POLYAMINE ANALOGS OF N-(N',N'-DIMETHYLAMINOETHANE)CARBOMOYL]CHOLESTEROL (DC-CHOL) AS AGENTS FOR GENE DELIVERY

Cationic liposomes are rapidly proving very effective at mediating the delivery of genes to cells in vitro. Moreover, the use of cationic li posomes for gene delivery in vivo is now under consideration. In previ ous work, we were able to demonstrate that cationic liposomes, formula ted from 3 N-(N',N'-dimethylaminoethane)carbamoyl]cholesterol (DC-Chol ) and the neutral phospholipid, dioleoyl L-alpha-phosphatidylethanolam ine (DOPE), were able to transfect the lungs of mice in vivo. However, it rapidly became apparent that substantial improvements in the gene delivery efficiency, by approximately two orders of magnitude, would b e needed for human lung transfection to be possible. In the following paper we describe the synthesis of a range of polyamine analogues of D C-Chol, which were formulated into cationic liposomes with DOPE and ev aluated for efficiency of gene delivery in vitro and in vivo in mice. We report that cationic liposomes formulated from DOPE and the novel p entamine loxycarbonyl-3,7,12-triazapentadecane-1,15-diamine (CTAP) wer e 100 times more efficient than DC-Chol/DOPE liposomes at gene deliver y in vivo (500 times more effective than DNA alone). Therefore, we bel ieve that CTAP/DOPE cationic liposomes should have clinical applicatio ns in human gene therapy approaches to the treatment of lung disorders as well as to other clinical conditions.