A Multimodal Nanotrap to Alleviate ARDS in Traumatic Injuries
Abstract
Background: This proposal is to address the Peer Reviewed Medical Research Program (PRMRP) portfolio of Respiratory Heath with the Topic Areas of Respiratory Health, Trauma, and Sustained-Release Drug Delivery. The casualties with blast lung injury, abdominal trauma, or trauma with significant tissue loss are particularly at risk of developing sepsis and acute respiratory distress syndrome (ARDS). All these critical illnesses have the common feature of hyperinflammation. Trauma and infection cause tissue damage, releasing a lot of alarm molecules, which stimulate immune cells to produce signaling molecules, called cytokines to fight infection and manage tissue damage. However, if these alarming and dangerous molecules and bugs spread into blood circulation, immune reactions become overwhelmed and dysregulated, which leads to a cytokine storm as known in the severe COVID-19 patients and causes sepsis and multiple organ damage including ARDS. Thus, the control of both infection and hyperinflammation during early emergency treatment is critical to saving the life of Warriors with traumatic/blast injuries. Unfortunately, such approaches are still lacking even in the fully equipped civilian hospital, especially for hyperinflammation control. No effective treatment available for sepsis should antibiotics fail. The mortality rate for sepsis especially with ARDS remains high, about 18%-50% depending on the disease stage and comorbidity. Antibodies or steroid drugs for inflammation control all failed to reduce mortality of sepsis, because of the complex and unstable immune system in sepsis and ARDS patients. Project Overview: We propose to fill this gap in emergency care by (1) developing clinical translatable blood purification therapy using our novel telodendrimer (TD) nanotrap (NT) resin to capture and remove the overflowing excessive sepsis-responsive molecules from the bloodstream, especially differentiating the pro-inflammatory and anti-inflammatory cytokines, thus controlling cytokine storm more effectively and preventing remote organ damage and ARDS. (2) TD NT can be incorporated into even small nanogels (~200 nm, about 1/1000 thickness of hair) as injectable or inhalable treatment to control inflammation directly in far-forward battlefield as emergency treatment. (3) In addition, potent antibiotics, e.g., polymyxin B and daptomycin as the last resort antibiotics (partly due to the toxicity) to overcome multidrug-resistant bacteria can be encapsulated in the immune-modulating nanogel for sustained drug release to control infection effectively and reduce drug toxicity. The goal of the study is to develop a translational multimodal TD NT platform approach to control both infection and inflammation as an emergency treatment for battle casualties with severe injury to prevent and treat sepsis and ARDS on the battlefield and continuously after evacuation in the field hospital. Recently, our TD hydrogel resin treatment significantly improved the survival, and even cure of sepsis in combination with a moderate dose of antibiotics in severe septic mouse models induced with severe abdominal tissue injury and peritoneal infection (published in Nature Communications 2020). In order to translate such therapeutic efficacy into the clinic, (1) we will first collect a minimum amount of blood from sepsis patients from the clinic (two teaspoons per patient) to validate our TD NT resin in scavenging human septic molecules, and further optimize TD NT for targeting different groups of signaling cytokine molecules. Thus, TD NT resins with different adsorption profiles can be applied based on patient immune status for precise immune modulation. (2) We will further design and test TD NT nanogel for both antibiotics’ encapsulation and immune modulation in vitro and in mouse models with severe sepsis with polymicrobial infection and traumatic injury to mimic battlefield casualties. (3) We will apply TD NT validated in human
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310590
Entities
People
- Juntao Luo
Organizations
- State University of New York Upstate Medical University
- United States Army