Assessing the Interactions of Auristatin Derivatives with Mixed Phospholipid-Sodium Dodecyl Sulfate Aggregate Dispersions.

Suvi-Katriina Ruokonen,Filip S Ekholm,Susanne K Wiedmer

doi:10.1021/acs.langmuir.9b00116

Suvi-Katriina Ruokonen, Filip S Ekholm + Show 1 more

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https://doi.org/10.1021/acs.langmuir.9b00116

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Abstract

The aim of this study was to assess what properties of the pseudostationary phases in electrokinetic capillary chromatography affect the interactions between monomethyl auristatin E (MMAE) and hydrophilically modified structural analogues thereof with various lipophilic phases. MMAE is a widely used cytotoxic agent in antibody–drug conjugates (ADC), which are used as selective biopharmaceutical drugs in the treatment of cancers. MMAE and its derivatives are highly lipophilic, yet they fail to interact with biomimicking phosphatidylcholine–phosphatidylserine liposomes. To reveal what properties affect the interaction of the auristatin derivatives with cell plasma membrane-mimicking vesicles, capillary electrokinetic chromatography was used with four different types of micellar and vesicular pseudostationary phases: pure vesicles, mixed vesicles, mixed micelles, and pure micelles. Vesicular phases were composed of pure phospholipids [dimyristoylphosphatidylcholine (DMPC) and dilauroylphosphatidylcholine (DLPC)] and phospholipid–surfactant mixtures [sodium dodecyl sulfate, (SDS) with DMPC and DLPC] while the micellar phases comprised pure surfactant (SDS) and surfactant–phospholipid mixtures (SDS–DMPC and SDS–DLPC). In addition, differential scanning calorimetry and dynamic light scattering were used to monitor the aggregate composition. Our data shows that the interaction between hydrophobic auristatin derivatives and hydrophobic pseudostationary phases critically depends on the type, size, and hydrogen bonding capability of the pseudostationary phases.

Highlights

Antibody−drug conjugates (ADCs) consist of cytotoxic agents linked to monoclonal antibodies and are considered to be promising precision medicines against diseases such as cancer
The interactions of auristatin derivatives with various pseudostationary phases in electrokinetic capillary chromatography were assessed to scrutinize which properties of the compounds and the pseudostationary phases affect the interactions
Hydrophobic monomethyl auristatin E (MMAE) as well as substrates 2 and 3 had high distribution constants (5000−40 000) when mixed phospholipid−surfactant micelles were used as pseudostationary phases (PSP); they did not interact with negatively charged POPC− POPS (80:20 mol %) liposomes

Summary

Introduction

Antibody−drug conjugates (ADCs) consist of cytotoxic agents linked to monoclonal antibodies and are considered to be promising precision medicines against diseases such as cancer. Obtaining information on the biophysical profiles (or hydrophilic character) of the cytotoxic agents is essential to the development of improved ADCs. In recent studies, we investigated the correlation of cytotoxic activity and hydrophobicity in a set of monomethyl auristatin E (MMAE) derivatives and ADCs thereof.[5−7] Our studies provided further evidence of the unique properties and advantages of hydrophilically modified MMAE derivatives both in their free form and as final ADCs. In recent studies, we investigated the correlation of cytotoxic activity and hydrophobicity in a set of monomethyl auristatin E (MMAE) derivatives and ADCs thereof.[5−7] Our studies provided further evidence of the unique properties and advantages of hydrophilically modified MMAE derivatives both in their free form and as final ADCs During these studies, it was noticed that there was a need for an improved method for assessing the relative hydrophobicity of the auristatins

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