Liposome-Mediated Chemotherapeutic Delivery Is Synergistically Enhanced by Ternary Lipid Compositions and Cationic Lipids

Abstract

Most small molecule chemotherapeutics must cross one or more cellular membrane barriers to reach their biochemical targets. Owing to the relatively low solubility of chemotherapeutics in the lipid membrane environment, high doses are often required to achieve a therapeutic effect. The resulting systemic toxicity has motivated efforts to improve the efficiency of chemotherapeutic delivery to the cellular interior. Toward this end, liposomes containing lipids with cationic head groups have been shown to permeabilize cellular membranes, resulting in the more efficient release of encapsulated drugs into the cytoplasm. However, the high concentrations of cationic lipids required to achieve efficient delivery remain a key limitation, frequently resulting in toxicity. Toward overcoming this limitation, here, we investigate the ability of ternary lipid mixtures to enhance liposomal delivery. Specifically, we investigate the delivery of the chemotherapeutic, doxorubicin, using ternary liposomes that are homogeneous at physiological temperature but have the potential to undergo membrane phase separation upon contact with the cell surface. This approach, which relies upon the ability of membrane phase boundaries to promote drug release, provides a novel method for reducing the overall concentration of cationic lipids required for efficient delivery. Our results show that this approach improves the performance of doxorubicin by up to 5-fold in comparison to the delivery of the same drug by conventional liposomes. These data demonstrate that ternary lipid compositions and cationic lipids can be combined synergistically to substantially improve the efficiency of chemotherapeutic delivery in vitro.

Lipid Phase Separation in Vesicles Enhances TRAIL-Mediated Cytotoxicity

“…Phase separation can be readily replicated in synthetic, self-assembled lipid systems . Phospholipid bilayers, in both planar and nanoparticle form, can undergo phase separation when the appropriate mixtures of membrane components are used. , Beyond a limited number of examples, , this rich physical phenomenon has rarely been exploited to better design therapeutic nanoparticles.…”

Self-Assembly of Amphiphilic Compounds as a Versatile Tool for Construction of Nanoscale Drug Carriers

“…The cationic surface charge is very beneficial when dealing with endosomal trafficking due to the negative charge of endosome membrane [ 147 , 209 ]. Trementozzi et al have characterized a ternary lipid composition that is able to release the contents in a triggerable manner, and addition of only 3 mol % of 1,2-dioleoyl-3-trimethylammonium propane to promote liposome-endosome affinity and fusion has shown a 5-fold increase of formulation cytotoxicity [ 210 ]. Another use of CLs, that has been gaining popularity, is co-delivery of anticancer agents and nucleic acids, since CLs are the only type of liposomes that are able to encapsulate both drugs and negatively charged nucleotides well.…”

Enhancing functionalized liposome avidity to cells via lipid phase separation

“…The copyright holder for this preprint this version posted October 21, 2022. ; https://doi.org/10.1101/2022.10.18.512758 doi: bioRxiv preprint separation to control ligand presentation on NPs has previously been used to enhance delivery of therapeutic cargo to cells 26,27 and increase apoptotic signaling in target cells. 28 Because many ligand-receptor binding systems are dependent on the surface concentration of the receptor, as well as the inter-ligand spacing on the targeting materials, 29,30 we wondered if lipid phase separation can be more broadly used to tune lipid nanoparticle avidity to cells for other types of binding interactions.…”