Direct Macromolecular Drug Delivery to Cerebral Ischemia Area using Neutrophil-Mediated Nanoparticles

Abstract

Delivery of macromolecular drugs to the brain is impeded by the blood brain barrier. The recruitment of leukocytes to lesions in the brain, a typical feature of neuroinflammation response which occurs in cerebral ischemia, offers a unique opportunity to deliver drugs to inflammation sites in the brain. In the present study, cross-linked dendrigraft poly-L-lysine (DGL) nanoparticles containing cis-aconitic anhydride-modified catalase and modified with PGP, an endogenous tripeptide that acts as a ligand with high affinity to neutrophils, were developed to form the cl PGP-PEG-DGL/CAT-Aco system. Significant binding efficiency to neutrophils, efficient protection of catalase enzymatic activity from degradation and effective transport to receiver cells were revealed in the delivery system. Delivery of catalase to ischemic subregions and cerebral neurocytes in MCAO mice was significantly enhanced, which obviously reducing infarct volume in MCAO mice. Thus, the therapeutic outcome of cerebral ischemia was greatly improved. The underlying mechanism was found to be related to the inhibition of ROS-mediated apoptosis. Considering that neuroinflammation occurs in many neurological disorders, the strategy developed here is not only promising for treatment of cerebral ischemia but also an effective approach for various CNS diseases related to inflammation.

Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures?

“…Due to early neutrophil infiltration into ischaemic brain tissues, neutrophils were considered as cargo vehicles to deliver macromolecular drugs to block reactive oxygen species‐mediated apoptosis following stroke . Clinical studies demonstrated that the neutrophil‐to‐lymphocyte ratio might be a strong prognostic marker in acute ischaemic stroke and that neutrophil extracellular traps are increased in patients with stroke .…”

“…62 Due to early neutrophil infiltration into ischaemic brain tissues, neutrophils were considered as cargo vehicles to deliver macromolecular drugs to block reactive oxygen species-mediated apoptosis following stroke. 63 Clinical studies demonstrated that the neutrophil-to-lymphocyte ratio might be a strong prognostic marker in acute ischaemic stroke 64 and that neutrophil extracellular traps are increased in patients with stroke. 65 Neutrophil extracellular traps are produced by activated myeloid cells, including neutrophils, as networks of DNA, histones and proteolytic enzymes, and are capable of activating platelets and contribute to the thrombotic processes.…”

Retracted: Ganoderic Acid A exerts the cytoprotection against hypoxia‐triggered impairment in PC12 cells via elevating microRNA‐153

“…The etiology of cerebral ischemia is closely linked to cerebral arteriosclerosis (Moroni et al, ), and chronic cerebral insufficiency is the most likely cause of dizziness, sleep disorders, and memory loss (Chen, Du, Xu, Liu, & Wang, ; Scheidt et al, ). Drug and operation are currently the cardinal treatments for cerebral ischemia (Powers et al, ; Zhang et al, ). Some patients with cerebral ischemia are curable; however, some patients require lifelong medication.…”

Advanced Functional Materials and Cell‐Based Therapies for the Treatment of Ischemic Stroke and Postischemic Stroke Effects

“…One of the most used biomaterial‐based nanostructures in the combinational studies are the polymeric ones. These nanostructures find several uses as supportive scaffolds for the delivery of MSCs, as nanoparticles for drug and gene delivery or as coatings for inorganic nanoparticles . Each of these nanostructures is able to encapsulate a variety of therapeutics, including antioxidants such as catalase,86a nanoceria, and edaravone, growth factors such as VEGF, and other neuroprotectants such as glyburide86b and the NR2B9C therapeutic peptide 86c.…”