(600g) Rigid-Liposomes with Engineered ‘Raft-Switches' for Controlled Release of Therapeutics

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 tumor. In drug delivery to metastatic tumors with developed vasculature, the preferential tumor accumulation and retention of liposomes is primarily dependent on their size (EPR effect), and results in adequate tumor adsorded doses. One major issue of concern, however, is the inadequate release of drug inside the tumors' cancer cells in vivo. pH-sensitive liposomes that release their ‘cargo' after their endocytosis by cancer cells have been extensively studied for this purpose, but have limited in vivo application due to either loss of the liposome pH-sensitive character in the biological milieu or due to their structural instability in vivo that results in low tumor accumulation (low tumor absorbed doses). We propose a novel type of liposomes that can combine efficient release of contents in cancer cells in vivo without loss of their intact structure, exhibiting, therefore, adequate tumor accumulation.

Increased phospholipid-membrane rigidity prevents liposome clearance, thus increasing liposome accumulation in tumors, and also enhances drug retention in liposomes during blood circulation. 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 normal organs. In conventional pH-sensitive liposomes, addition of PEGylated lipids that increase the circulation times, aborts their pH-sensitive character.

We have developed pH-sensitive liposomes with rigid membranes that combine complete release of contents in the acidic endosome, and, potentially, long blood circulation times. To achieve this, we designed and engineered liposomes containing raft-forming rigid lipids that are triggered to assemble into rafts as a response to the endosomal pH. At physiological pH (during circulation) the liposome membrane is ‘homogeneous' and the contents cannot leak. At the endosomal pH, raft-formation takes place, and the encapsulated contents are released.

The liposomal membrane is composed of rigid lipids, and is covered with PEG-chains that reportedly increase blood circulation times. PEGylation does not interfere with the pH-sensitive properties of the developed liposomes. Serum proteins accelerate the release of contents at the endosomal pH.

These liposomes will potentially combine high tumor absorbed doses and high drug bioavailability in vivo.