Microenvironment-Responsive Hydrogel Reduces Seizures After Traumatic Brain Injury in Juvenile Rats by Reducing Oxidative Stress and Hippocampal Inflammation.

Traumatic brain injury (TBI) is the primary cause of child mortality and disability worldwide. It can result in severe complications that significantly impact children's quality of life, including post-traumatic epilepsy (PTE). An increasing number of studies suggest that TBI-induced oxidative stress and neuroinflammatory sequelae (especially, inflammation in the hippocampus region) may lead to the development of PTE. Due to the blood-brain barrier (BBB), typical systemic pharmacological therapy for TBI cannot deliver berberine (BBR) to the targeted location in the early stages of the injury, although BBR has strong anti-inflammatory properties. To break through this limitation, a microenvironment-responsive gelatin methacrylate (GM) hydrogel to deliver poly(propylene sulfide)60 (PPS60) and BBR (GM/PB) is developed for regulating neuroinflammatory reactions and removing reactive oxygen species (ROS) in the brain trauma microenvironment through PPS60. In situ injection of the GM/PB hydrogel efficiently bypasses the BBB and is administered directly to the surface of brain tissue. In post-traumatic brain injury models, GM/PB has the potential to mitigate oxidative stress and neuroinflammatory responses, facilitate functional recovery, and lessen seizing. These findings can lead to a new treatment for brain injuries, which minimizes complications and improves the quality of life.

An injectable refrigerated hydrogel for inducing local hypothermia and neuroprotection against traumatic brain injury in mice.

BACKGROUND: Hypothermia is a promising therapy for traumatic brain injury (TBI) in the clinic. However, the neuroprotective outcomes of hypothermia-treated TBI patients in clinical studies are inconsistent due to several severe side effects. Here, an injectable refrigerated hydrogel was designed to deliver 3-iodothyronamine (T1AM) to achieve a longer period of local hypothermia for TBI treatment. Hydrogel has four advantages: (1) It can be injected into injured sites after TBI, where it forms a hydrogel and avoids the side effects of whole-body cooling. (2) Hydrogels can biodegrade and be used for controlled drug release. (3) Released T1AM can induce hypothermia. (4) This hydrogel has increased medical value given its simple operation and ability to achieve timely treatment. METHODS: Pol/T hydrogels were prepared by a low-temperature mixing method and characterized. The effect of the Pol/T hydrogel on traumatic brain injury in mice was studied. The degradation of the hydrogel at the body level was observed with a small animal imager. Brain temperature and body temperature were measured by brain thermometer and body thermometer, respectively. The apoptosis of peripheral nerve cells was detected by immunohistochemical staining. The protective effect of the hydrogels on the blood-brain barrier (BBB) after TBI was evaluated by the Evans blue penetration test. The protective effect of hydrogel on brain edema after injury in mice was detected by Magnetic resonance (MR) in small animals. The enzyme linked immunosorbent assay (ELISA) method was used to measure the levels of inflammatory factors. The effects of behavioral tests on the learning ability and exercise ability of mice after injury were evaluated. RESULTS: This hydrogel was able to cool the brain to hypothermia for 12 h while maintaining body temperature within the normal range after TBI in mice. More importantly, hypothermia induced by this hydrogel leads to the maintenance of BBB integrity, the prevention of cell death, the reduction of the inflammatory response and brain edema, and the promotion of functional recovery after TBI in mice. This cooling method could be developed as a new approach for hypothermia treatment in TBI patients. CONCLUSION: Our study showed that injectable and biodegradable frozen Pol/T hydrogels to induce local hypothermia in TBI mice can be used for the treatment of traumatic brain injury.

A Novel Targeted Nanoparticle for Traumatic Brain Injury Treatment: Combined Effect of ROS Depletion and Calcium Overload Inhibition.

Survival after severe traumatic brain injury (TBI) depends on minimizing or avoiding secondary insults to the brain. Overproduction of reactive oxygen species (ROS) and Ca2+ influx at the damaged site are the key factors that cause secondary injury upon TBI. Herein, a TBI-targeted lipid covered radical scavenger nanoparticle is developed to deliver nimodipine (Np) (CL-PPS/Np), in order to inhibit Ca2+ influx in neurons by Np and to scavenge ROS in the brain trauma microenvironment by poly(propylene sulfide)60 (PPS60 ) and thus prevent TBI-associated secondary injury. In post-TBI models, CL-PPS/Np effectively accumulates into the wound cavity and prolongs the time of systemic circulation of Np. CL-PPS/Np can markedly protect the integrity of blood-brain barrier, prevent brain edema, reduce cell death and inflammatory responses, and promote functional recovery after TBI. These findings may provide a new therapy for TBI to prevent the spread of the secondary injury.

ROS-Responsive Nanoparticle as a Berberine Carrier for OHC-Targeted Therapy of Noise-Induced Hearing Loss.

Overproduction of reactive oxygen species (ROS) and inflammation are two key pathogeneses of noise-induced hearing loss (NIHL), which leads to outer hair cell (OHC) damage and hearing loss. In this work, we successfully developed ROS-responsive nanoparticles as berberine (BBR) carriers (PL-PPS/BBR) for OHC-targeted therapy of NIHL: Prestin-targeting peptide 2 (PrTP2)-modified nanoparticles (PL-PPS/BBR), which effectively accumulated in OHC areas, and poly(propylene sulfide)120 (PPS120), which scavenged ROS and converted to poly(propylene sulfoxide)120 in a ROS environment to disintegrate and provoke the rapid release of BBR with anti-inflammatory and antioxidant effects. In this study, satisfactory anti-inflammatory and antioxidant effects of PL-PPS/BBR were confirmed. Immunofluorescence and scanning electron microscopy (SEM) images showed that PL-PPS/BBR effectively accumulated in OHCs and protected the morphological integrity of OHCs. The auditory brainstem response (ABR) results demonstrated that PL-PPS/BBR significantly improved hearing in NIHL guinea pigs after noise exposure. This work suggested that PL-PPS/BBR may be a new potential treatment for noise-associated injury with clinical application.

In Situ implantable, post-trauma microenvironment-responsive, ROS Depletion Hydrogels for the treatment of Traumatic brain injury.

Traumatic brain injury (TBI) generates excess reactive oxygen species (ROS), which can exacerbate secondary injury and result in disability and death. Secondary injury cascades can trigger the release of uncontrolled ROS into the surrounding normal brain tissue, forming an extended pool of ROS, which leads to massive neuronal death. Here, we developed an injectable, post-trauma microenvironment-responsive, ROS depletion hydrogel embedded curcumin (Cur) (TM/PC) for reducing ROS levels in damaged brain tissue to promote the regeneration and recovery of neurons. Hydrogel was composed of three parts: (1) Hydrophobic poly (propylene sulfide)120 (PPS120) was synthesized, with a ROS quencher and H2O2-responsive abilities, to embed Cur. (2) Matrix metalloproteinase (MMP)-responsive triglycerol monostearate (TM) was used to cover the PPS120 to form a TM/P hydrogel. (3) Cur could further eradicate the ROS, promoting the regeneration and recovery of neurons. In two postoperative TBI models, TM/PC hydrogel effectively responded the TBI surgical environment and released drug. TM/PC hydrogel significantly depleted ROS and reduced brain edema. In addition, reactive astrocytes and activated microglia were decreased, growth-associated protein 43 (GAP43) and doublecortin (DCX) were increased, suggested that TM/PC hydrogel had the strongest anti-inflammatory effect and effectively promoted nerve regeneration after TBI. This study provides new information for the management of TBI to prevent the secondary spread of damage.

Combined Delivery of Temozolomide and siPLK1 Using Targeted Nanoparticles to Enhance Temozolomide Sensitivity in Glioma.

INTRODUCTION: Temozolomide (TMZ) is the first-line chemotherapeutic option to treat glioma; however, its efficacy and clinical application are limited by its drug resistance properties. Polo-like kinase 1 (PLK1)-targeted therapy causes G2/M arrest and increases the sensitivity of glioma to TMZ. Therefore, to limit TMZ resistance in glioma, an angiopep-2 (A2)-modified polymeric micelle (A2PEC) embedded with TMZ and a small interfering RNA (siRNA) targeting PLK1 (siPLK1) was developed (TMZ-A2PEC/siPLK). MATERIALS AND METHODS: TMZ was encapsulated by A2-PEG-PEI-PCL (A2PEC) through the hydrophobic interaction, and siPLK1 was complexed with the TMZ-A2PEC through electrostatic interaction. Then, an angiopep-2 (A2) modified polymeric micelle (A2PEC) embedding TMZ and siRNA targeting polo-like kinase 1 (siPLK1) was developed (TMZ-A2PEC/siPLK). RESULTS: In vitro experiments indicated that TMZ-A2PEC/siPLK effectively enhanced the cellular uptake of TMZ and siPLK1 and resulted in significant cell apoptosis and cytotoxicity of glioma cells. In vivo experiments showed that glioma growth was inhibited, and the survival time of the animals was prolonged remarkably after TMZ-A2PEC/siPLK1 was injected via their tail vein. DISCUSSION: The results demonstrate that the combination of TMZ and siPLK1 in A2PEC could enhance the efficacy of TMZ in treating glioma.

Hypoxic Radiosensitizer-Lipid Coated Gold Nanoparticles Enhance the Effects of Radiation Therapy on Tumor Growth.

Radiotherapy (RT) has become one of the most effective treatments for malignant tumor. Intra-tumoral hypoxia is recognized as a chief reason that induces resistance to radiation. Moreover, the toxicities of RT to normal tissues limits the usage of high doses of radiation to eliminate cancer cells. Therefore, developing an effective radiosensitizer is critical for improving the curative effects of RT. In the present study, we developed angiopep-2 (A2) modified hypoxic lipid radiosensitizer (HLR) coated gold nanoparticles (GNPs) (referred to as A2-HRGNPs) to increase the RT sensitivity of tumors. The A2-HRGNPs are comprised of the following two functional components: (1) HLR enhances the RT sensitivity on hypoxic tumor cells; (2) alkylthiol modified GNPs (DGNPs) increase radiation effects by a dose enhancing effect in RT. Our findings suggest that the synergistic radiosensitizing effects of A2-HRGNPs can significantly enhance radiosensitization effects and thus, inhibit tumor growth in vivo.