PB0189 - Echogenic Liposomal Tissue Plasminogen Activator (tPA) Carrier – From the Circulation to the Pleural Space.

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

AK

Andrey A. Komissarov, PhD

Professor
Department of Cellular and Molecular Biology, School of Medicine, The University of Texas Health Science Center at Tyler
Tyler, Texas, United States

Co-Author(s)

MR

Maryam Ranjpour

Post-Doctoral Researcher
Department of Cellular and Molecular Biology, School of Medicine, The University of Texas Health Science Center at Tyler
Tyler, Texas, United States
BF

Brion Frierson

Research Assistant
Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX
Houston, Texas, United States
RE

Rebekah L. Emerine

Research Associate
Department of Cellular and Molecular Biology, School of Medicine, The University of Texas Health Science Center at Tyler
Tyler, Texas, United States
SC

Sunil Christudas

Post-Doctoral Researcher
Department of Cellular and Molecular Biology, School of Medicine, The University of Texas Health Science Center at Tyler
Tyler, Texas, United States
CD

Christian Jordan De Vera

Research Associate
Department of Cellular and Molecular Biology, School of Medicine, The University of Texas Health Science Center at Tyler
Tyler, Texas, United States
KS

Krishna Sarva

Research Associate
Department of Cellular and Molecular Biology, School of Medicine, The University of Texas Health Science Center at Tyler
Tyler, Texas, United States
AA

Ali O. Azghani

Professor
Department of Biology, The University of Texas at Tyler, TX
Tyler, Texas, United States
MK

Melvin E. Klegerman

Professor
Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX
Houston, Texas, United States
TP

Tao Peng

Post-Doctoral Researcher
Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX
Houston, Texas, United States
SH

Shaoling Huang

Professor
Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX
Houston, Texas, United States
DM

David D. Mcpherson

Professor
Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX
Houston, Texas, United States
SI

Steven Idell

Professor
Department of Cellular and Molecular Biology, School of Medicine, The University of Texas Health Science Center at Tyler, TX
Tyler, Texas, United States
GF

Galina Florova

Professor
Department of Cellular and Molecular Biology, School of Medicine, The University of Texas Health Science Center at Tyler
Tyler, Texas, United States

Background: Empyema, pleural sepsis, results in pleural fibrosis combined with severe loculation, pleural thickening, restricted drainage, and slow intrapleural fibrinolysis.

Aims: Encapsulated liposomal formulations of tPA(Alteplase), TELIP, previously tested in the circulation, combined with transthoracic ultrasound enhances fibrinolysis due to increased intrapleural half-life of the fibrinolysin.

Methods: TELIP was produced and assessed in vitro, ex vivo, and in vivo in a rabbit model of acute/early empyema.

Results: Optimized TELIP contains 2.0-5.0x109 echogenic liposomes (700-900nm diameter) per mg of lipid formulation and features up to 3% by weight of Alteplase tightly associated with liposomes with 15-25% of true encapsulated fibrinolysin. Encapsulated tPA is stable in pleural fluid ex vivo (>6h) and in vivo (>2h) could be released by imaging ultrasound (MI=1.8, 4x2min). While TELIP, like Alteplase, binds to fibrin, it does not compete significantly with plasmin and minimally affects the rate of fibrinolysis in vitro. The efficacy of TELIP alone and in combination with transthoracic ultrasound was next tested in a rabbit model of acute infectious pleural injury. Optimized TELIP 0.4 mg/kg (0.32 tightly bound and 0.08 true encapsulated Alteplase) did not perform as a Minimal Effective Dose (100% effective treatment for a group of 5-6 animals) when “opened” with a single transthoracic ultrasound treatment at 1(n=3) or 2(n=3) h after injection. An increase in the number of transthoracic ultrasound treatments to four (prior to TELIP injection, and at 2, 4, and 8h after injection did not meet MED efficacy requirements.

Conclusion(s): Optimized TELIP possesses unique properties, which may make it effective for thrombolysis in the circulation, where size of the clot is smaller, and levels of plasminogen are higher than those in empyema. Other plasminogen activators may increase efficacy of echogenic liposomal carriers in empyema.

This research was funded by the National Institutes of Health and the National Heart, Lung, and Blood Institute R01HL152059(A.A.K., M.E.K).