Bioengineered Boronic Ester Modified Dextran Polymer Nanoparticles as Reactive Oxygen Species Responsive Nanocarrier for Ischemic Stroke Treatment

Abstract

Ischemic stroke is a leading cause of long-term disability and death worldwide. Current drug delivery vehicles for the treatment of ischemic stroke are less than satisfactory, in large part due to their short circulation lives, lack of specific targeting to the ischemic site, and poor controllability of drug release. In light of the upregulation of reactive oxygen species (ROS) in the ischemic neuron, we herein developed a bioengineered ROS-responsive nanocarrier for stroke-specific delivery of a neuroprotective agent, NR2B9C, against ischemic brain damage. The nanocarrier is composed of a dextran polymer core modified with ROS-responsive boronic ester and a red blood cell (RBC) membrane shell with stroke homing peptide (SHp) inserted. These targeted "core-shell" nanoparticles (designated as SHp-RBC-NP) could thus have controlled release of NR2B9C triggered by high intracellular ROS in ischemic neurons after homing to ischemic brain tissues. The potential of the SHp-RBC-NP for ischemic stroke therapy was systematically evaluated in vitro and in rat models of middle cerebral artery occlusion (MCAO). In vitro results showed that the SHp-RBC-NP had great protective effects on glutamate-induced cytotoxicity in PC-12 cells. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) testing further demonstrated that the bioengineered nanoparticles can drastically prolong the systemic circulation of NR2B9C, enhance the active targeting of the ischemic area in the MCAO rats, and reduce ischemic brain damage.

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

“…This may utilize targeting moieties that specifically target the BBB and/or the infarcted area. In view of this, several peptides have been proposed in the literature that targets the endothelial cells of the BBB (e.g., angiopep‐2), the infarcted tissue (e.g., stroke homing peptide), or cell‐penetrating peptides45d that have the ability to enhance the uptake of the bearing nanostructures.…”

“…Other combinational approaches made use of glycan‐based nanostructures such as chitosan and dextran, that were respectively loaded with growth factors and apoptosis inhibitors (Z‐Asp(OMe)‐Glu(OMe)‐(OMe)‐fluoro methyl ketone (Z‐DEVD‐FMK)), as well as neuroprotectants, as the previously mentioned NR2B9C peptide . Surface functionalization was also performed using antibodies against the transferrin receptor or peptides such as the stroke homing peptide (SHp) . It has to be noted that some of these nanotherapeutics were designed in a way to respond to factors that are characterizing ischemic stroke conditions, such as the overproduction of thrombin, MMP‐9,86b and ROS .…”

“…Surface functionalization was also performed using antibodies against the transferrin receptor or peptides such as the stroke homing peptide (SHp) . It has to be noted that some of these nanotherapeutics were designed in a way to respond to factors that are characterizing ischemic stroke conditions, such as the overproduction of thrombin, MMP‐9,86b and ROS . This responsiveness allowed for a controlled release of the encapsulated therapeutics leading to improved therapeutic effects.…”

Sensors, Imaging Agents, and Theranostics to Help Understand and Treat Reactive Oxygen Species Related Diseases

“…The system was used for H 2 O 2 ‐activated drug delivery, in which, H 2 O 2 oxidized the copolymer to increase the lower‐critical‐solution temperature to above 37 °C, thus activating drug release. Moreover, Xin and co‐workers reported another H 2 O 2 ‐responsive delivery system for the effective treatment of ischemic stroke. A dextran‐based nanoparticle modified by boronic esters was constructed.…”

Applications of Liposomal Drug Delivery Systems to Develop Neuroprotective Agents for the Treatment of Ischemic Stroke

“…Other teams used red blood cells (RBCs) as a drug delivery carrier. Danielyan et al found that conjugation of t-PA to RBCs prolongs and localizes the activity of t-PA within the bloodstream and used the conjugate as a thromboprophylactic agent referred to as RBC/t-PA. 53) Preinjection of RBC/t-PA brought about rapid lysis of nascent cerebral thrombi, rapid and durable reperfusion, and reduction in morbidity and mortality in a mouse model of cerebral thrombosis caused by injection of preformed fibrin emboli into MCA. Lv et al developed a bioengineered ROS-responsive nanoparticle using RBC membranes which imparts the natural characteristics of RBCs including biocompatibility, immune-evading ability, and long-term circulating ability in the bloodstream to the nanoparticles.…”