Designer lipids for drug delivery: From heads to tails

Aditya G. Kohli, Paul H. Kierstead, Vincent J. Venditto, Colin L. Walsh, Francis C. Szoka

Research output: Contribution to journalReview articlepeer-review

130 Scopus citations


For four decades, liposomes composed of both naturally occurring and synthetic lipids have been investigated as delivery vehicles for low molecular weight and macromolecular drugs. These studies paved the way for the clinical and commercial success of a number of liposomal drugs, each of which required a tailored formulation; one liposome size does not fit all drugs! Instead, the physicochemical properties of the liposome must be matched to the pharmacology of the drug. An extensive biophysical literature demonstrates that varying lipid composition can influence the size, membrane stability, in vivo interactions, and drug release properties of a liposome. In this review we focus on recently described synthetic lipid headgroups, linkers and hydrophobic domains that can provide control over the intermolecular forces, phase preference, and macroscopic behavior of liposomes. These synthetic lipids further our understanding of lipid biophysics, promote targeted drug delivery and improve liposome stability. We further highlight the immune reactivity of novel synthetic headgroups as a key design consideration. For instance it was originally thought that synthetic PEGylated lipids were immunologically inert; however, it's been observed that under certain conditions PEGylated lipids induce humoral immunity. Such immune activation may be a limitation to the use of other engineered lipid headgroups for drug delivery. In addition to the potential immunogenicity of engineered lipids, future investigations on liposome drugs in vivo should pay particular attention to the location and dynamics of payload release.

Original languageEnglish
Pages (from-to)274-287
Number of pages14
JournalJournal of Controlled Release
StatePublished - Sep 28 2014

Bibliographical note

Funding Information:
This work was supported by NIH grants R01 GM061851 , R01 EB003008 , and R21AI093135 and by grant R613-CR11 from the Cystic Fibrosis Foundation (A. Verkman Principal Investigator). VJV was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number F32AI095062 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


  • Biophysics
  • Immunology
  • Liposomes
  • Payload release
  • Targeting

ASJC Scopus subject areas

  • Pharmaceutical Science


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