Title:
Development of stimuli-sensitive liposomes for biomedical applications

Kenji Kono
Department of Applied Chemistry, Osaka Prefecture University

Abstract:
Liposomes (phospholipid vesicles) are regarded as ideal carriers for drugs and bioactive molecules, because of their high biocompatibility and biodegradability. Stimuli-responsive liposomes, which exhibit functions such as drug release and membrane fusion in response to stimuli, are of importance for precision drug delivery. For example, temperature-responsive liposomes are considered to be useful for target-specific drug delivery, because these liposomes are able to release drugs at the target tissues, which are mildly heated. We developed highly temperature-sensitive liposomes by surface modification with thermosensitive polymers, which change their property from hydrophilic to hydrophobic around 40oC. These liposomes retained drugs at physiological temperature, but released them above the transition temperature of the polymers. When the polymer-modified liposomes encapsulating doxorubicin were administered intravenously to tumor-bearing mice and subsequently mild heating at 43-45oC was applied to the tumor site, tumor growth was strongly suppressed. We also attempted to prepare multifunctional liposomes with temperature-responsive and imaging functions by the incorporation of dendron-based lipid having Gd-chelates into the temperature-sensitive liposomes. We could follow accumulation of the Gd-lipid-containing liposomes in the tumor with MRI.
pH-Sensitive liposomes that are destabilized under weakly acidic condition are considered to be useful as a delivery vehicle of membrane-impermeable molecules into a cell. It is known that liposomes are taken up by cells through endocytosis and are trapped in endosome, which has a weakly acidic environment. Therefore, when exposed to the weakly acidic environment of endosome, pH-responsive liposomes cause destabilization of endosomes and fuse with endosomal membrane, resulting in release of their contents into cytosol. We have attempted to develop highly pH-sensitive liposomes by surface modification with pH-sensitive poly(glycidol) derivatives. Poly(glycidol) has a backbone similar to biocompatible poly(ethylene glycol) and hydroxyl groups on side chains, which can be used to introduce carboxyl groups. We prepared various types of poly(glycidol) derivatives by reacting it with various kinds of acid anhydrides. Liposomes modified with these carboxylated poly(glycidol)s are stable at neutral pH but are destabilized below pH about 6. We are trying to use these pH-sensitive liposomes as an antigen delivery vehicle for activation of tumor immunotherapy.