Tuning Targeted Liposome Avidity to Cells via Lipid Phase Separation

Abstract

The addition of both cell-targeting moieties and polyethylene glycol (PEG) to nanoparticle (NP) drug delivery systems is a standard approach to improve the biodistribution, specificity, and uptake of therapeutic cargo. The spatial presentation of these molecules affects avidity of the NP to target cells in part through an interplay between the local ligand concentration and the steric hindrance imposed by PEG molecules. Here, we show that lipid phase separation in nanoparticles can modulate liposome avidity by changing the proximity of PEG and targeting protein molecules on a nanoparticle surface. Using lipid-anchored nickel-nitrilotriacetic acid (Ni-NTA) as a model ligand, we demonstrate that the attachment of lipid anchored Ni-NTA and PEG molecules to distinct lipid domains in nanoparticles can enhance liposome binding to cancer cells by increasing ligand clustering and reducing steric hindrance. We then use this technique to enhance the binding of RGD-modified liposomes, which can bind to integrins overexpressed on many cancer cells. These results demonstrate the potential of lipid phase separation to modulate the spatial presentation of targeting and shielding molecules on lipid nanocarriers, offering a powerful tool to enhance the efficacy of NP drug delivery systems.

Effects of Phospholipid Structure on the Acoustic Cavitation of Functionalized Mesoporous Silica Nanoparticles: Implications for Image-Guided Drug Delivery

“…More generally, liposomes and lipid nanoparticles represent the dominant fraction of nanotechnologies approved in the clinic. Liposome composition can be modified for selective cell targeting and circulation time by changing headgroup charge, lateral lipid phase, and phase separation. − Cancer cells in particular rely on different pathways to acquire fatty acids necessary for growth, and certain lipid types are overrepresented in certain tumor types. Colorectal and breast cancer cells preferentially uptake polyunsaturated fatty acids, which is a potential avenue for increasing the efficiency of drug delivery to tumors.…”

Simply and Cheaply Prepared Liposomal Membrane for Nanocarriers: High Encapsulation Efficiency Based on Broad Regulation of Surface Charges and pH-Switchable Performance

“…In addition, the liposome nanoparticles are prone to phase transition under external stimuli (such as high temperature, pH, enzyme, and external force field), which leads to reassembly and drug leakage. Traditional coating materials PEG minimize the nonspecific interaction in vivo, thus prolonging the circulation time . However, it also markedly reduces their cellular uptake for immunogenicity and antigenicity, leading to a poor therapeutic effect.…”