Designer lipids for drug delivery: from heads to tails

Abstract

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.

Keywords: Biophysics; Immunology; Liposomes; Payload release; Targeting.

Figure 1. Modulating liposome behavior

Liposome behavior can be controlled across a number of length scales: (A) engineering of individual lipids (B) modification of bilayer biophysics and (C) inclusion of lipids that direct macroscopic liposome behavior and interactions.

Figure 2. Overview of lipid engineering

Potential modifications to a single lipid are highlighted along with their potential functional consequences.

Figure 3. Three key steps in liposome drug delivery

After intravenous administration, liposomes circulate in the bloodstream and accumulate at the disease site. Directing liposome headgroup interactions allows for targeting to the appropriate cellular or tissue compartment. Finally, membrane thickness, fluidity and interfacial charge orientation control payload release.

Figure 4

Polymer headgroup lipids for extended circulation of liposomes.

Figure 5. Pathways to B cell activation

(A) Short polymers or monomeric haptens fail to activate B cells. (B) Long polymers, such as PEG, or (C) multivalent haptens on liposomes can activate B cells by cross-linking B cell receptors. (D) Inclusion of TLR4 agonists alongside haptens can also activate B cells.

Figure 6. Nucleolipid headgroup structures

Predicted forces governing interactions with nucleic acids are shown.

Figure 7

Structure of Tris-NTA lipid.

Figure 8

Structure of sterol modified lipids (SMLs).

Figure 9. Structures of lipids with inverted headgroup architecture

Structures of inverse zwitterlipids (IZ) lipids.

Figure 10. Biophysical properties of IZ lipids

(A) IZ lipids (AQ, SB) preferentially interact with ions according to the Hofmeister series. (B) IZ lipids have elevated T_m compared to PC lipids.

Figure 11. Prodrug structures

Selected structures of prodrugs that have advanced into the clinic.