Development of a Long-circulating Liposomal Carrier Coated with Serum Albumin via Ligand

Introduction: Polyethylene glycol (PEG)-modified liposome is known as the most succeeded drug carrier because of its long blood half-life. However, it has a problem with its repeated administration because it is rapidly... [ view full abstract ]

Introduction: Polyethylene glycol (PEG)-modified liposome is known as the most succeeded drug carrier because of its long blood half-life. However, it has a problem with its repeated administration because it is rapidly removed from blood after the second administration by produced antibodies against PEG. Here, we focused on serum albumin (SA) for an alternative molecule to provide stealth property to liposome. SA is the most abundant protein in plasma (~40 g/L). Since SA can avoid glomerular filtration and degradation in endocytosis, it has a long blood half-life (20 days). Moreover, SA works as an endogenous drug carrier for exogenous drugs and can avoid being caught by immune system. We utilized SA to camouflage the surface of liposome to prolong its blood circulation time. Here, we propose modification of the liposome surface via SA-specific ligands. As such a ligand, we selected octadecanedioic acid, which is reported to bind to albumin. Because of the remaining terminal carboxyl group of octadecanedioic acid after modification of PEG-lipid, insertion of the ligand into hydrophobic liposome’s bilayer will be prevented.
Method: Octadecacnedioic acid-modified lipid (1) was synthesized. Then, a liposome containing lipid 1 (1LL) was prepared by a hydration method. To confirm the stability of 1LL in physiological saline, 1LL was incubated in DPBS containing SA from bovine (BSA) at r.t. Change of liposome’s size was monitored for a week.
Results and Discussion: In the absence of BSA, 1LL aggregated in DPBS after 2 days. On the other hand, in the presence of BSA, 1LL kept narrow size distribution and dispersed stably for a week. It was speculated that the aggregation of 1LL was caused by hydrophobic interaction between ligands, however, the hydrophobic interaction seems to be suppressed by coating of 1LL with SA. This result indicates that 1LL was successfully coated with SA, contributing significant stabilization of 1LL in physiological saline. 1LL would be applicable to a drug carrier with enhanced blood circulation. Result of blood circulation time of the liposome in mice will be presented.