Membrane interactions in drug delivery: Model cell membranes and orthogonal techniques

Highlights

• Membrane interactions are essential in drug delivery and need to be well understood.

• Bilayer model membranes include vesicles, surface-confined bilayers and nanodiscs.

• A multitude of different techniques can be used for studying membrane interactions.

• Combining techniques can provide more reliable and in-depth information.

• Well-designed membrane interaction studies should translate better in vivo.

Abstract

To generate the desired effect in the human body, the active pharmaceutical ingredient usually needs to interact with a receptor located on the cell membrane or inside the cell. Thus, understanding membrane interactions is of great importance when it comes to the development and testing of new drug molecules or new drug delivery systems. Nowadays, there is a tremendous selection of both model cell membranes and of techniques that can be used to characterize interactions between selected model cell membranes and a drug molecule, an excipient, or a drug delivery system. Having such a wide selection of model cell membranes and techniques available makes it sometimes challenging to select the optimal combination for a specific study. Furthermore, it is difficult to compare results obtained using different model cell membranes and techniques, and not all in vitro studies translate as well to an estimation of the in vivo biological activity or understanding of mode of action. This review provides an overview of the available lipid bilayer-based model cell membranes and of the most widely employed techniques for studying membrane interactions. Finally, the need for employing complimentary characterization techniques in order to acquire more reliable and in-depth information is highlighted.

Introduction

The term “drug delivery” encompasses the method and route by which a therapeutic agent – a drug molecule – is administered. For most drugs, regardless of the dosage form (e.g. capsules, tablets, solutions, or gels) and of the administration route (e.g. pulmonary, oral, or cutaneous), a critical step in generating a biological effect is represented by the interaction of the drug with a receptor located either on the cell membrane or inside the cell. [1] For the active pharmaceutical ingredient (API) to reach its target in sufficiently high amounts, drug delivery systems (DDS) are employed. Thus, the study of cell membrane interactions provides information of vital importance for the development of new drugs and DDS.

Certain aspects related to drug – membrane interactions can be investigated directly by using live cells [2] and functional read-out methods. However, due to experimental limitations and the inherent challenges posed by working with live cells, often cell membrane extracts [3] or, more commonly, model cell membranes [4,5] are instead used in such studies. Recently, intracellular photoactivated hydrogelation was reported as a method for rapid cytosolic immobilization, which allows preservation of fluid and functional plasma membrane interfaces for the study of interactions with cells. [6] This approach seems particularly promising for future studies, as it enabled preservation of the cell surface functions while conferring robustness to the cells.

Applying orthogonal methods to model cell membranes can provide detailed high value mechanistic insight into e.g. specific crucial properties of the API or DDS and elucidate modes of membrane interactions and transport, and can thus provide important supplements to efficacy studies in cells or live animals when designing and developing novel drugs and novel dosage forms.

The aim of this review is to provide an overview of the model cell membranes and techniques most often employed in investigating membrane interactions for drug delivery, with focus on how combining orthogonal techniques can help provide more information. Section 3 briefly describes cell membranes in terms of their structure, properties and role in drug delivery. Section 4 introduces model cell membranes and discusses different types of lipid bilayer-based model cell membranes. Section 5 provides a comprehensive list of the most widespread techniques applied to model cell membrane characterization, while Section 6 focuses on the choice of techniques and complementarity. The review ends with a summary and outlook section which emphasizes that more complex studies that intelligently combine different characterization techniques have a better chance at providing more complete information, which may in turn translate to a better estimation of the drug's in vivo activity based on studies performed using model cell membranes.