Enhanced Intravenous Transgene Expression in Mouse Lung Using Cyclic-Head Cationic Lipids

Abstract

Herein, we report enhanced intravenous mouse lung transfection using novel cyclic-head-group analogs of usually open-head cationic transfection lipids. Design and synthesis of the new cyclic-head lipid N,N-di-n-tetradecyl-3,4-dihydroxy-pyrrolidinium chloride (lipid 1) and its higher alkyl-chain analogs (lipids 2-4) and relative in vitro and in vivo gene transfer efficacies of cyclic-head lipids 1-4 to their corresponding open-head analogs [lipid 5, namely N,N-di-n-tetradecyl-N,N-(2-hydroxyethyl)ammonium chloride and its higher alkyl-chain analogs, lipids 6-8] have been described. In stark contrast to comparable in vitro transfection efficacies of both the cyclic- and open-head lipids, lipids 1-4 with cyclic heads were found to be significantly more efficient (by 5- to 11-fold) in transfecting mouse lung than their corresponding open-head analogs (5-8) upon intravenous administration. The cyclic-head lipid 3 with di-stearyl hydrophobic tail was found to be the most promising for future applications.

Cationic liposomes as non‐viral carriers of gene medicines: Resolved issues, open questions, and future promises

“…In another recent study, inspired by the previously reported high gene transfer activities of cationic lipids with one or two 2-hydroxyethyl functionalities in the polar head-group regions, 36,39,[41][42][43] we designed and synthesized a novel cationic lipid containing three 2-hydroxyethyl functionalities in the head-group region and evaluated its in vitro gene transfer efficacies in multiple cultured cells. 75 These findings demonstrate that the transfection efficacies of fatty acid-laden lipoplexes are worth evaluating particularly when traditional cationic liposomes prepared with either cholesterol or DOPE co-lipids fail to transfect cultured cells.…”

“…Interestingly, as mentioned below under the section on ''pre-clinical successes,'' the in vivo lung transfection efficacies of the cyclic-head lipids were found to be remarkably superior to their open-head analogs. 43 Recently, we have observed that the in vitro gene delivery efficiencies of cationic lipids with hydroxyalkyl head-groups get adversely affected by increased covalent distances between the hydroxyl functionality and the cationic centers. 72 Our recent findings have demonstrated that even truly minor structural modification, such as inclusion of an additional one methylene group in the head-group region (lipid 8, Fig.…”

“…5) with five-carbon spacer unit in the head-group region. 71 With a view to probe the relative transfection efficacies of non-glycerol-based open-head hydroxyl group containing cationic lipids with their cyclic-head counterparts, we designed and synthesized four novel cyclic-head cationic lipid analogs 43 (5-8, Fig. 4) of our previously reported open-head lipids (1-4, Fig.…”

Haloperidol-associated Stealth Liposomes

“…To extend the current study toward targeting breast cancer in tumor-bearing mice we chose to include DODEAC as the base cationic lipid, which has a proven in vivo biodistribution profile (30). The idea of including polyethylene glycol in cationic lipid-mediated gene transfection in vivo is to suppress the usual nonspecific lung affinity by increasing the longevity of the liposome in the body.…”

“…However, with a PEG spacer between the lipid and HP, there is efficient ligand-mediated targeting by the liposome. Additionally, the PEG moiety also provides improved stability and an increased circulation halflife of the liposome in vivo (29,30,21,22).…”