Immunological response to nitroglycerin-loaded shear-responsive liposomes in vitro and in vivo

Buscema, M. et al. (2017) Immunological response to nitroglycerin-loaded shear-responsive liposomes in vitro and in vivo. Journal of Controlled Release, 264, pp. 14-23. (doi: 10.1016/j.jconrel.2017.08.010) (PMID:28803115)

Abstract

Liposomes formulated from the 1,3-diamidophospholipid Pad-PC-Pad are shear-responsive and thus promising nano-containers to specifically release a vasodilator at stenotic arteries. The recommended preclinical safety tests for therapeutic liposomes of nanometer size include the in vitro assessment of complement activation and the evaluation of the associated risk of complement activation-related pseudo-allergy (CARPA) in vivo. For this reason, we measured complement activation by Pad-PC-Pad formulations in human and porcine sera, along with the nanopharmaceutical-mediated cardiopulmonary responses in pigs. The evaluated formulations comprised of Pad-PC-Pad liposomes, with and without polyethylene glycol on the surface of the liposomes, and nitroglycerin as a model vasodilator. The nitroglycerin incorporation efficiency ranged from 25% to 50%. In human sera, liposome formulations with 20 mg/mL phospholipid gave rise to complement activation, mainly via the alternative pathway, as reflected by the rises in SC5b-9 and Bb protein complex concentrations. Formulations having a factor of ten lower phospholipid content did not result in measurable complement activation. The weak complement activation induced by Pad-PC-Pad liposomal formulations was confirmed by the results obtained by performing an in vivo study in a porcine model, where hemodynamic parameters were monitored continuously. Our study suggests that, compared to FDA-approved liposomal drugs, Pad-PC-Pad exhibits less or similar risks of CARPA.

• Item Type: Articles
• Additional Information: The authors thank the Swiss National Science Foundation (SNSF) via the National Research Program (NRP) 62 ‘Smart Materials’ (Grant No. 126090), which partially funded this work, as well as the European Union Seventh Framework Programme (FP7/2007-2013) grant No. NMP-2012-LARGE-6-309820 (NanoAthero) and (TransInt), FP-7-HEALTH-2013-Innovation-1 (2013) (602923-2) (TheraGlio), and the support by the ‘Applied Materials and Nanotechnology Center of Excellence’, Miskolc University.
• Keywords: Nanomedicine, drug delivery, complement activation, pathway, metastable liposome, porcine model, biophysics, shear-responsive nano-container.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gerganova, Gabriela
• Authors: Buscema, M., Matviykiv, S., Mészáros, T., Gerganova, G., Weinberger, A., Mettal, U., Mueller, D., Neuhaus, F., Stalder, E., Ishikawa, T., Urbanics, R., Saxer, T., Pfohl, T., Szebeni, J., Zumbueh, A., and Müller, B.
• Subjects: Q Science > Q Science (General); Q Science > QC Physics; Q Science > QD Chemistry; Q Science > QP Physiology; R Medicine > R Medicine (General); R Medicine > RM Therapeutics. Pharmacology
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Journal of Controlled Release
• Publisher: Elsevier
• ISSN: 0168-3659
• ISSN (Online): 1873-4995
• Published Online: 10 August 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Journal of Controlled Release 264: 14-23
• Publisher Policy: Reproduced under a Creative Commons License