RESUMEN
Discoidal lipid nanoparticles mimicking native high-density lipoproteins (HDL) are promising delivery vehicles of drugs and/or imaging agents. However, little is known about the in vivo biodistribution of such discoidal lipid nanoparticles compared to liposomes, clinically available spherical lipid nanoparticles. Recently, it has been reported that synthetic polymers instead of apolipoproteins can be complexed with phospholipid to form discoidal nanoparticles. In the present study, with the aim of developing phospholipid-synthetic polymer complexes for future clinical applications, the biodistribution of such particles in normal mice was investigated. Lipid nanoparticles comprising 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and styrene maleic acid copolymer (SMA), having sizes similar to native HDL, were prepared using the freeze-sonication method. POPC-SMA complexes remained stable at 37°C for at least 3 days in buffer. By devising ways to avoid detrimental effects accompanied by pH reduction and nonspecific binding of 111 In to SMA, POPC-SMA complexes were successfully labeled with 111 In without affecting particle integrity. The biodistribution of POPC-SMA complexes in normal mice was similar to that of discoidal lipid nanoparticles composed of POPC and apolipoprotein A-I, the major protein constituent of native HDL. Unlike liposomes, the accumulation of POPC-SMA complexes in the spleen was low, suggesting that these complexes are not recognized as foreign substances. To the best of our knowledge, this is the first in vivo study of HDL-mimicking phospholipid-synthetic polymer complexes.
Asunto(s)
Materiales Biomiméticos/química , Materiales Biomiméticos/farmacocinética , Radioisótopos de Indio , Lipoproteínas HDL/metabolismo , Maleatos/química , Maleatos/farmacocinética , Fosfatidilcolinas/química , Poliestirenos/química , Poliestirenos/farmacocinética , Animales , Marcaje Isotópico , Masculino , Ratones , Nanopartículas/química , Distribución TisularRESUMEN
Discoidal high-density lipoproteins generated by the apolipoprotein-mediated solubilization of membrane lipids in vivo can be reconstituted with phospholipids and apolipoproteins in vitro. Recently, it has been reported that such particles can be prepared using the hydrolyzed acid form of styrene-maleic anhydride copolymer (SMAaf) instead of apolipoproteins, but characterization of its physicochemical properties has remained less elucidated. In the present study, with the aim of applying SMAaf-based lipid nanoparticles as novel delivery vehicles of drugs and/or imaging agents, we investigated the preparation conditions and evaluated the physicochemical properties of lipid-SMAaf complexes. SMAaf induced spontaneous turbidity clearance of dimyristoylphosphatidylcholine (DMPC) vesicles accompanied by the formation of smaller particles not only at the phase transition temperature of DMPC but also above it. Such reductions in the turbidity were not observed with some other amphiphilic synthetic polymers tested under the same experimental conditions. Size exclusion chromatography analyses showed that homogeneously sized particles were prepared at lipid to SMAaf weight ratios of less than 1/1.5. Dynamic light scattering and transmission electron microscopy revealed that gel-filtered DMPC-SMAaf complexes were approximately 8-10 nm in diameter and discoidal in shape. The DMPC-SMAaf complexes were relatively stable even after lyophilization but were sensitive to pH changes. Fluorescence techniques demonstrated that the gel to liquid-crystalline phase transition temperature of DMPC in the discoidal complexes broadened significantly relative to that of liposomes, despite their common bilayer structure, which is a typical feature of discoidal lipid nanoparticles. These results provide fundamental insights into discoidal SMAaf-based lipid nanoparticles for the development of novel delivery vehicles.