Synthesis and characterization of betaine-like diacyl lipids: zwitterionic lipids with the cationic amine at the bilayer interface

Abstract

We synthesized and characterized a series of zwitterionic, acetate-terminated, quaternized amine diacyl lipids (AQ). These lipids have an inverted headgroup orientation as compared to naturally occurring phosphatidylcholine (PC) lipids; the cationic group is anchored at the membrane interface, while the anionic group extends into the aqueous phase. AQ lipids preferentially interact with highly polarizable anions (ClO4−) over less polarizable ions (Cl−), in accord with the Hofmeister series, as measured by the change in zeta potential of AQ liposomes. Conversely, AQ lipids have a weaker association with calcium than do PC lipids. The transition temperatures (Tm) of the AQ lipids are similar to the Tm observed with phosphatidylethanolamine (PE) lipids of the same chain length. AQ lipids form large lipid sheets after heating and sonication; however, in the presence of cholesterol, (Chol) these lipids form stable liposomes that encapsulate carboxyfluorescein. The AQ:Chol liposomes retain their contents in the presence of serum at 37 °C, and when injected intravenously into mice, their organ biodistribution is similar to that observed with PC:Chol liposomes. AQ lipids demonstrate that modulating the headgroup charge orientation significantly alters the biophysical properties of liposomes. For the drug carrier field, these new materials provide a non-phosphate containing zwitterlipid for the production of lipid vesicles.

Comparison of Carboxybetaine with Sulfobetaine as Lipid Headgroup Involved in Intermolecular Interaction between Lipids in the Membrane

“…DPPC (>99% purity) was purchased from Yuka Sangyo (Tokyo, Japan) and used without further purification. DPCB and DPSB were synthesized according to previously published methods (refs (12) and (17) for DPCB and DPSB, respectively). The purity of these lipids was confirmed by thin layer chromatography (DPCB; R f = 0.64, CHCl 3 /MeOH = 9:1, visualized by iodine or bromocresol green, DPSB; R f = 0.60, CHCl 3 /MeOH = 8:2, visualized by iodine).…”

Liposomes with Water as a pH‐Responsive Functionality for Targeting of Acidic Tumor and Infection Sites

“…First, dioctadecyl (tertbutoxycarbonyl) glutamate (compound 2)was synthesized to provide compound 1 with hydrophobic tail groups. [16] To this end, 1-octadecanol was allowed to react with compound 1 and purified using column chromatography. [28] Next, the Boc-protection was removed from compound 2 using 50 %TFA in DCM to expose the terminal amino group (compound 3)t hat was subsequently coupled with the carboxyl group of isonicotinic acid to obtain compound 4.…”

Designer lipids for drug delivery: From heads to tails

“…Divalent cations, especially Ca 2+ , are of particular interest because they are ubiquitous in biological systems and can interact with lipid headgroups to cause membrane destabilization via aggregation, fusion, or alteration of surface charge [142]. CP, CPe, AQ and SB liposomes do not aggregate in the presence of physiological levels of Ca 2+ , and IZ liposomes interact with Ca 2+ less than PC liposomes [143–145]. Reduced divalent cation interactions make IZ liposomes interesting candidates to investigate as in vivo delivery systems.…”

“…AQ liposomes have similar pharmacokinetics and biodistribution to PC liposomes, but have dramatically different biophysical properties that may be exploited for thermo-responsive systems [145]. Further, CP and CS lipids may be useful in enzyme-triggered systems.…”