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

Marzia Buscema, Sofiya Matviykiv, T. Mészáros, Gabriela Gerganova, Andreas Weinberger, Ute Mettal, Dennis Mueller, Frederik Neuhaus, Etienne Stalder, Takashi Ishikawa, Rudolf Urbanics, Till Saxer, Thomas Pfohl, J. Szebeni, Andreas Zumbuehl, Bert Müller

Research output: Article

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)14-23
Number of pages10
JournalJournal of Controlled Release
Volume264
DOIs
Publication statusPublished - okt. 28 2017

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Complement Activation
Nitroglycerin
Liposomes
Swine
Vasodilator Agents
Phospholipids
Hypersensitivity
In Vitro Techniques
Serum
Arteries
Hemodynamics
1,3-dipalmitamidopropan-2-yl 2-(trimethylammonio)ethyl phosphate
Safety
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Immunological response to nitroglycerin-loaded shear-responsive liposomes in vitro and in vivo. / Buscema, Marzia; Matviykiv, Sofiya; Mészáros, T.; Gerganova, Gabriela; Weinberger, Andreas; Mettal, Ute; Mueller, Dennis; Neuhaus, Frederik; Stalder, Etienne; Ishikawa, Takashi; Urbanics, Rudolf; Saxer, Till; Pfohl, Thomas; Szebeni, J.; Zumbuehl, Andreas; Müller, Bert.

In: Journal of Controlled Release, Vol. 264, 28.10.2017, p. 14-23.

Research output: Article

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, Zumbuehl, A & Müller, B 2017, 'Immunological response to nitroglycerin-loaded shear-responsive liposomes in vitro and in vivo', Journal of Controlled Release, vol. 264, pp. 14-23. https://doi.org/10.1016/j.jconrel.2017.08.010
Buscema, Marzia ; Matviykiv, Sofiya ; Mészáros, T. ; Gerganova, Gabriela ; Weinberger, Andreas ; Mettal, Ute ; Mueller, Dennis ; Neuhaus, Frederik ; Stalder, Etienne ; Ishikawa, Takashi ; Urbanics, Rudolf ; Saxer, Till ; Pfohl, Thomas ; Szebeni, J. ; Zumbuehl, Andreas ; Müller, Bert. / Immunological response to nitroglycerin-loaded shear-responsive liposomes in vitro and in vivo. In: Journal of Controlled Release. 2017 ; Vol. 264. pp. 14-23.
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AU - Buscema, Marzia

AU - Matviykiv, Sofiya

AU - Mészáros, T.

AU - Gerganova, Gabriela

AU - Weinberger, Andreas

AU - Mettal, Ute

AU - Mueller, Dennis

AU - Neuhaus, Frederik

AU - Stalder, Etienne

AU - Ishikawa, Takashi

AU - Urbanics, Rudolf

AU - Saxer, Till

AU - Pfohl, Thomas

AU - Szebeni, J.

AU - Zumbuehl, Andreas

AU - Müller, Bert

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AB - 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.

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KW - Complement activation

KW - Drug delivery

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KW - Porcine model

KW - Shear-responsive nano-container

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