemic mixture (R and S) was denoted as DL; R and S refer to Rectus and Sinister), obtaining DL-DHLA-AuNCs and R-DHLA-AuNCs, respectively. In addition, zinc-modified DL-DHLA and R-DHLA stabilized AuNCs (i.e., DL-DHLA-AuNCs-Zn and R-DHLA-AuNCs-Zn) were investigated. Among these AuNCs, R-DHLA-AuNCs-Zn showed the most remarkable therapeutic effect for promoting the polarization of pro-inflammatory macrophages and reducing neuronal ROS-induced apoptosis and inflammation in vitro and in vivo; the lesion size was decreased and the survival rate of ventral neurons is higher.ConclusionsR-DHLA-AuNCs-Zn have comprehensive therapeutic capabilities, especially the immune-suppressing effects for the therapy of SCI, which is promising to relieve the pain or even recover SCI for the patients.

Project description:BackgroundSpinal cord injury (SCI) is one of the serious neurological diseases that occur in young people with high morbidity and disability. However, there is still a lack of effective treatments for it. Stem cell (SC) treatment of SCI has gradually become a new research hotspot over the past decades. This article is aimed at reviewing the research progress of SC therapy for SCI.MethodsReview the literature and summarize the effects, strategies, related mechanisms, safety, and clinical application of different SC types and new approaches in combination with SC in SCI treatment.ResultsA large number of studies have focused on SC therapy for SCI, most of which showed good effects. The common SC types for SCI treatment include mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs). The modes of treatment include in vivo and in vitro induction. The pathways of transplantation consist of intravenous, transarterial, nasal, intraperitoneal, intrathecal, and intramedullary injections. Most of the SC treatments for SCI use a number of cells ranging from tens of thousands to millions. Early or late SC administration, application of immunosuppressant or not are still controversies. Potential mechanisms of SC therapy include tissue repair and replacement, neurotrophy, and regeneration and promotion of angiogenesis, antiapoptosis, and anti-inflammatory. Common safety issues include thrombosis and embolism, tumorigenicity and instability, infection, high fever, and even death. Recently, some new approaches, such as the pharmacological activation of endogenous SCs, biomaterials, 3D print, and optogenetics, have been also developed, which greatly improved the application of SC therapy for SCI.ConclusionMost studies support the effects of SC therapy on SCI, while a few studies do not. The cell types, mechanisms, and strategies of SC therapy for SCI are very different among studies. In addition, the safety cannot be ignored, and more clinical trials are required. The application of new technology will promote SC therapy of SCI.

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Intravenous immune-modifying nanoparticles as a therapy for spinal cord injury in mice.

Publications

Intravenous immune-modifying nanoparticles as a therapy for spinal cord injury in mice.

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