Monomethyl Auristatin E Grafted-Liposomes to Target Prostate Tumor Cell Lines.

Ariana Abawi,Chloé Devillard,Benoit Joseph,Thierry Granjon,Julien Bompard,Giovanna Lollo,Anna Bérot,Leslie Gudimard,Ofelia Maniti,Valentina Andretto,Emma Petiot,Agnès Girard-Egrot,Xiaoyi Wang

doi:10.3390/ijms22084103

Abstract

Novel nanomedicines have been engineered to deliver molecules with therapeutic potentials, overcoming drawbacks such as poor solubility, toxicity or short half-life. Lipid-based carriers such as liposomes represent one of the most advanced classes of drug delivery systems. A Monomethyl Auristatin E (MMAE) warhead was grafted on a lipid derivative and integrated in fusogenic liposomes, following the model of antibody drug conjugates. By modulating the liposome composition, we designed a set of particles characterized by different membrane fluidities as a key parameter to obtain selective uptake from fibroblast or prostate tumor cells. Only the fluid liposomes made of palmitoyl-oleoyl-phosphatidylcholine and dioleoyl-phosphatidylethanolamine, integrating the MMAE-lipid derivative, showed an effect on prostate tumor PC-3 and LNCaP cell viability. On the other hand, they exhibited negligible effects on the fibroblast NIH-3T3 cells, which only interacted with rigid liposomes. Therefore, fluid liposomes grafted with MMAE represent an interesting example of drug carriers, as they can be easily engineered to promote liposome fusion with the target membrane and ensure drug selectivity.

Highlights

To increase targeting ability towards specific cells and tissues, active agents need an appropriate delivery system [1,2]
We focus on the targeted delivery of Monomethyl Auristatin E (MMAE), a synthetic derivative of dolastatin 10, a linear pentapeptide originally isolated from the extracts of the sea hare Dolabella auriculari, first described in the 1990s [36,37]
To summarize, following the model of antibody–drug conjugates (ADCs), an MMAE warhead was grafted onto fusogenic liposomes made up of phosphatidylcholines of different chain lengths and fusogenic lipid DOPE

Summary

Introduction

To increase targeting ability towards specific cells and tissues, active agents need an appropriate delivery system [1,2]. The clinical interest of liposomes relies on their composition: they are nanosized vesicles made of lipid bilayers surrounding a hydrophilic aqueous core. Their structure resembles the ones of the cell’s membranes, which makes them nontoxic, biocompatible and biodegradable, and prone to interact with cells. Like most sub-micrometer-sized drug carriers, liposomes attain the tumor site through a passive targeting mechanism [13,14,15,16,17], but active targeting strategies using modifications in membrane protein composition have been described. Liposomes grafted with ligands specific to overexpressed membrane receptors [18,19,20,21] or with lectins to target a change in the carbohydrate composition of the membrane [22] have already been reported in the literature as examples of active targeting

Methods

Results

Conclusion