Dexamethasone in pH sensitive archaeosomes: design and characterization

ALTUBE MARÍA JULIA; SELZER SOLANGE; MORILLA MARÍA JOSE; ROMERO EDER LILIA

Manchester

Conferencia; 3rd International Conference on Nanotechnology in Nanomedicine; 2015

Drug delivery employing pH sensitive carriers may offer a massive release of drugs such ashydrosoluble, anti-inflammatory dexamethasone-phosphate (DEXP) to the cell cytoplasm [1], enabling DEXP binding to its cytoplasmic glucocorticoid receptor. This could be achieved for instance, by loading DEXP in pH sensitive liposomes (pHsL),structures that after a phase transition triggered by the endosomal acidity, fuse with the endosomal bilayers. We had previously shown however, that vesicles made of archaeolipids extracted from hyperhalophile archaea (AHA) are significantly more taken up by in vitro macrophages than phosphatidylcholine liposomes [2]. Thus, in this work we propose a new method to increase the cytoplasmic delivery of DEXP, based on the use of a new type of carriers, the AHA-containing- pH liposomes, or pH sensitive archaeosomes (pHsA). The rationale behind the engineering of pHsA is that the provision of an endocytic uptake higher than that of classical pHsL, leads to a higher cytoplasmic delivery of DEXP. The best suited pHsA formulation was 1:0.07:0.7 w:w dioleoyl-phosphatidylethanolamine:cholesteryl hemisuccinate:AHA. With this formulation, the release of vesicular hydrophilic content to the cytoplasm was 1.3-fold and 3.5-fold higher than pHsL in J774 macrophages and A549 alveolar type II respectively. This difference was owed to the higher uptake of pHsA (1.7-fold and 3-fold higher than pHsL by J774 and A549 respectively). A competition assay with polyinosinic acid showed that scavenger receptors might be involved in the uptake of AHA by J774. Finally, DEXP loaded in pHsA (160 nm mean diameter and -35 mV Z potential) reduce pro-inflammatory cytokine secretion (IL-6, IL-1β, IL-12) by J774 after activation with LPS without reducing cellular viability.[1]U.S. Huth, R. Schubert, R. Peschka-SussJ ContRel, 110, 490(2006).[2] L.H. Higa, P. Schilrreff, A.P. Perez, M.A. Iriarte, D.I. Roncaglia, M.J. Morilla, E.L. Romero Nanomedicine: NBM, 8, 1319 (2012).