(136) Dual Targeted Theranostic Nanomedicines for Local and Systemic Non-Opioid Analgesia in Trauma

Abstract

Acute neuropathic pain (ANP) resulting from civilian and combat traumatic injuries has dramatic impact on society at large as it poses with significant personal and economic burden. With opioid abuse epidemic currently in public eye across all levels of society, it is pertinent new therapeutic modalities are needed to effectively treat and resolve ANP. Neuroinflammation is recognized as one of the primary drivers of acute neuropathic to chronic pain transition leading to prolonged disability and loss of productivity. We hypothesize that the lack of molecular and cellular targeting specificity to effectively engage key cellular players in the neuronal injury milieu leads to non-opioid and local analgesia pain control failures in some patients. Here we present novel nanomedicine strategies for targeted non-opioid drug delivery directly to the key cells at the site of injury, immune cells and nerves. Since drug delivery is cell targeted, smaller drug doses are expected to produce similar or improved therapeutic effects over non-targeted therapies. Further we achieve overall dramatically decreased systemic exposure (up to 1000 fold), which can diminish unwanted side effects. Presented nanomedicine formulations provide sustained drug release leading to dosing frequency decrease and extended duration of therapeutic effects (up to 30 days or longer). As designed, these pain directed nanomedicines could improve patient response to treatment while minimizing systemic exposure/overdose risk, tolerance and/or dependency. To the best of our knowledge this is the first example of dual administration (systemic and local) nanomedicine design for acute post-trauma pain applicable to both civilian and military settings. We present fabrication and optimization of immune cell and nerve targeted nanoformulations. Evaluation for controlled release kinetics and safety of the these systems with optimized drug payloads in vivo in rat models of nerve injury and mouse inflammatory pain models following local and systemic administration is also presented.