Targeted treatment for radiculopathy via engineered PLA2-responsive multifunctional micelles

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ABSTRACT Nerve root trauma is a leading cause of radiculopathy from spinal injury, stenosis, or disc herniation and often produces a complex cascade of neuropathological responses, including pain, which can often become chronic. Many pharmacologic approaches have been pursued to treat trauma-induced radiculopathy, such as opioid analgesics and non-opioid analgesics. However bioavailability, pharmacokinetics, tolerability, broad mechanisms of action and side effects of current conventional treatment approaches carry a substantial risk of toxicity and addiction. In addition, the lack of effectiveness and limited therapies emerging with any robust clinical success, underscore the need to develop more effective treatment strategies for painful radiculopathy. Neuroinflammation has a potent role in initiating pain following nerve root trauma and contributes to its maintenance in a host of pathologies. Phospholipase-A2 (PLA2) enzymes are potent modulators in the development of inflammation. We have evidence of elevated PLA2 in the spinal cord after painful nerve root injury and have experience in the construction of PLA2-responsive platforms for drug delivery. We further demonstrate that the PLA2-responsive micelles are substantially effective in preventing the onset of pain in rats. We hypothesize that PLA2 could both be a unique signature of local and spinal neuroinflammation and also provide a novel therapeutic target for the treatment of pain that develops with radiculopathy after nerve root injury. The overall goal of this proposal is to develop a novel interventional platform for greater effectiveness in radiculopathy treatment. In an attempt to achieve this goal, we will develop PLA2-responsive multifunctional nanoparticles (PRMNs) that incorporate magnetic resonance (MR) contrast agents and anti- inflammatory and neuromodulatory drugs. High resolution MR imaging is expected to provide insight into the pathological state and the localization of the drug. The PLA2-responsive property will allow for the self- modulation of drug release based on the level of PLA2 activity that is induced by the injury and/or pain state. We will test whether PRMNs can provide a novel strategy to treat pain in a clinically relevant rat model of nerve root trauma. To the best of our knowledge, no studies have sought to combine and/or leverage this aspect of the inflammatory and PLA2-response for developing effective pain treatment. We hypothesize that this theranostic agent, which integrates both diagnostic and therapeutic functions into a single system, offers a unique opportunity and tremendous potential for monitoring and treating patients with direct clinically translational impact. The specific aims for the proposal are 1) PRMNs will be synthesized and characterized in vitro; 2) evaluate the drug release, anti-inflammatory effectiveness and cytotoxicity of PRMNs in vitro; and 3) evaluate pain and neuroinflammation after PRMN treatment of nerve root trauma in a well-established model in the rat.