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A New Best Practice for Validating Tail Vein Injections in Rat with Near-infrared-Labeled Agents

Intravenous (IV) administration of agents into the tail vein of rats can be both difficult and inconsistent. Optimizing tail vein injections is a key part ...

Duquesne University

Accidental and iatrogenic trauma are major causes of peripheral nerve injury. Healing after nerve injury is complex and often incomplete, which can lead to acute or chronic pain and functional impairment. Current assessment methods for nerve regeneration lack sensitivity and objectivity. There is a need for reliable and reproducible, noninvasive strategies with adequate spatial and temporal resolution for longitudinal evaluation of degeneration or regeneration after injury/treatment. Methods for noninvasive monitoring of the efficacy and effectiveness of neurotherapeutics in nerve regeneration or of neuropathic pain are needed to ensure adequacy and responsiveness to management, especially given the large variability in the patient populations, etiologies, and complexity of nerve injuries. Surrogate biomarkers are needed with positive predictive correlation for the dynamics and kinetics of neuroregeneration. They can provide direct real-time insight into the efficacy and mechanisms of individualized therapeutic intervention. Here, we review the state-of-the-art tools, technologies, and therapies in peripheral nerve injury and regeneration as well as provide perspectives for the future. We present compelling evidence that advancements in nanomedicine and innovation in nanotechnology such as nanotheranostics hold groundbreaking potential as paradigm shifts in noninvasive peripheral nerve imaging and drug delivery. Nanotechnology, which revolutionized molecular imaging in cancer and inflammatory disease, can be used to delineate dynamic molecular imaging signatures of neuroinflammation and neuroregeneration while simultaneously monitoring cellular or tissue response to drug therapy. We believe that current clinical successes of nanotechnology can and should be adopted and adapted to the science of peripheral nerve injury and regeneration.

Peripheral Nerve Nanoimaging: Monitoring Treatment and Regeneration.

Neuroinflammation involving macrophages elevates Prostaglandin E, associated with neuropathic pain. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) inhibits cyclooxygenase, reducing PGE. However, NSAIDs cause physiological complications. We developed nanoemulsions incorporating celecoxib and near infrared dye. Intravenous injected nanoemulsion is incorporated into monocytes that accumulate at the injury; revealed in live animals by fluorescence. A single dose (celecoxib 0.24 mg/kg) provides targeted delivery in chronic constriction injury rats, resulting in significant reduction in the visualized inflammation, infiltration of macrophages, COX-2 and PGE. Animals exhibit relief from hypersensitivity persisting at least four-days. The total body burden of drug is reduced by >2000 fold over oral drug delivery.

Low-dose NSAIDs reduce pain via macrophage targeted nanoemulsion delivery to neuroinflammation of the sciatic nerve in rat.

Pain nanomedicine is an emerging field in response to current needs of addressing the opioid crisis in the USA and around the world. Our group has focused on the development of macrophage-targeted perfluorocarbon nanoemulsions as inflammatory pain nanomedicines over the past several years. We present here, for the first time, a quality by design approach used to design pain nanomedicine. Specifically, we used failure mode, effects, and criticality analysis (FMECA) which identified the process and composition parameters that were most likely to impact nanoemulsion critical quality attributes (CQAs). From here, we applied a unique combination approach that compared multiple linear regression, boosted decision tree regression, and partial least squares regression methods in combination with correlation plots. The presented combination approach allowed for in-depth analyses of which formulation steps in the nanoemulsification processes control nanoemulsion droplet diameter, stability, and drug loading. We identified that increase in solubilizer (transcutol) content increased drug loading and decreased nanoemulsion stability. This was mitigated by inclusion of perfluorocarbon oil in the internal phase. We observed negative correlation (R = 0.4357, p value 0.0054) between the amount of PCE and the percent diameter increase (destabilization), and no correlation between processing parameters and percent diameter increase over time. Further, we identified that increased sonication time decreases nanoemulsion drug loading but does not significantly impact droplet diameter or stability. We believe the methods presented here can be useful in the development of various nanomedicines to produce higher-quality products with enhanced manufacturing and design control.

Jelena Janjic

Chronic Pain Research Consortium,
Graduate School of Pharmaceutical Sciences

Duquesne University

A New Best Practice for Validating Tail Vein Injections in Rat with Near-infrared-Labeled Agents

Jelena Janjic

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Chronic Pain Research Consortium,Graduate School of Pharmaceutical Sciences

Duquesne University

A New Best Practice for Validating Tail Vein Injections in Rat with Near-infrared-Labeled Agents

Chronic Pain Research Consortium,
Graduate School of Pharmaceutical Sciences