title: Synthesis and characterization of PEGylated bolaamphiphiles with enhanced retention in liposomes.
abstract: Long-circulating liposomes are typically prepared with poly(ethylene glycol)- (PEG-) modified lipids, where the lipid portion is inserted in the lipid bilayers as an anchor and the hydrophilic PEG coats the surface to prevent liposome aggregation and rapid clearance in vivo. However, these steric protection effects are compromised upon systemic administration due to low retention of PEGylated lipids within liposome membranes upon dilution. Hence, a series of PEGylated bolaamphiphiles (PEG-bolas) were for the first time developed to increase retention in the lipid bilayer, presumably leading to enhanced integrity of the PEG protective layer upon dilution. We hypothesized that PEG-bolas with a sufficiently long hydrophobic domain and rigid central group could predominantly adopt a membrane-spanning configuration, taking full advantage of steric protection offered by PEG and enhanced retention in liposomes enabled by the bola geometry. In this paper, liposomes stabilized by PEG-bolas comprised of a biphenyl core and twelve-carbon alkyl chain not only exhibited similar storage and biological stability compared to conventional PEGylated lipid stabilized liposomes, but also significantly improved retention upon dilution. Our findings facilitate new designs of liposome-stabilizing agents and can be applied to improve the delivery efficiency of liposomal delivery vehicles in vivo.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Yingyue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry, Stern College for Women, Yeshiva University, New York, NY 10016, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Mintzer
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. Electronic address: keuhrich@rutgers.edu.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Uhrich
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000388:Air / Q000032:analysis; D002784:Cholesterol / Q000737:chemistry; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry* / Q000494:pharmacology; D008081:Liposomes / Q000737:chemistry* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D010316:Particle Size; D010587:Phagocytosis / Q000187:drug effects; D011092:Polyethylene Glycols / Q000737:chemistry*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry; D013499:Surface Properties; D014867:Water / Q000737:chemistry
chemical_list: D005663:Furans; D008051:Lipid Bilayers; D008081:Liposomes; D011728:Pyridones; C543575:bolaamphiphile; D014867:Water; D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols; D002784:Cholesterol
keywords: Bolaamphiphile; Drug delivery; Liposomes; Long-circulation; PEGylated lipids; Steric stabilization