Liposomal Formulation of a PLA2-Sensitive Phospholipid-Allocolchicinoid Conjugate: Stability and Activity Studies In Vitro.

Maria K Kobanenko,Natalia R Onishchenko,Ekaterina S Shchegravina,Daria S Tretiakova,Ivan A Boldyrev,Alexey Yu Fedorov,Elena L Vodovozova,Nadezhda V Antipova

doi:10.3390/ijms23031034

Abstract

To assess the stability and efficiency of liposomes carrying a phospholipase A2-sensitive phospholipid-allocolchicinoid conjugate (aC-PC) in the bilayer, egg phosphatidylcholine and 1-palmitoyl-2-oleoylphosphatidylglycerol-based formulations were tested in plasma protein binding, tubulin polymerization inhibition, and cytotoxicity assays. Liposomes L-aC-PC10 containing 10 mol. % aC-PC in the bilayer bound less plasma proteins and were more stable in 50% plasma within 4 h incubation, according to calcein release and FRET-based assays. Liposomes with 25 mol. % of the prodrug (L-aC-PC25) were characterized by higher storage stability judged by their hydrodynamic radius evolution yet enhanced deposition of blood plasma opsonins on their surface according to SDS-PAGE and immunoblotting. Notably, inhibition of tubulin polymerization was found to require that the prodrug should be hydrolyzed to the parent allocolchicinoid. The L-aC-PC10 and L-aC-PC25 formulations demonstrated similar tubulin polymerization inhibition and cytotoxic activities. The L-aC-PC10 formulation should be beneficial for applications requiring liposome accumulation at tumor or inflammation sites.

Highlights

Colchicine is an antimitotic alkaloid isolated from the Colchicum autumnale plant
To assess the stability and efficiency of liposomes carrying a phospholipase A2-sensitive phospholipid-allocolchicinoid conjugate in the bilayer, egg phosphatidylcholine and 1-palmitoyl-2-oleoylphosphatidylglycerol-based formulations were tested in plasma protein binding, tubulin polymerization inhibition, and cytotoxicity assays
In search for a stable liposomal formulation for aC-PC with high prodrug loading, egg phosphatidylcholine (ePC)-based compositions supplemented with cholesterol and/or POPG were screened

Summary

Introduction

Colchicine is an antimitotic alkaloid isolated from the Colchicum autumnale plant. It binds the β subunit of tubulin, preventing the contacts between the α/β-tubulin heterodimers and microtubule elongation, which in turn results in the G2/M cell cycle arrest and apoptosis [1,2]. Low-dose colchicine has been approved to treat familial Mediterranean fever and acute gout flares. It is widely studied as an anti-inflammatory agent in various cardiovascular diseases [4,5,6]. Colchicine is considered as a promising anti-inflammatory drug to treat COVID-19 [7,8,9]: 36 relevant trials are registered at https://clinicaltrials.gov/as of 11 December 2021. Application of colchicine in cancer therapy is limited by its high general toxicity [10]

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