Development of facile synthetic pathways to plasmenyl -type lipids and their utilization in the development of acid -sensitive vinyl ether-based pegylated liposomes

Facile and direct synthetic pathways to plasmenyl-type lipids for liposomal drug delivery and biological activity studies are described. Racemic plasmenylcholines and plasmenyl-type antitumor lipids were prepared via reductive cleavage reactions of acrolein acetals in the stereoselective formation of (Z)-vinyl ether linkages. Chiral plasmenylcholines were also prepared via lithioalkoxy allyl intermediates, generated from allyl ether with sec-BuLi, in the key (Z)-vinyl ether bond formation step. Both methodologies are the most direct pathways to the synthesis of plasmenyl-type lipids to date. These two (Z)-vinyl ether bond forming reactions were successfully applied for the preparations of PEG-lipid conjugates linked via (Z)-vinyl ether bond and utilized for acid triggered release of liposomal cargo. Drug delivery applications of these conjugates requires efficient contents release into the target cell cytoplasm. Utilizing rational approaches, including some computational chemistry and reported kinetic data of vinyl ethers with different stereoelectronic properties, new types of PEG-lipid conjugates with controlled acid sensitivity were designed. Four PEG-lipid conjugates containing different acid-sensitive vinyl ethers were prepared and the contents release of liposomes containing these conjugates measured by calcein release assay. The observed leakage rates suggest that control of the acid sensitivity of vinyl ether linked conjugate is a very promising approach for efficient cytoplasmic drug delivery