ARDS is an acute, diffuse, inflammatory lung injury caused by a variety of insults, most commonly pneumonia, sepsis, and aspiration1. With ~200,000 US cases per year, a mortality of ~40%, and no approved drugs, ARDS represents a major unmet medical need2. Unfortunately, more than a dozen drugs have failed in ARDS clinical trials3, perhaps for three reasons4: 1) ARDS patients are unstable, so drugs with mild side effects may increase mortality5. 2) ARDS is heterogeneous, so acting on one pathway may be insufficient. 3) The inhaled route is severely hampered by the flooded alveoli of ARDS5.
We aim to solve these problems by creating nano-scale drug carriers that deliver multiple drugs specifically to affected alveoli. Towards that end, we created PELs: pulmonary endothelium-targeted liposomes, which are liposomes (100-nanometer spherical phospholipid bilayers) coated with antibodies that bind the pulmonary endothelium. Intravenous PELs accumulate in the alveolar endothelium, localizing drug effects. We now propose to load PELs with drugs that modulate the nitric oxide (NO) pathway. NO is a powerful anti- inflammatory, but data have been conflicting on its utility in ARDS. Part of the conflict is because inhaled NO does not reach flooded alveoli and IV NO donor drugs cause off-target effects. Additionally, during ARDS superoxide (a reactive oxygen species) is increased, and superoxide converts NO into pro-inflammatory peroxynitrite. The scientific objective of this proposal is to determine if PEL-mediated delivery of NO to the pulmonary endothelium alleviates lipopolysaccharide (LPS)-induced acute lung injury (ALI), a mouse model similar to human ARDS.
The Aims are thus: 1) Determine if PEL-mediated delivery of NO donor drugs decreases LPS- induced ALI, based on assays of alveolar protein leak and leukocyte count, and serum cytokine levels. 2) Determine if PELs containing SOD ameliorate ARDS, alone or in combination with NO donor PELs. These studies may provide a new therapeutic, and will give insight into NO's role in ARDS. The proposal's other key objective is to train the candidate in the field of targeted drug delivery. Ths will compromise didactic coursework, individualized mentoring, and hands-on training in tools such as nanocarrier production, analytical chemistry, and animal models of ARDS.
ARDS is an acute inflammatory lung disease that affects 200,000 US patients annually, has a 40% mortality, and currently has no approved drugs. We have developed nanometer-scale drug carriers that can strongly concentrate drugs in the inflamed areas of the lungs. We will use those carriers to deliver drugs that modulate the signaling molecule nitric oxide, thereby providing insight into nitric oxide's role in ARDS, and perhaps providing a future ARDS therapeutic.
| Brenner, Jacob S (2017) Nanomedicine for the Treatment of Acute Respiratory Distress Syndrome. The 2016 ATS Bear Cage Award-winning Proposal. Ann Am Thorac Soc 14:561-564 |
