Sex-based differences of antioxidant enzyme nanoparticle effects following traumatic brain injury

Tarudji, Aria W.; Miller, Hunter A.; Curtis, Evan T.; Porter, Christopher L.; Madsen, Gary L.; Kievit, Forrest M.

doi:10.1016/j.jconrel.2023.01.065

Cited by 13 publications

(15 citation statements)

References 118 publications

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“…Of note, NPC3 treated female CCI mice did not perform better than female CCI mice suggesting NPC3 treatment did not provide any additional therapeutic benefit above the natively higher antioxidant expression levels [ 19 ] in female brain. This, combined with our recent work with antioxidant enzyme loaded NPs in male and female mice, [ 10 ] strongly suggest there is a threshold of total antioxidant activity in the brain following CCI, above which no additional therapeutic benefit is observed. This underscores the importance of the need for multiple therapeutic targets to improve therapeutic efficacy following TBI.…”

Section: Discussionmentioning

confidence: 61%

“…The therapeutic window is essential in antioxidant treatments due to the bell‐shaped response curve of antioxidant treatment in TBI, [ 14c,14e,14f ] in which suboptimal dosing of antioxidants would give a suboptimal reduction in oxidative stress or even exacerbate the injury progression. [ 10,14a‐e ] Here, we found the therapeutic window of NPC3 was between 2.1–20.8 mg kg −1 NPC3 for male CCI mice and 5.5–27.6 mg kg −1 NPC3 for female CCI mice. Since the therapeutic windows of males and females were studied separately (Figure 2B), the difference in dose between sexes should not act as a confounding variable in this study since both doses were within the middle of their respective therapeutic windows.…”

Section: Discussionmentioning

confidence: 74%

“…Another possible reason for the bell‐shaped response curve might be due to the physiological role of oxidative stress, in which suboptimal dosing of antioxidants would give a suboptimal reduction in oxidative stress or even exacerbate the injury progression. [ 10,14 ]…”

Section: Resultsmentioning

confidence: 99%

“…A dihydroethidium (DHE; Thermo Fisher Scientific) assay was performed as previously described with modifications. [ 2b,9,10,34 ] Briefly, a bolus IP administration of DHE (500 µL of 1.25 mg mL −1 ) was injected into each mouse at 3 h post‐CCI. Mice were transcardially perfused at 1 h after DHE injection with ice‐cold 4% paraformaldehyde (PFA) in phosphate buffer.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, our recent results with antioxidant enzyme loaded nanoparticles suggest there are important sex‐based differences in the therapeutic efficacy of antioxidant treatments. [ 10 ] Indeed, female humans and rodents are more likely to have a better outcome following severe TBI. [ 11 ] Sexual dimorphism in TBI has been attributed to progesterone, but progesterone treatment did not show significant improvement in TBI patients.…”

Section: Introductionmentioning

confidence: 99%

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Antioxidant Theranostic Copolymer‐Mediated Reduction in Oxidative Stress Following Traumatic Brain Injury Improves Outcome in a Mouse Model

Tarudji,

Gee,

Miller

et al. 2023

Advanced Therapeutics

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Following a traumatic brain injury (TBI), excess reactive oxygen species (ROS) and lipid peroxidation products (LPOx) are generated and lead to secondary injury beyond the primary insult. A major limitation of current treatments is poor target engagement, which has prevented success in clinical trials. Thus, nanoparticle‐based treatments have received recent attention because of their ability to increase accumulation and retention in damaged brain. Theranostic neuroprotective copolymers (NPC3) containing thiol functional groups can neutralize ROS and LPOx. Immediate administration of NPC3 following injury in a controlled cortical impact (CCI) mouse model provides a therapeutic window in reducing ROS levels at 2.08‐20.83 mg/kg in males and 5.52‐27.62 mg/kg in females. This NPC3‐mediated reduction in oxidative stress improves spatial learning and memory in males, while females show minimal improvement. Notably, NPC3‐mediated reduction in oxidative stress prevents the bilateral spread of necrosis in male mice, which was not observed in female mice and likely accounts for the sex‐based spatial learning and memory differences. Overall, these findings suggest sex‐based differences to oxidative stress scavenger nanoparticle treatments, and a possible upper threshold of antioxidant activity that provides therapeutic benefit in injured brain since female mice benefit from NPC3 treatment to a lesser extent than male mice.This article is protected by copyright. All rights reserved

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Antioxidant Theranostic Copolymer‐Mediated Reduction in Oxidative Stress Following Traumatic Brain Injury Improves Outcome in a Mouse Model

Tarudji,

Gee,

Miller

et al. 2023

Advanced Therapeutics

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Reprograming Clots for In Vivo Chemical Targeting in Traumatic Brain Injury

Kandell,

Wu,

Kwon

2024

Advanced Materials

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Traumatic brain injury (TBI) is a critical public health concern, yet there are no therapeutics available to improve long‐term outcomes. Drug delivery to TBI remains a challenge due to the blood‐brain barrier and increased intracranial pressure. In this work, we developed a chemical targeting approach to improve delivery of materials to the injured brain. We hypothesized that the provisional fibrin matrix could be harnessed as an injury‐specific scaffold that can be targeted by materials via click chemistry. To accomplish this, we engineered the brain clot in situ by delivering fibrinogen modified with strained cyclooctyne (SCO) moieties, which incorporated into the injury lesion and was retained there for days. We subsequently observed improved intra‐injury capture and retention of diverse, clickable azide‐materials including a small molecule azide‐dye, 40 kDa azide‐PEG nanomaterial, and a therapeutic azide‐protein in multiple dosing regimens. To demonstrate therapeutic translation of this approach, we achieved a reduction in reactive oxygen species levels in the injured brain after the delivery of the antioxidant catalase. Further, colocalization between azide and SCO‐fibrinogen was specific to the brain over off‐target organs. Taken together, we established a chemical targeting strategy leveraging endogenous clot forma which can be applied to improve therapeutic delivery after TBI.This article is protected by copyright. All rights reserved

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Brain Delivery of Protein Therapeutics by Cell Matrix‐Inspired Biomimetic Nanocarrier

Huang,

Fu,

Wang

et al. 2024

Advanced Materials

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Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood‐brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, we used the cell matrix components hyaluronic acid (HA) and protamine (PRTM) to self‐assemble with proteins to form a protein‐loaded biomimetic core and then incorporated it into ApoE3‐reconstituted high‐density lipoprotein (rHDL) to form a protein‐loaded biomimetic nanocarrier (Protein‐HA‐PRTM‐rHDL). This cell matrix‐inspired biomimetic nanocarrier facilitated the penetration of protein therapeutics across the BBB and enabled their access to intracellular target sites. Specifically, CAT‐HA‐PRTM‐rHDL facilitated rapid intracellular delivery and release of CAT via macropinocytosis‐activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduced the latency of TBI mice and doubled the number of crossing platforms), and enhanced motor function and prolonged survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix‐inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases.This article is protected by copyright. All rights reserved

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Sex-based differences of antioxidant enzyme nanoparticle effects following traumatic brain injury

Cited by 13 publications

References 118 publications

Antioxidant Theranostic Copolymer‐Mediated Reduction in Oxidative Stress Following Traumatic Brain Injury Improves Outcome in a Mouse Model

Antioxidant Theranostic Copolymer‐Mediated Reduction in Oxidative Stress Following Traumatic Brain Injury Improves Outcome in a Mouse Model

Reprograming Clots for In Vivo Chemical Targeting in Traumatic Brain Injury

Brain Delivery of Protein Therapeutics by Cell Matrix‐Inspired Biomimetic Nanocarrier

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