Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device used to provide prolonged cardiac and respiratory support in critically ill patients with life- threatening heart and lung failure. Patients on ECMO receive multiple drugs to treat critical illnesses, underlying diseases, support cardiovascular functions, prevent infections, and maintain sedation [1]. The optimal dosing for the majority of these drugs are unclear [2], [3], [4], [5]. Pharmacokinetics (PK) of drugs in patients on ECMO can be altered by physiological changes triggered by the circuit (e.g., inflammation) and underlying critical illness, as well as drug adsorption to the ECMO circuit. Drug adsorption to ECMO circuit components, primarily due to hydrophobicity and/or electrostatic interactions, results in lower drug exposures and can lead to therapeutic failure [6], [7], [8], [9], [10]. Hydrophobic interactions occur between drugs and the polymeric surfaces of the inner ECMO circuit. They adsorb to the poly(vinyl chloride) surface of ECMO tubing and the poly(methyl pentene) surface of the oxygenator [11], [12], [13]. Electrostatic interactions occur between drugs and the surface coatings commonly applied to ECMO circuit components to minimize the inflammatory response. When the drug and surface are oppositely charged, the degree of ionization can influence adsorption [14], [15], [16]. Extensive research has shown that ECMO circuit components such as the oxygenator and tubing are known to adsorb drugs such as midazolam, lorazepam, morphine, fentanyl, propofol, vancomycin and gentamicin [7], [13], [17], [18], [19].

Propofol (Diprivan®) is a commonly used anesthetic with a substantial protein binding of 95–99 % and lipophilic properties (logP = 4.1) [20]. It is highly adsorbed to the ECMO circuit components resulting in sub-optimal dosing and treatment failures. Propofol’s baseline concentration decreases to 70 % after the first 30 min with only 11 % remaining after five hours [21], [22], [23]. The prevention of adsorption through drug encapsulation would allow for the drug to become more available and properly sedate the patient. This can be achieved by encapsulating propofol in delivery systems with a hydrophilic shell, hence preventing its adsorption to ECMO circuit components (Fig. 1).

There are multiple encapsulation strategies such as using micellar structures, or liposomes tethered with poly(ethylene glycol) (PEG) that can create hydrophilic shells around hydrophobic drugs. Micelles are nanosized self-assembled colloids that are typically formed by amphiphilic block copolymers consisting of a hydrophilic exterior shell and a hydrophobic interior [24]. Having a hydrophobic interior allows for drugs with poor solubility to be encapsulated in micelles. On the other hand, liposomes are self-assembled bilayer structures consisting of a hydrophilic core and hydrophobic bilayer [25]. Liposomes can encapsulate drugs with poor water solubility in their lipid bilayers and be tethered with PEG. Encapsulating propofol in structures with hydrophilic shells can avoid its interactions with the ECMO circuit components.

We have previously demonstrated in ex vivo ECMO circuits that encapsulation of propofol in micellar systems significantly reduces propofol adsorption [26]. In this study we have encapsulated propofol in additional micellar structures and in liposomes tethered with PEG (Fig. 2). We selected P188 micellar system with a higher poly(ethylene oxide) content (80 %) compared to P407 (70 %) studied previously. This encapsulation approach provides a larger hydrophilic shell around propofol. We compared P188 with P407 loaded micelles that have a higher lipophilicity than P188, hence providing a more stable structure upon encapsulation of propofol. The rationale for selecting PEGylated liposomes is that they can be made in a range of different sizes and are typically more stable in the blood stream when compared to micelles. We characterized the aforementioned propofol loaded delivery systems for their average size, poly dispersity index (PDI), encapsulation efficiency, and stability. The delivery systems were tested for their in vitro cytocompatibility and complement activation. The adsorption profile of the encapsulated propofol formulations was tested in an in-house in vitro ECMO adsorption assay made for high throughput screening.