Lipid-drug conjugate nanoparticles of the hydrophilic drug diminazene-cytotoxicity testing and mouse serum adsorption.
Sleeping sickness is a widely distributed disease in great parts of Africa. It is caused by Trypanosoma brucei gambiense and rhodiense, transmitted by the Tse-Tse fly. After a hemolymphatic stage, the parasites enter the central nervous system where they cannot be reached by hydrophilic drugs. To potentially deliver the hydrophilic antitrypanosomal drug diminazene diaceturate to the brain of infected mice, the drug was formulated as lipid-drug conjugate (LDC) nanoparticles (NP) by combination with stearic- (SA) and oleic acid (OA). To estimate the in vivo compatibility, the particles were incubated with human granulocytes. Because as potential delivery mechanism the absorption of specific serum proteins (ApoE, Apo AI and Apo AIV) was found to be responsible for the delivery of nanoparticles to the brain, demonstrated using PBCA nanoparticles coated with polysorbate 80 (LDL uptake mechanism) the nanoparticles were incubated with mouse serum and the adsorption pattern was determined using the 2-D PAGE technique. As a result of this study, the cytotoxic potential was shown to decrease when diminazene is part of the particle matrix compared to pure fatty acid nanoparticles and the mouse serum protein adsorption pattern differs from the samples studied earlier in human serum. Especially, the fact concerning Apo-E that could be detected when the particles were incubated in human serum is absent after the mouse serum incubation, potentially, is a critical point for the delivery via the LDL-uptake mechanism but the data demonstrate that LDC nanoparticles, with 33% (wt/wt) drug loading capacity possess the potential to act as a delivery system for hydrophilic drugs like diminazene diaceturate and that further studies have to demonstrate the usability as a brain delivery system.
Olbrich
Carsten
C
Department of Pharmaceutics, The Free University of Berlin, Kelchstr. 31, D-12169 Berlin, Germany. carsten.olbrich@schering.de
Gessner
Andrea
A
Schröder
Werner
W
Kayser
Oliver
O
Müller
Rainer H
RH
D000327:Adsorption; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D004133:Diminazene / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D015180:Electrophoresis, Gel, Two-Dimensional; D005079:Excipients; D006098:Granulocytes / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007525:Isoelectric Focusing; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D008863:Microspheres; D010316:Particle Size; D013229:Stearic Acids / Q000737:chemistry; D013499:Surface Properties; D013778:Tetrazolium Salts; D013844:Thiazoles
D001798:Blood Proteins; D005079:Excipients; D008055:Lipids; D013229:Stearic Acids; D013778:Tetrazolium Salts; D013844:Thiazoles; C031183:stearic acid; C022616:thiazolyl blue; D004133:Diminazene