Enhanced Delivery of Thrombolytic Carriers for Empyema - PROJECT SUMMARY
Empyema (EMP) is increasing in frequency worldwide and is associated with a mortality rate of up to 20% in
patients older than 65 years. Thoracic surgery for treating EMP is invasive and many patients have co-morbidities
that preclude its use. Bleeding remains a major concern and occurs in up to about 5-15% of EMP patients treated
with intrapleural fibrinolytic therapy (IPFT). These factors offer a premise for the identification of more effective,
well-tolerated forms of IPFT that better address the molecular mechanisms governing intrapleural fibrinolysis,
particularly in advanced-stage EMP. The need for more efficacious, innovative forms of IPFT represents a gap
in the field that is of high priority and addressed in this project. The objective of our study is to identify novel
interventions that improve therapeutic outcomes in subjects with EMP using a fibrin-targeted delivery of
encapsulated plasminogen activators (PAs) combined with ultrasound sonofibrinolysis (US) in a validated model
of Streptococcus pneumoniae induced EMP in rabbits. Liposomal carriers with single chain (sc) tissue (sctPA)
and urokinase (scuPA), and resistant to plasminogen activator inhibitor 1 “molecular cage” type complexes with
α-macroglobulin (αM/uPA) will be tested. Our preliminary data demonstrate that (i) transthoracic US or sctPA-
based liposomes (TELIP) with nanomolar affinity to fibrin improve therapeutic outcomes of an otherwise
ineffective dose of fibrinolysin; (ii) US promotes intrapleural formation of αM/uPA, which correlates with success
of IPFT in pleural injury. Our hypothesis is that combining intrapleural delivery of low doses of a fibrinolysin
encapsulated within fibrin targeted carriers with ultrasound sonofibrinolysis will additively increase the
intrapleural half-life of plasminogen activators and rate of fibrinolysis, enhancing the efficacy of IPFT in acute
and chronic S. pneumoniae induced EMP. The hypothesis will be tested in three Specific Aims: 1. Determine
the minimal effective doses (MEDs) of echogenic liposomal carriers for treatment of S. pneumoniae induced
EMP in rabbits. 2. Identify the ultrasound mechanical index and treatment schedule that optimizes outcomes of
IPFT in rabbits with S. pneumoniae induced EMP. 3. Use the additivity of transthoracic ultrasound and fibrin-
targeted carrier delivery to increase the efficacy of IPFT in S. pneumoniae induced EMP. Our project team
consists of two groups with expertise in translational research, IPFT, management of EMP, therapeutic
commercialization, and liposomal carrier formulation and delivery. By applying state-of-the-art biochemical,
biophysical, physiologic, tissue analysis and imaging techniques, we will accomplish the Research Plan to
address the current gaps in empyema treatment and expand our understanding of sonochemical mechanisms.
If, as expected, this project succeeds, a new, well-tolerated, more effective and clinically tractable paradigm for
IPFT will emerge that may ultimately improve outcomes in patients with empyema.
