Development of novel pH-responsive liposomes composed of anionic lipids and pH-sensitive cationic lipids for efficient drug release in weakly acidic environments.

Liposomes are utilized as a tumor-targeted drug delivery carrier. However, due to their rigid lipid membrane, drug release in tumor tissues is often poor, which limits their therapeutic efficacy. To overcome this drawback, the construction of liposomes that release their payload in response to the weakly acidic tumor microenvironment has been examined. We herein developed pH-responsive liposomes based on a new concept mediated by electronic interactions between anionic lipids and pH-sensitive cationic lipids. Liposomes composed of DSPG, a saturated anionic lipid, and DODAP, an unsaturated pH-sensitive cationic lipid, were stable at pH 7.4, and were significantly disrupted and released calcein at pH 6.0. Moreover, the replacement of DODAP with DODMA in the liposomal composition shifted the pH at which liposomal disruption occurred from 6.0 to 6.5. In addition, liposomes composed of DOPG, an unsaturated anionic lipid, and DODAP or DPPG, a saturated anionic lipid, and DPDAP, a saturated pH-sensitive cationic lipid, showed excellent pH responsiveness. In a cellular uptake study, the amount of intracellular DSPG/DODAP liposomes was markedly lower at pH 6.0 than at pH 7.4. These results suggest the potential of the developed pH-responsive liposomes to improve the therapeutic efficiency of liposomal anticancer drugs.