Neuro-Immuno Modulating Analgesic (NiMA) Nanomedicine Platform for Treatment of Diabetic Neuropathy
Abstract
Topic Areas: (1) Diabetes – Research on interventions to prevent or treat diabetes complications, including diabetic retinopathy, nephropathy, neuropathy, cardiomyopathy, and impaired wound healing. (2) Tissue Regeneration – Development of novel therapies to repair neurosensory damage, maintain the distal end organ interface, or regenerate the neuromuscular junction for reinnervation of end organs during peripheral nerve regeneration. Background: The Millennium Cohort Study, launched in 2001 (which includes all Service branches and components), revealed widespread obesity and diabetes in Service members. A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), painful injury to the nerves that typically begins in the hands and feet, which can lead to significant disability and loss of quality of life. High incidence of diabetes poses an additional threat to overall health and readiness when nerve regrowth is required as part of healing (such as after undergoing surgery or suffering physical trauma). Current pain relief options are effective in only half of the patients affected with DPN. An additional challenge in the treatment of DPN is that current therapies do not necessarily support nerve repair, which is critical to restore normal function and sensation and reduce pain. The impact of poorly managed DPN is a significant unmet military healthcare problem that lacks a comprehensive strategy to address current treatment deficiencies. Rationale: Recent research has made the surprising discovery that a peptide hormone, angiotensin II (Ang II), previously recognized for its role in controlling blood pressure, is an important mediator of symptoms similar to those found in DPN patients. Blocking the effects of Ang II is thought to be protective to nerves, as well as acting as an anti-inflammatory. Ang II production from injured nerves in DPN is associated with attraction of white blood cells (macrophages). Our prior and ongoing work confirms that targeting these white blood cells with anti-inflammatory drugs (COX-2 inhibitors, such as celecoxib) can reduce pain in rodent models of nerve injury. Based on these findings, we conclude that COX-2 and Ang II pathways are critically important for the development of pain and neuropathy in diabetes. Our overall goal is to develop and demonstrate the translational feasibility and efficacy of a novel Neuro-Immuno Modulating Analgesic (NiMA) platform to specifically treat DPN. We hypothesize that NiMA will achieve optimal, sustained release of the COX-2 and Ang II-inhibiting drug combination in target tissues, as well as selective uptake by injured neurons and infiltrating white blood cells. Such targeted and site-specific release will improve the efficacy of both drugs, while maintaining low systemic blood levels, allowing for non-toxic, long-term mitigation of DPN symptoms. The NiMA system will be evaluated in our laboratories in established mouse and rat models of type 2 diabetes (we opted for models of type 2 diabetes, since the majority of human DPN patients are type 2 diabetic). Aim 1: Fabricate and optimize the NiMA platform in vitro and evaluate stability, drug release and other parameters. Aim 2: Determine the controlled drug release and safety of the NiMA system in a mouse model of DPN. Aim 3: Assess the effectiveness of the locally embedded NiMA system in reducing nerve dysfunction and promoting nerve healing in DPN rats after surgery. Study Design: NiMA is designed as two sets of microscopic particles: white blood cell-targeting nanoemulsions and nerve-targeting microemulsions. This will allow us to deliver a combination of COX-2 and Ang II inhibitors to the appropriate cells. We hypothesize that this dual targeting approach will relieve pain and neuronal dysfunction and promote nerve regeneration at the site of DPN. In addition, the nanosized particles that contain the drugs are fluorescent, which allows us to mon
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010277
Entities
People
- Andrew J Shepherd
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army