Phosphatidylserine- and phosphatidylglycerol-enriched phospholipids as anti-inflammatory agents
Phospholipids as excipients of nano-scaled formulations gained interest over the last decades. Due to their natural origin, they are highly biocompatible and therefore well tolerated.1) Special interest has been dedicated to the anionic phospholipids phosphatidylserine (PS) and phosphatidylglycerol (PG). For both immuno-modulating properties have been described. PS is localized in the inner leaflet of the plasma membrane.2) During apoptosis, it is translocated to the outer leaflet, where it serves as an ‚eat me‘ signal for macrophages.3) The phagocytosis of PS-presenting cell corpses is paralleled by a macrophage polarization from pro-(M1) to anti-inflammatory (M2), resulting in the resolution of inflammation.4) Beside PS, also for PG immuno-modulating properties were described. PG is a component of the lung surfactant and reduces the interfacial tension of the alveolar air/liquid interface.5) Beyond, it shows anti-inflammatory properties in vivo, e.g. in pulmonary diseases such as infections with respiratory syncytial virus6), Mycoplasma pneumoniae7) and influenza typ A virus.8) Mechanistically, for PG interactions within the LPS-binding cascade with effects on the TLR-4 receptor were described.9) Although for both PLs immuno-modulating properties were described, systematic and comparative studies are rare.
Aim of this project was therefore to establish the basis for a systematic exploration of PS- and PG-enriched nanodispersions with the design, manufacturing, and characterization of well-defined phospholipid nano-formulations for possible medical applications. In order to achieve safe and efficient high-quality products that meet pharmaceutical requirements, Quality by Design Principles according to ICH guideline Q8 (R2)10) were applied and the FDA Guidance for Industry for ‚Liposomal Drug Products‘ was followed.
Benefit for the community
Our research provides the basis for the systematic investigation of PS- and PG-enriched nanodispersions. Exploring conventional and stabilized (‘stealth’) liposomes as well as mixed micelles systematically and comparatively, the application possibilities for PS and PG to be used in pharmaceutical applications are increased. Furthermore, we focus on possible medical applications, especially in the field of myocardial infarct repair.11) Here, in close interdisciplinary cooperation between pharmacists, chemists, veterinarians, and medical doctors, preclinical in vivo studies are performed, focusing on the investigation of the biodistribution and therapeutic efficacy of selected phospholipid formulations in healthy and infarcted animals.
Conventional, stabilized (‚stealth‘) liposomes as well as bile salt mixed micelles were investigated. Physicochemically, liposomes and mixed micelles differed in terms of size and flexibility. During biological in vitro characterization, neither formulation showed cytotoxic nor hemolytic properties. On LPS/mIFNγ stimulated mouse peritoneal macrophages conventional and ‚stealth‘ liposomes as well as mixed micelles formulations showed immuno-modulating properties (dose-dependent decrease of TNFα-production). Although liposomes and mixed micelles differed in terms of their physicochemical properties, they showed comparable immuno-modulating properties. Our results highlight liposomes, either conventional or ‘stealth’ as well as mixed micelles as nanodispersions for PS and PG, suitable for parenteral administration.
The use of natural and synthetic phospholipids as pharmaceutical excipients
Eur. J. Lipid Sci. Technol. 116, 1088-1107
Regulation of phospholipid asymmetry in the erythrocyte membrane
Curr. Opin. Hematol. 15, 191-195
“Eat me” imaging and therapy
Adv. Drug Deliv. Rev. vol. 99, 2-11
Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer
Cell Death Differ. 23, 962-978
Interaction of the lipid and protein components of pulmonary surfactant Role of phosphatidylglycerol and calcium
Biochim. Biophys. Acta 647, 159-168
Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus-induced inflammation and infection
Proc. Natl. Acad. Sci. U. S. A. 107, 320-325
Pulmonary surfactant phosphatidylglycerol inhibits Mycoplasma pneumoniae-stimulated eicosanoid production from human and mouse macrophages
J. Biol. Chem. 286, 7841-7853
Phosphatidylglycerol suppresses influenza A virus infection
Am. J. Respir. Cell. Mol. Biol. 46, 479-487
Phospholipid regulation of innate immunity and respiratory viral infection
J. Biol. Chem. 294, 4282-4289
Pharmaceutical quality by design in academic nanomedicine research: stifling innovation or creativity through constraint?
J. Interdiscip. Nanomed. 3, 175-182
Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair
Proc. Natl. Acad. Sci. U. S. A. 108, 1827-1832
Phosphatidylserine (PS) and phosphatidylglycerol (PG) nanodispersions as potential anti-inflammatory therapeutics: Comparison of in vitro activity and impact of pegylation
Nanomedicine 23, 102096
Phosphatidylserine (PS)- and phosphatidylglycerol-(PG)-enriched mixed micelles (MM): a new nano-drug delivery system with anti-inflammatory potential?
Eur. J. Pharm. Sci. 105451
Towards the Development of Long Circulating Phosphatidylserine (PS)- and Phosphatidylglycerol (PG)-Enriched Anti-Inflammatory Liposomes: Is PEGylation Effective?
Pharmaceutics 13, 282