In cancer therapies, advances in liposome research show strong potential in vitro, but, in the clinic, disseminated metastatic cancer is still incurable. This is largely due to low tumor absorbed doses and low drug bioavailability within the cancer cells that constitute the tumors. Increased phospholipid membrane rigidity prevents liposome clearance, and thus, enhances liposome accumulation in tumors. But, after endocytosis, conventional rigid-membrane liposomes have limited capacity to release their contents during the acidification of the endosomal lumen, resulting in low drug bioavailability in cancer cells. On the other hand, conventional pH-sensitive liposomes have significantly shorter blood-circulation times which translate into decreased tumor uptake, and higher toxicity. In conventional pH-sensitive liposomes, addition of PEGylated lipids that increase the circulation times, significantly compromises their pH-sensitive character.

We have developed a new generation of liposomes that combine membrane rigidity and pH-sensitivity. We have designed and engineered liposomes with lipids that phase-separate and form domains in the plane of the membrane at low pH resulting in release of encapsulated contents. The membrane is covered with PEGylated lipids that reportedly increase blood circulation times. Liposomes were characterized for size, surface charge, pH sensitivity and stability in the presence of serum proteins. Liposomes were immunolabeled with an anti-HER2/neu antibody and studies were performed to evaluate binding, internalization and content release in human ovarian cancer cells.