Spleen‐Targeted Glabridin‐Loaded Nanoparticles Regulate Polarization of Monocyte/Macrophage (M_o/M_φ) for the Treatment of Cerebral Ischemia‐Reperfusion Injury

Abstract

ischemia can cause an ischemic core and salvageable surrounding tissue (termed as penumbra). The penumbra has been regarded as a pharmacological target for ischemic stroke treatment. [2] Restoring cerebral blood flow is currently the most effective approach for reducing the number of damaged neuron in the ischemic penumbra. [3] Although intravenous thrombolysis can effectively restore blood supply in the penumbra, its use is limited by a short time window during which it can be safely and effectively performed. [4] Additionally, restoring blood flow can arouse a cerebral ischemicreperfusion (I-R) injury, which results in the amplification of the inflammatory response and the aggravation of secondary damage. The infiltration of peripheral monocytes/macrophages (M o /M ϕ ) is a crucial inflammatory injury mechanism, which induces neuronal apoptosis and nervous system dysfunction. In addition, a recent study has also highlighted the pivotal role of M o /M ϕ in the repair process, indicating that regulation of the balance of M o /M ϕ can be an effective method for the treatment of cerebral I-R injury. [5] The spleen is an immediate reservoir of M o /M ϕ , which has more M o /M ϕ than the entire circulatory system. [6] The spleen is also the primary source of inflammatory cells, which can infiltrate the ischemic penumbra during the early phase of an ischemic stroke. [7] In the ischemic penumbra, M o /M ϕ can be classically activated to the M1 phenotype of macrophages (M1-macrophage), secrete pro-inflammatory cytokines, and release oxygen free radicals. [8] Due to their heterogeneity and high versatility, M o /M ϕ can also be polarized into M2-macrophages, which are involved in anti-inflammatory and repair processes through their capability to secrete anti-inflammatory cytokines. [9] Therefore, reducing the number of splenic M1-macrophages and increasing the number of splenic M2-macrophages can effectively protect neurons from the damaged microenvironment in the penumbra.Glabridin (Gla) possesses multiple pharmacological activities, including antioxidant, anti-inflammatory, and neuroprotective. [10] As a peroxisome proliferator-activated receptor-γ (PPARγ) specific antagonist, Gla is also involved in cell proliferation and differentiation. [11] Previous studies demonstrated that PPAR-γ activation could result in the M2 polarization of During cerebral ischemia-reperfusion (I-R) injury, the infiltration of monocyte/ macrophages (M o /M ϕ ) into the ischemic penumbra causes inflammatory damage but also regulates tissue repair in the penumbra. The regulation and balance of M o /M ϕ polarization is considered as a potential therapeutic target for treating cerebral I-R injury. Herein, these findings demonstrate that glabridin (Gla)-loaded nanoparticles (i.e., NP Gla -5k) can effectively inhibit M1-polarization and enhance M2-polarization of M o /M ϕ . Positron emission tomography (PET) imaging shows that NP Gla -5k can selectively accumulate in the spleen following intravenous injection. Spleen-targeted Cy5-NP Gla -5k can...

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