Journal of Controlled Release, 9 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA (1989) 177- 186 Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands CONTROL OF RELEASE OF ENCAPSULATED MOLECULES FROM POLYMERIZED MIXED LIPOSOMES INDUCED BY PHYSICAL OR CHEMICAL STIMULI Shinji Takeoka, Hiroyuki Ohno*, Narutoshi Hayashi and Eishun Tsuchida** Department of Polymer Chemistry, Waseda University, Tokyo 160 (Japan) (Received July 11, 1987; accepted in revised form January 9, 1989) zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLK Small unilamellar mixed liposomes composed of polymerizable and non-polymerizable lipids are polymerized zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA to prepare stimuli-responsive poly merized liposomes. Encapsulated 5(6)-carboxyflu- orescein (CF) is released from non-polymerizable regions by phy sical and/or chemical stimuli. As the liposome structure is maintained by polymerized lipid frames, the release is stopped by re- moving the stimuli. This process can be repeated several times. CF is released rapidly at the phase transition temperature of the non-polymerizable lipids, e.g., at 37 and 19” C for dipalmitoylphos- phatidylcholine and dimyristoylphosphatidylcholine, respectively. The temperature dependence is further affected by the size of the phase- separated domains. Polymerized mixed liposomes hav- ing larger phase-separated domains show a sharper response to the phase transition. In case of polymerized mixed liposomes containingphosphatidylethanolamine, CF is released as a function of PH. The release rate is very small at pH 11, but it increases with pH decreasing to 7.5, which is attributed to the structural change of the bilayer induced by the change in dissociation of the head groups. On the other hand, in case of polymerized mixed liposomes containing phosphati- dylserine, release of CF is accelerated by the addition of Ca’+ ions and is restored to the initial rate by eliminating Ca2+ ions with ethylenediamine tetraacetic acid sodium salt (EDTA). The CF release response is obtained repeatedly by the alternating addition of Ca2+ ion and EDTA. Liposomes have been applied as safe and ef- fective microcapsules especially for drug carrier purposes [ 1,2]. They are, however, not so sta- ble in biological conditions, and several studies have therefore been initiated to improve their stability. Polymerization of the component lip- ids is one of several potential techniques to sta- bilize the liposome structure. Many polymer- izable amphiphiles have hitherto been synthesized and their polymerizability in lipo- *Present address: Faculty of Technology, Tokyo University of Agriculture and Technology, Koganei Tokyo 184, Japan. **To whom correspondence should be addressed. somal form has been analyzed [ 3-111. We have already revealed that it was quite important to select a polymerization method allowing to pre- pare actually stable liposome systems [ 12-141. In other words, some membrane characteristics including membrane stability for the polymer- ized liposomes strongly depend on the polymer- ization method and conditions [ 141. In spite of improvement in stability, polymerized lipo- somes lose their fundamental characteristics such as cooperative phase transition behavior, response towards exogenous stimuli and so on [121. In our previous paper, mixed lipid liposomes composed of polymerizable and nonpolymeriz- 0168-3659/89/$03.50 0 1989 Elsevier Science Publishers B.V.