Cholesterol-tuned liposomal membrane rigidity directs tumor penetration and anti-tumor effect

Abstract

Recently, liposomes have been widely used in cancer therapeutics, but their anti-tumor effects are suboptimal due to limited tumor penetration. To solve this problem, researchers have made significant efforts to optimize liposomal diameters and potentials, but little attention has been paid to liposomal membrane rigidity. Herein, we sought to demonstrate the effects of cholesterol-tuned liposomal membrane rigidity on tumor penetration and anti-tumor effects. In this study, liposomes composed of hydrogenated soybean phospholipids (HSPC), 1,2-distearoyl- sn -glycero-3-phosphoethanolamine- N -[methoxy(polyethylene glycol)-2000] (DSPE-PEG 2000 ) and different concentrations of cholesterol were prepared. It was revealed that liposomal membrane rigidity decreased with the addition of cholesterol. Moderate cholesterol content conferred excellent diffusivity to liposomes in simulated diffusion medium, while excessive cholesterol limited the diffusion process. We concluded that the differences of the diffusion rates likely stemmed from the alterations in liposomal membrane rigidity, with moderate rigidity leading to improved diffusion. Next, the in vitro tumor penetration and the in vivo anti-tumor effects were analyzed. The results showed that liposomes with moderate rigidity gained excellent tumor penetration and enhanced anti-tumor effects. These findings illustrate a feasible and effective way to improve tumor penetration and therapeutic efficacy of liposomes by changing the cholesterol content, and highlight the importance of liposomal membrane rigidity.

Dual-targeting nanovesicles enhance specificity to dynamic tumor cells in vitro and in vivo via manipulation of αvβ3-ligand binding

“…Lipid vesicles were composed of HSPC/CH/DSPE-PEG (3:1:1, w / w / w ). Cholesterol was used to reduce the rigidity of the lipid membrane and enhance the penetration of lipid vesicles 25 . All DOX-loaded lipid vesicles (lipids:DOX = 10:1, w / w ) were prepared using the lipid film hydration method.…”

Engineering Exosome-Like Nanovesicles Derived from Asparagus cochinchinensis Can Inhibit the Proliferation of Hepatocellular Carcinoma Cells with Better Safety Profile

“…Based on the literatures, we hypothesized that this may be related to differences in the composition and properties of cell membranes. [30][31][32] In addition, the specific integrin proteins of ACNVs may also determine cell tropism. 11,33,34 To further investigate the endocytosis mechanism of ACNVs, HepG2 cells were incubated with endocytosis inhibitors (chlorpromazine hydrochloride, amiloride, nystatin, and cytochalasin D).…”

The Efficacy of Cholesterol-Based Carriers in Drug Delivery

“…The authors reported a decrease in the membrane rigidity of the liposomes as the cholesterol content increased. The aforementioned findings suggest that when the liposomal membranes are less rigid, there is an increase in surface contact with the cells resulting in a prolonged cellular uptake [ 62 ].…”

“…Lip3 and Lip2 displayed moderate rigidity inhibiting tumor spheroid growth and exhibited high tumor penetration with excellent tumor growth inhibition in vivo. The results showed that moderate liposomal rigidity resulted in better diffusivity making cholesterol-tuned liposomes a promising system for delivery drugs to tumor cells [ 62 ].…”