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Bergamo, Marta

University of British Columbia

Macroaggregated albumin microparticles (MAA) are particles routinely used in the clinic as imaging agents for the diagnosis of pulmonary embolism (PE) due to their ability to passively target the lungs. Since albumin is biocompatible and biodegradable, MAA represents an attractive carrier for the delivery of drugs to the lungs. Particularly, there is still a great need for lung targeting delivery systems of fibrinolysis-enhancing drugs for the treatment of PE. While these drugs are effective in resolving blood clots entrapped in the pulmonary vasculature, they are administered intravenously resulting in severe side effects limiting their clinical use. Therefore, it is critical to develop formulations for their targeted delivery to reduce systemic exposure, thus improving their safety profile. The aim of this project was to formulate the anticoagulant tiplaxtinin with albumin microparticles for delivery to the lungs. MAA loaded with tiplaxtinin (MATi particles) were prepared by one-pot synthesis of the drug with bovine serum albumin (BSA) at controlled conditions. Particles were characterized for their size, drug loading, stability, and cytotoxicity. Acute toxicity of the particles was investigated in vivo by intravenous administration of MATi particles prepared with radiolabeled BSA (¹¹¹In-MATi) to healthy mice. Dual radiolabeling of the MATi particles was obtained by labeling tiplaxtinin with an additional radioisotope (³H). This allowed us to investigate the biodistribution of the albumin particles and the drug simultaneously and compare it to the unformulated tiplaxtinin following intravenous administration into healthy mice. MATi particles had a size distribution comparable to clinically used MAA, averaged a drug loading of 26%, showed good stability, and signs of toxicity observed were affected by the drug itself. In vivo, 60% of injected dose accumulated in the lungs upon injection and showed no overt signs of toxicity. When delivered with the particles, up to a 12-fold increase of tiplaxtinin was observed in the lungs compared to the unformulated drug. MATi particles allowed to overcome the solubility issue of tiplaxtinin and thereby could be administered at a higher concentration compared to unformulated drug. Future work involves the investigations of MATi particles in a disease model.

Text

2025-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88067

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/