BBB pathophysiology–independent delivery of siRNA in traumatic brain injury

Small interfering RNA (siRNA)–based therapeutics can mitigate the long-term sequelae of traumatic brain injury (TBI) but suffer from poor permeability across the blood-brain barrier (BBB). One approach to overcoming this challenge involves treatment administration while BBB is transiently breached after injury. However, it offers a limited window for therapeutic intervention and is applicable to only a subset of injuries with substantially breached BBB. We report a nanoparticle platform for BBB pathophysiology–independent delivery of siRNA in TBI. We achieved this by combined modulation of surface chemistry and coating density on nanoparticles, which maximized their active transport across BBB. Engineered nanoparticles injected within or outside the window of breached BBB in TBI mice showed threefold higher brain accumulation compared to nonengineered PEGylated nanoparticles and 50% gene silencing. Together, our data suggest that this nanoparticle platform is a promising next-generation drug delivery approach for the treatment of TBI.

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BBB pathophysiology independent delivery of siRNA in traumatic brain injury

10.1101/2020.06.26.173393 ◽

2020 ◽

Author(s):

Wen Li ◽

Jianhua Qiu ◽

Xiang-Ling Li ◽

Sezin Aday ◽

Jingdong Zhang ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Surface Chemistry ◽

Engineered Nanoparticles ◽

Long Term Effects ◽

Post Injury ◽

Pegylated Nanoparticles ◽

Treatment Administration ◽

Repeated Dosing

AbstractSmall interfering RNA (siRNA) represents a powerful strategy to mitigate the long-term sequelae of traumatic brain injury (TBI). However, poor permeability of siRNA across the blood brain barrier (BBB) poses a major hurdle. One approach to overcome this challenge involves treatment administration while the BBB is physically breached post-injury. However, this approach is only applicable to a subset of injuries with substantial BBB breach and can lead to variable therapeutic response due to the heterogeneity of physical breaching of BBB in TBI. Moreover, since physical breaching of BBB is transient, this approach offers a limited window for therapeutic intervention, which is not ideal as repeated dosing beyond the transient window of physically breached BBB might be required. Herein, we report a nanoparticle platform for BBB pathophysiology-independent delivery of siRNA in TBI. We achieved this by combined modulation of surface chemistry and coating density, which maximized the active transport of nanoparticles across BBB. Intravenous injection of engineered nanoparticles, within or outside the window of physically breached BBB in TBI mice resulted in 3-fold higher brain accumulation compared to conventional PEGylated nanoparticles and demonstrated up to 50% gene silencing. To our knowledge, this is the first reported example of BBB pathophysiology-independent drug delivery in TBI, and the first time combined modulation of surface chemistry and coating density has been shown to tune BBB penetration of nanoparticles. Taken together, our approach offers a clinically relevant approach to develop siRNA therapeutics for preventing long-term effects of TBI and deserves further exploration.

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Small interfering RNA directed against CTMP reduces acute traumatic brain injury in a mouse model by activating Akt

Neurological Research ◽

10.1179/1743132814y.0000000353 ◽

2014 ◽

Vol 36 (5) ◽

pp. 483-490 ◽

Cited By ~ 6

Author(s):

Shangfeng Zhao ◽

Jidi Fu ◽

Fang Liu ◽

Radhika Rastogi ◽

Jialiang Zhang ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mouse Model ◽

Small Interfering Rna ◽

Acute Traumatic Brain Injury ◽

Interfering Rna

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Traumatic Brain Injury: A Trauma Surgeon's Perspective

Perspectives on Neurophysiology and Neurogenic Speech and Language Disorders ◽

10.1044/nnsld22.3.82 ◽

2012 ◽

Vol 22 (3) ◽

pp. 82-89

Author(s):

Oscar D. Guillamondegui

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Multidisciplinary Approach ◽

Trauma Team ◽

The United States ◽

Long Term Outcomes ◽

Term Care ◽

Injured Brain ◽

The Moment

Traumatic brain injury (TBI) is a serious epidemic in the United States. It affects patients of all ages, race, and socioeconomic status (SES). The current care of these patients typically manifests after sequelae have been identified after discharge from the hospital, long after the inciting event. The purpose of this article is to introduce the concept of identification and management of the TBI patient from the moment of injury through long-term care as a multidisciplinary approach. By promoting an awareness of the issues that develop around the acutely injured brain and linking them to long-term outcomes, the trauma team can initiate care early to alter the effect on the patient, family, and community. Hopefully, by describing the care afforded at a trauma center and by a multidisciplinary team, we can bring a better understanding to the armamentarium of methods utilized to treat the difficult population of TBI patients.

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Prosodic Impairment Associated With Traumatic Brain Injury

Perspectives on Neurophysiology and Neurogenic Speech and Language Disorders ◽

10.1044/nnsld19.3.97 ◽

2009 ◽

Vol 19 (3) ◽

pp. 97-102

Author(s):

Billy Irwin

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Detailed Analysis ◽

Acoustic Characteristics ◽

Individual Variations

Abstract Purpose: This article discusses impaired prosody production subsequent to traumatic brain injury (TBI). Prosody may affect naturalness and intelligibility of speech significantly, often for the long term, and TBI may result in a variety of impairments. Method: Intonation, rate, and stress production are discussed in terms of the perceptual, physiological, and acoustic characteristics associated with TBI. Results and Conclusions: All aspects of prosodic production are susceptible to the effects of damage resulting from TBI. There are commonly associated prosodic impairments; however, individual variations in specific aspects of prosody require detailed analysis.

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