Archaeosomal nanocarriers improve pharmacokinetics and bioavailability of vancomycin after oral administration

Abstract

Vancomycin, a glycopeptide antibiotic, is typically administered intravenously (IV) for severe Gram-positive bacterial infections. While the oral route offers higher patient adherence, it is limited by poor mucosal transport, restricting its use to intestinal infections. To address these challenges, this study explores the encapsulation of vancomycin into archaeosomes -phospholipid-based nanocarriers incorporating archaeal lipids, which exhibit exceptional stability in the gastrointestinal environment and interact specifically with enterocytes. Previous work demonstrated that lipid nanocarrier formulations benefit from the incorporation of the archaeal lipid calditolglycerocaldarchaeol (GCTE), facilitating mucosal barrier penetration and increasing bioavailability in vivo. In this study, we investigated the effects of archaeal lipid extract (ALE) and purified caldarchaeol (GDGT) on the pharmacokinetics and oral bioavailability of vancomycin in male Wistar rats. Our findings reveal that archaeosomal formulations significantly increase systemic exposure by prolonging circulation time and enhancing plasma drug concentrations, combined with high biocompatibility. Notably, the oral bioavailability (as measured by the area under the curve, AUC) increased 9-fold with GDGT liposomes and 4-fold with ALE liposomes compared to free vancomycin. These results highlight the potential of archaeal lipid-based drug delivery systems to enable oral administration of therapeutics that are traditionally injection-only.

Introduction

Successful drug delivery development is highly dependent on the physicochemical properties of the active pharmaceutical ingredient (API) and its ability to effectively overcome biological barriers (Laffleur and Keckeis, 2020). For oral administration, the harsh environment of the gastrointestinal (GI) tract, along with the presence of degrading enzymes and poor mucosal permeability, often impedes efficient drug absorption. Consequently, oral drug delivery is frequently associated with low bioavailability especially for APIs prone for degradation, such as peptides and proteins (Homayun et al., 2019). This often necessitates subcutaneous (SC) or intravenous (IV) administration of pharmaceuticals, despite their significant drawbacks in terms of patient adherence and high costs (Rangel et al., 2017; Spellberg and Lipsky, 2012). To address these challenges, delivery vehicles are employed to enhance API stability in bodily fluids and facilitate transportation into the bloodstream. Among them, lipid-based nanocarriers, such as liposomes, are particularly promising due to their structural similarity to biological membranes. This resemblance can facilitate interactions with cells and tissues, potentially improving drug delivery and bioavailability (Fricker et al., 2010; He et al., 2019).

Archaeosomes represent a class of liposomes that incorporate either naturally derived isoprenoid-based archaeal lipids, as they are found in the cell membrane of archaea, or synthetic analogs thereof. Due to technical challenges during chemical synthesis, these lipids are however primarily extracted from biomass of extremophilic archaeal organisms, such as Sulfolobus acidocaldarius (Rastädter et al., 2020). Archaeal lipids offer unique advantages over conventional lipids: they incorporate ether bonds rather than the ester bond found in fatty acid-based lipids, and exhibit sn-2,3 stereochemistry, making them resistant to acid-induced and enzymatic hydrolysis (Kaur et al., 2016). Additionally, they occur as bilayer spanning diether lipids and monolayer spanning tetraether lipids (TELs), most prominently the lipids calditolglycerocaldarchaeol (GCTE) and caldarchaeol (GDGT), providing significant rigidity enhancements to the lipid membrane (Romero and Morilla, 2023; Uhl et al., 2017). These features ensure the protection of labile drug molecules against bile salts and low pH in the GI tract (Jensen et al., 2015). This increased structural integrity also contributes to improved colloidal stability during long-term storage (Sedlmayr et al., 2023; Uhl et al., 2017). Furthermore, a high association of archaeal lipid-based vesicles with enterocytes has been reported, promoting oral drug absorption (Morilla et al., 2011; Sedlmayr et al., 2023; Werner et al., 2024b).

Accordingly, archaeal lipids have been studied as excipients for oral drug delivery vehicles, demonstrating increased in vivo oral bioavailability of unstable and poorly absorbed substances, such as peptides, proteins, and small molecules (Li et al., 2010; Morilla et al., 2011; Parmentier et al., 2011; Uhl et al., 2016). However, so far, little is known about their effects on the drug pharmacokinetics after oral administration.

Vancomycin, a glycopeptide antibiotic, serves as a last-line treatment for serious infections caused by staphylococci, enterococci and other Gram-positive bacteria (Dinu et al., 2020). Due to its low mucosal penetration as a BCS class III drug, vancomycin is typically administered IV if not used for the local treatment of intestinal infections caused by Clostridioides difficile and Staphyllococcus aureus (Rubinstein and Keynan, 2014). An oral formulation of vancomycin for systemic therapy could offer benefits in terms of patient convenience and improved compliance in line with antimicrobial stewardship guidelines (Ansari et al., 2024). In addition to its clinical importance, vancomycin represents an excellent model API for studying mucosal transport. It meets key requirements for an effective oral drug delivery system, including high aqueous solubility, resistance to proteolytic degradation, minimal first-pass metabolism, and low conversion by cytochrome P450 (Cao et al., 2018). Besides, it is not a substrate for intestinal influx or efflux transporters, and thus, vancomycin’s low oral bioavailability can be attributed primarily to its poor mucosal permeation, making it an ideal candidate for investigating how vesicles and excipients impact on mucosal permeability (Sauter et al., 2020).

Previously, we have demonstrated the beneficial effects of archaeal lipids on the oral delivery of vancomycin. The incorporation of 5 mol% GCTE to lecithin-cholesterol-based liposomes nearly doubled the vancomycin plasma concentration in rodents one hour after oral administration compared to liposomes without GCTE. Moreover, blood levels were tripled compared to the unencapsulated substance (Uhl et al., 2017). The oral efficacy of the formulation can be further enhanced by using 1 mol% of a phospholipid conjugated with a cyclic and enzymatically stable cell penetrating peptide (Uhl et al., 2021).

Based on these promising preliminary results, in the current study, we investigated the performance of archaeal lipid-based formulations on the pharmacokinetics and oral bioavailability of vancomycin. Therefore, we examined the effect of an archaeal lipid extract (ALE) of S. acidocaldarius, a mixture of five archaeal lipids (Quehenberger et al., 2020), and an additional formulation containing purified GDGT on the oral delivery of vancomycin in male Wistar rats. Relevant pharmacokinetics of the liposomal formulations were determined and compared to the free drug. Our results demonstrate the substantial impact of archaeal lipids on the pharmacokinetics of vancomycin, such as prolonged circulation time and increased oral bioavailability, and indicate promising use with other difficult to administer therapeutics.

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Viktor Sedlmayr, Julian Quehenberger, David Wurm, Mikko Gynther, Rebecca Vieth, Valerie Dürr, Pascal Gesse, Oliver Spadiut, Gert Fricker, Philipp Uhl, Archaeosomal nanocarriers improve pharmacokinetics and bioavailability of vancomycin after oral administration, European Journal of Pharmaceutical Sciences,
Volume 212, 2025, 107159, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107159.

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