This is a copy of the slides presented at the meeting but not formally written up for the volume.
In the past four decades lipid vesicles (liposomes) have evolved from widely used biomembrane models into important drug and gene carriers. The phosphatidylcholine phospholipids PC used in the drug carriers are biocompatible and biodegradable but they function as a relatively inert shell and require the incorporation of cholesterol to maintain the drug encapsulated in the liposome; The PC are also incapable of associating with ligands and have very weak interactions with nucleic acids. Moreover, they are not particularly good for cytoplasmic delivery of the encapsulated cargo. Recently, we have devised three classes of new lipids and have improved the synthesis of a fourth class that enable the preparation of a bioresponsive targeted carrier with improved nucleic acid delivery. Class 1 are low pH sensitive and include a diortho ester PEG lipid or a di-orthoester PC. Class two are redox sensitive lipids and include thiocholesterol based and thio diacyl chain based lipids that can be used in a sequential assembly process to encapsulate nucleic acid drugs in a charge neutral or negatively charged nanolipid particle. Class 3 is a new family of lipids that provide increased in vivo bilayer stability without the need for crosslinking of the bilayer. Class 4 is an improved synthesis of a triNTA diacyl lipid. This lipid can be used to attach His-6 containing molecules to the bilayer vesicle after the liposomes have been prepared and loaded with drugs. These lipids form a tool kit that can be used to prepare a variety of targeted drug, protein and nucleic acid delivery vesicles with attached targeting ligands. The synthesis, characterization and use of these lipids in a variety of drug delivery applications will be described. Suported by NIH EB003008 & NIH GM061851.