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Selected Publication:
Jain, P.
Development of liposomal drug delivery systems for inhalative application of iloprost
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2014. pp. 105
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- Authors Med Uni Graz:
- Jain Pritesh
- Advisor:
- Frank Sasa
- Olschewski Andrea
- Prassl Ruth
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- Abstract:
- Prostacyclin analogues (prostanoids) are standard therapeutic options for vasoconstrictive diseases, including pulmonary hypertension and Raynaud’s phenomenon. Although effective, the systemic application is expensive and has several side effects. For the therapy of pulmonary arterial hypertension, inhaled application of stable analogues of prostacyclin represents a well established alternative treatment leading to selective vasodilation of well-ventilated regions of the lung. However, the short half-life of the drugs reduces patient compliance. To improve drug efficiency we tested liposomal nanoparticles as carrier systems. In this study, we synthesized liposomal nanoparticles tailored for the prostacyclin analogue, iloprost, and evaluated their pharmacologic efficacy on mouse intra pulmonary arteries using wire myograph. Six formulations for iloprost were optimised and termed as LI-1 to LI-6. The use of cationic lipids, stearylamine or 1,2-di-(9Z-octadecenoyl)-3-trimethylammonium-propane (DOTAP) in liposomes promoted iloprost encapsulation to at least 50%. Addition of cholesterol modestly reduced iloprost encapsulation. Liposomal nanoparticle formulations were characterized using biophysical techniques and tested for toxicity and pharmacologic efficacy in vitro and ex vivo, respectively. Liposomes did not affect the viability of human pulmonary artery smooth muscle cells. Compared to an equivalent concentration of free iloprost, four out of the six polymer-coated liposomal formulations exhibited significantly enhanced vasodilation on mouse pulmonary arteries. Encapsulated iloprost in PEGylated liposomes exhibited concentration dependent relaxation of arteries. Strikingly, half the concentration of iloprost in liposomes elicited similar pharmacologic efficacy as non-encapsulated iloprost. Nebulisation data revealed that the vibrating mesh nebuliser can efficiently nebulise cationic liposomes and had the minimum impact on the integrity of liposomal formulations. Cationic liposomes can encapsulate iloprost at high efficacies and can serve as potential iloprost carriers to improve its therapeutic efficacy.