Tris Lipidation: A Chemically Flexible Technology For Modifying The Delivery Of Drugs and Genes

SUMMARY1. One of the major challenges in the development of pharmaceuticals is their formulation with other materials to give them the desired bioavailability profile when administered into the body.2. We have developed a flexible platform technology (Tris lipidation) to simply and effectively alter the lipophilicity of drugs. As implied by the name, the technology uses the common buffer Tris as a linker between the drugs of interest and a domain of variable hydrophobicity.3. We demonstrate, using a mouse melanoma model, that Tris‐lipidated conjugates of the widely used cytotoxic and anti‐inflammatory drug methotrexate (MTX) display enhanced potency in the local treatment of tumours and reduced systemic toxicity when compared with the unconjugated drug.4. With genes now being predicted to be the pharmaceuticals of the future, we show that Tris‐lipidated cationic peptides can efficiently deliver DNA into (transfect) cells in culture. Furthermore, by comparing the abilities of variants of these Tris‐based cationic lipids to transfect cultured cells, we demonstrate that modifications made to variable regions of Tris‐lipidated compounds can dramatically alter their delivery profiles.