Evaluating accessibility of intravenously administered nanoparticles at the lesion site in rat and pig contusion models of spinal cord injury

Gao, Yue; Vijayaraghavalu, Sivakumar; Stees, Melinda; Labhasetwar, Vinod

doi:10.1016/j.jconrel.2019.03.026

Cited by 29 publications

(30 citation statements)

References 42 publications

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“…In a rat reperfusion injury model, PLGA NPs loaded with both catalase and SOD mitigated the inflammatory response, prevented apoptosis of neuronal cells, and protected the blood brain barrier from ROS-mediated reperfusion injury as compared to blank NPs (10). Intravenous administration to rat and pig models of SCI found a dose-dependent localization of NPs to the site of injury, and in rats, the NPs could be detected at the site of epicenter even at 4 weeks post-injury (33). The dose for our study (6 mg/kg) was determined based on these previous publications.…”

Section: Discussionmentioning

confidence: 94%

A Pilot Study on the Safety of a Novel Antioxidant Nanoparticle Delivery System and Its Indirect Effects on Cytokine Levels in Four Dogs

et al. 2020

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Acute spinal cord injury consists of a primary, traumatic event followed by a cascade of secondary events resulting in ongoing cell damage and death. There is great interest in prevention of these secondary effects to reduce permanent long-term neurologic deficits. One such target includes reactive oxygen species released following injury, which can be enzymatically converted into less harmful molecules by superoxide dismutase and catalase. Canine intervertebral disc herniation has been suggested as a naturally occurring model for acute spinal cord injury and its secondary effects in people. The aims of this study were to test the safety of a novel antioxidant delivery system in four healthy dogs and to indirectly test effect of delivery via cytokine measurement. All dogs experienced adverse events to some degree, with two experiencing adverse events considered to be severe. The clinical signs, including combinations of bradycardia, hypotension, hypersalivation, pale gums, and involuntary urination, were consistent with complement activation-related pseudoallergy (CARPA). CARPA is a well-known phenomenon that has been reported to occur with nanoparticle-based drug delivery, among other documented causes. Two dogs also had mild to moderate changes in their blood cell count and chemistry, including elevated alanine transferase, and thrombocytopenia, which both returned to normal by day 7 post-administration. Cytokine levels trended downwards over the first 3 days, but many were elevated at measurement on day 7. Intradermal testing suggested catalase as a potential cause for reactions. No long-term clinical signs were observed, and necropsy results revealed no concerning pathology. Additional evaluation of this product, including further characterization of reactions to catalase containing components, dose-escalation, and desensitization should be performed before evaluation in clinically affected dogs.

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Section: Discussionmentioning

confidence: 94%

A Pilot Study on the Safety of a Novel Antioxidant Nanoparticle Delivery System and Its Indirect Effects on Cytokine Levels in Four Dogs

et al. 2020

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“…These events, together with factors conferring neuronal susceptibility, likely produced cell death close to the injury site. Adult minipigs weight only between 20 and 85 kg depending on the species, 78 and therefore are gaining ground against domestic pigs as experimental model in SCI 37,39,[42][43][44][45][46][47][78][79][80] and other biomedical research fields. 78 There is no doubt that adult pigs of manageable weight will be preferable to domestic piglets for SCI research unless the objectives of the study specifically relate to pediatric injuries.…”

Section: Kinematics Of Locomotionmentioning

confidence: 99%

“…Despite the translational advantages of research data gathered in swine, the use of this model in the SCI field has not yet consolidated. Most studies using pigs deal with thoracic SCI, 37,39,[42][43][44][45][46][47][48][49] whereas a few have produced cervical sevoflurane (1.7 % -2 %) together with remifentanil (26 mg/kg/h IV) and rocuronium (1.2 mg/kg/h IV). Mechanical ventilation (Fabius Tiro, Dräger) was set at 12-14 breaths/min with a tidal volume of 10-15 ml/kg.…”

Section: Introductionmentioning

confidence: 99%

Neuropathological and Motor Impairments after Incomplete Cervical Spinal Cord Injury in Pigs

Cerro

Barriga-Martín

Vara

et al. 2021

Journal of Neurotrauma

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Humans, primates, and rodents with cervical spinal cord injury (SCI) show permanent sensorimotor dysfunction of the upper/fore limb as consequence of axonal damage and local neuronal death. This work aimed at characterizing a model of cervical SCI in domestic pigs in which hemisection with excision of one centimeter of spinal cord was performed to reproduce the loss of neural tissue observed in human neuropathology. Posture and motor control were assessed over 3 months by scales and kinematics of treadmill locomotion.Histological measurements included lesion length, atrophy of the adjacent spinal cord segments, and neuronal death. In some animals, the retrograde neural tracer aminostilbamidine was injected in segments caudal to the lesion to visualize propriospinal projection neurons. Neuronal loss extended for 4-6 mm from the lesion borders and was more severe in the ipsilateral, caudal spinal cord stump. Axonal Wallerian degeneration was observed caudally and rostrally, associated to marked atrophy of the white matter in the spinal cord segments adjacent to the lesion. The pigs showed chronic monoplegia or severe monoparesis of the foreleg ipsilateral to the lesion, whereas the trunk and the other legs had postural and motor impairments that substantially improved during the first month postlesion. Adaptations of the walking cycle like those reported for rats and humans ameliorated the negative impact of focal neurological deficits on locomotor performance. These results provide a baseline of behavior and histology in a porcine model of cervical spinal cord hemisection that can be used for translational research in SCI therapeutics.

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“…It is suggested that ROS scavenging can suppress the inflammation in secondary injury following TSCI. 21 , 44 Therefore, we investigated the in vivo anti-inflammatory properties of the Se-CQDs at 5 days post operation. The immunostaining of the spinal cord showed an increase in the numbers of cells positive for CD68 (a marker of microglia) in the lesion sites of rats from the saline treatment group.…”

Section: Resultsmentioning

confidence: 99%

<p>Selenium-Doped Carbon Quantum Dots Efficiently Ameliorate Secondary Spinal Cord Injury via Scavenging Reactive Oxygen Species</p>

Luo¹,

Wang²,

Liu³

et al. 2020

IJN

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Background The excess production of reactive oxygen species (ROS) after traumatic spinal cord injury (TSCI) has been identified as a leading cause of secondary injury, which can significantly exacerbate acute damage in the injured spinal cord. Thus, scavenging of ROS has emerged as an effective route to ameliorate secondary spinal cord injury. Purpose Selenium-doped carbon quantum dots (Se-CQDs) with the ability to scavenge reactive oxygen species were prepared and used for efficiently ameliorating secondary injury in TSCI. Methods Water-soluble Se-CQDs were easily synthesized via hydrothermal treatment of l -selenocystine. The chemical structure, size, and morphology of the Se-CQDs were characterized in detail. The biocompatibility and protective effects of the Se-CQDs against H 2 O 2 -induced oxidative damage were investigated in vitro. Moreover, the behavioral test, bladder function, histological observation, Western blot were used to investigate the neuroprotective effect of Se-CQDs in a rat model of contusion TSCI. Results The obtained Se-CQDs exhibited good biocompatibility and remarkable protective effect against H 2 O 2 -induced oxidative damage in astrocytes and PC12 cells. Moreover, Se-CQDs displayed marked anti-inﬂammatory and anti-apoptotic activities, which thereby reduced the formation of glial scars and increased the survival of neurons with unscathed myelin sheaths in vivo. As a result, Se-CQDs were capable of largely improving locomotor function of rats with TSCI. Conclusion This study suggests that Se-CQDs can be used as a promising therapeutic platform for ameliorating secondary injury in TSCI.

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Evaluating accessibility of intravenously administered nanoparticles at the lesion site in rat and pig contusion models of spinal cord injury

Cited by 29 publications

References 42 publications

A Pilot Study on the Safety of a Novel Antioxidant Nanoparticle Delivery System and Its Indirect Effects on Cytokine Levels in Four Dogs

A Pilot Study on the Safety of a Novel Antioxidant Nanoparticle Delivery System and Its Indirect Effects on Cytokine Levels in Four Dogs

Neuropathological and Motor Impairments after Incomplete Cervical Spinal Cord Injury in Pigs

<p>Selenium-Doped Carbon Quantum Dots Efficiently Ameliorate Secondary Spinal Cord Injury via Scavenging Reactive Oxygen Species</p>

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