Reduction of Oxidative Stress and Excitotoxicity by Mesenchymal Stem Cell Biomimetic Co-Delivery System for Cerebral Ischemia-Reperfusion Injury Treatment.

A cerebral ischemia-reperfusion injury is ensued by an intricate interplay between various pathological processes including excitotoxicity, oxidative stress, inflammation, and apoptosis. For a long time, drug intervention policies targeting a single signaling pathway have failed to achieve the anticipated clinical efficacy in the intricate and dynamic inflammatory environment of the brain. Moreover, inadequate targeted drug delivery remains a significant challenge in cerebral ischemia-reperfusion injury therapy. In this study, a multifunctional nanoplatform (designated as PB-006@MSC) is developed using ZL006-loaded Prussian blue nanoparticles (PBNPs) camouflaged by a mesenchymal stem cell (MSC) membrane (MSCm). ZL006 is a neuroprotectant. It can be loaded efficiently into the free radical scavenger PBNP through mesoporous adsorption. This can simultaneously modulate multiple targets and pathways. MSCm biomimetics can reduce the nanoparticle immunogenicity, efficiently enhance their homing capability to the cerebral ischemic penumbra, and realize active-targeting therapy for ischemic stroke. In animal experiments, PB-006@MSC integrated reactive oxygen species (ROS) scavenging and neuroprotection. Thereby, it selectively targeted the cerebral ischemic penumbra (about fourfold higher accumulation at 24 h than in the non-targeted group), demonstrated a remarkable therapeutic efficacy in reducing the volume of cerebral infarction (from 37.1% to 2.3%), protected the neurogenic functions, and ameliorated the mortality.

Enhanced the treatment of ischemic stroke through intranasal temperature-sensitive hydrogels of edaravone and borneol inclusion complex.

Since ischemic stroke occurs by a combination of multiple mechanisms, therapies that modulate multiple mechanisms are required for its treatment. The combination of edaravone (EDA) and borneol can significantly ameliorate the symptoms of neurological deficits in cerebral ischemia-reperfusion model in rats. In this study, the solubility of borneol and edaravone was improved by hydroxypropyl-ß-cyclodextrin and PEG400. Furthermore, a nasal temperature-sensitive hydrogel containing both edaravone and borneol inclusion complex (EDA-BP TSGS) was developed to overcome the obstacles of ischemic stroke treatment including the obstruction of the blood-brain barrier (BBB) and the unavailability and untimely of intravenous injection. The effectiveness of the thermosensitive hydrogel was investigated in transient middle cerebral artery occlusion/reperfusion model rats (MCAO/R). The results showed that EDA-BP TSGS could significantly alleviate the symptoms of neurological deficits and decrease the cerebral infarct area and the degree of brain damage. In summary, nasal EDA-BP TSGS is a secure and effective brain-targeting formulation that may provide a viable option for the clinical prophylaxis and treatment of ischemic stroke.

Smart Liposomal Nanocarrier Enhanced the Treatment of Ischemic Stroke through Neutrophil Extracellular Traps and Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase-Stimulator of Interferon Genes (cGAS-STING) Pathway Inhibition of Ischemic Penumbra.

Brain inflammation is regarded as one of the leading causes that aggravates secondary brain injury and hinders the prognosis of ischemic stroke. After ischemic stroke, high quantities of peripheral neutrophils are recruited to brain lesions and release neutrophil extracellular traps (NETs), leading to the aggravation of blood-brain barrier (BBB) damage, activation of microglia, and ultimate neuronal death. Herein, a smart multifunctional delivery system has been developed to regulate immune disorders in the ischemic brain. Briefly, Cl-amidine, an inhibitor of peptidylarginine deiminase 4 (PAD4), is encapsulated into self-assembled liposomal nanocarriers (C-Lipo/CA) that are modified by reactive oxygen species (ROS)-responsive polymers and fibrin-binding peptide to achieve targeting ischemic lesions and stimuli-responsive release of a drug. In the mouse model of cerebral artery occlusion/reperfusion (MCAO), C-Lipo/CA can suppress the NETs release process (NETosis) and further inhibit the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway in an ischemic brain. In addition, MCAO mice treated with C-Lipo/CA significantly mitigated ischemic and reperfusion injury, with a reduction in the area of cerebral infarction to 12.1%, compared with the saline group of about 46.7%. These results demonstrated that C-Lipo/CA, which integrated microglia regulation, BBB protection, and neuron survival, exerts a potential therapy strategy to maximize ameliorating the mortality of ischemic stroke.

Reduced malignant glioblastoma recurrence post-resection through the anti-CD47 antibody and Temozolomide co-embedded in-situ hydrogel system.

Infiltrative glioma growth makes surgical excision incomplete, and the residual tumor cells proliferate rapidly. Residual glioma cells evade phagocytosis by macrophages through upregulating anti-phagocytosis molecule CD47, which binds to the signal regulatory protein alpha (SIRPα) of macrophages. Specifically, blocking the CD47-SIRPα pathway is a potential strategy for post-resection glioma treatment. In addition, the anti-CD47 antibody (α-CD47) in combination with temozolomide (TMZ) caused an enhanced pro-phagocytic effect due to the TMZ not only destroying DNA but also inducing endoplasmic reticulum stress response of glioma cells. However, the obstruction of the blood-brain barrier makes systemic combination therapy not ideal for post-resection glioma treatment. Herein, we designed a temperature-sensitive hydrogel system based on a moldable thermosensitive hydroxypropyl chitin (HPCH) copolymer to encapsulate both α-CD47 and TMZ as α-CD47&TMZ@Gel for in situ postoperative cavity administration. Through the in vitro and in vivo evaluations, α-CD47&TMZ@Gel significantly inhibited glioma recurrence post-resection through enhancement of pro-phagocytosis of macrophages, recruitment, and activation of CD8+ T cells and NK cells.

Multifunctional Hybrid Hydrogel System Enhanced the Therapeutic Efficacy of Treatments for Postoperative Glioma.

Glioma is the most lethal brain tumor with a poor prognosis, and a combination of multiple therapeutic strategies is critical for postoperative glioma treatment. Herein, a multifunctional hybrid hydrogel system (designated as CP&CL@RNPPTX-Gel) was developed for local treatment of postoperative glioma. The system was composed of self-illuminating chlorin e6 (Ce6) conjugated with luminol molecule (CL)-loaded glioma-targeting paclitaxel prodrug nanoparticles and copper peroxide nanodots (CP NDs) coembedded into a three-dimensional thermosensitive hydroxypropyl chitin hydrogel frame. After injection of CP&CL@RNPPTX-Gel into the cavity of postoperative glioma, the solution could be cross-linked into the gel as a drug reservoir under body temperature stimulation. Then, the sustained-released CP NDs decomposed into Cu2+ and H2O2 in the acidic microenvironment of the glioma cells to exert chemodynamic therapy (CDT). Meanwhile, Cu2+ could catalyze the self-luminescence of CL to induce photodynamic therapy (PDT) without external excitation light. Moreover, paclitaxel prodrug nanoparticles degraded into paclitaxel to restrain residual glioma cells in response to intracellular reduced glutathione (GSH). The in vitro and in vivo results showed that CP&CL@RNPPTX-Gel had great potential as a multifunctional hybrid hydrogel system with remarkable therapeutic effects for postoperative glioma treatment via a combination of chemotherapy, CDT, and PDT.

Enhanced treatment of cerebral ischemia-Reperfusion injury by intelligent nanocarriers through the regulation of neurovascular units.

Reperfusion injury is one of the major causes of disability and death caused by ischemic stroke, and drug development focuses mainly on single neuron protection. However, different kinds of cells in the neurovascular units (NVUs), including neurons, microglia and vascular endothelial cells, are pathologically changed after cerebral ischemia-reperfusion injury, resulting in an urgent need to develop a drug delivery system to comprehensively protect the kinds of cells involved in the NVU. Herein, we have constructed a c(RGDyK) peptide modified, NF-κB inhibitor caffeic acid phenethyl ester (CAPE)-loaded and reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier (R-Lipo-CAPE) to target ischemic lesions and then remodel the NVU to reduce the progression of cerebral ischemia-reperfusion injury. The R-Lipo-CAPE liposomes were approximately 170 nm with a zeta potential of -30.8 ± 0.2 mV. The in vitro CAPE release behavior from R-Lipo-CAPE showed an RNS-dependent pattern. For in vivo studies, transient middle cerebral artery occlusion/reperfusion (MCAO) model mice treated with R-Lipo-CAPE had the least neurological impairment and decreased brain tissue damage, with an infarct area of 13%, compared with those treated with saline of 53% or free CAPE of 38%. Furthermore, microglia in the ischemic brain were polarized to the tissue-repairing M2 phenotype after R-Lipo-CAPE treatment. In addition, R-Lipo-CAPE-treated mice displayed a prominent down-regulated expression of MMP-9 and restored expression of the tight junction protein claudin-5. This proof-of-concept indicates that R-Lipo-CAPE is a promising nanomedicine for the treatment of cerebral ischemia-reperfusion injury through the regulation of neurovascular units. STATEMENT OF SIGNIFICANCE: Based on the complex mechanism and difficulty in treatment of cerebral ischemia-reperfusion injury, the overall regulation of neurovascular unit has become an extremely important target. However, little nanomedicine has been directed to remodel the neurovascular units in targeted cerebral ischemia-reperfusion injury therapy. Here, c(RGDyK) peptide modified reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier loaded with a NF-κB inhibitor (CAPE), was designed to simultaneously regulate various cells in the microenvironment of cerebral ischemia-reperfusion injury to remodel the neurovascular units. Our in vitro and in vivo data showed that the intelligent nanocarrier exerted the ability of pathological signal stimuli-responsive drug release, cerebral ischemia-reperfusion injury site targeting and neurovascular units remodeling through reducing neuron apoptosis, regulating microglia polarization and repairing vascular endothelial cell. Overall, the intelligent liposomal drug delivery system was a promising and safe nanomedicine in the perspective of cerebral ischemia-reperfusion injury treatment.