Dennis To

Biodegradable poly(ε-caprolactone) (PCL) was rotaxanated with α-cyclodextrin (α-CD) and an α-CD/2-hydroxypropyl-α-CD (HP-α-CD) mixture. Stoppering was achieved using 2-mercaptosuccinic acid (MSA) via disulfide linkage. The structures of these polymeric supramolecular entities were confirmed by ¹H NMR, with 75–80 wt% threaded CD, while the molar mass of the polyrotaxanes was around 18 kDa, determined by gel permeation chromatography. The aqueous solubility was as low as 20.2 ± 1.2 g L⁻¹ for the α-CD-based polyrotaxane but considerably increased to 74.7 ± 6.0 g L⁻¹ by the introduction of threaded HP-α-CD into the polymeric axis. Dethreading of the polyrotaxanes was triggered by the removal of the stopper molecules via disulfide-exchange reactions using glutathione. Additionally, the polyester axis proved to be fully degradable by lipase. Cellular uptake of these polyrotaxanes was investigated by flow cytometry and confocal microscopy. The results showed an almost up to 50-fold higher cellular uptake of polyrotaxanes than free CD. These disulfide end-stoppered polyrotaxanes of biodegradable PCL represent a promising tool for intracellular delivery of CDs and offer novel treatment possibilities for lysosomal storage dysfunctions.

It was the aim of this study to evaluate the potential of reverse micelles (RM) and hydrophobic ion pairs (HIP) for incorporation of semaglutide into self-emulsifying oral drug delivery systems. Reverse micelles loaded with semaglutide were formed with a cationic (ethyl lauroyl arginate, ELA) and an anionic surfactant (docusate, DOC), whereas HIP were formed between semaglutide and ELA. Maximum solubility of the peptide and the rate of dissolution was evaluated in various lipophilic phases (glycerol monocaprylocaprate:caprylic acid 1:4 (m/m), glycerol monolinoleate:caprylic acid 1:4 (m/m) and glycerol monocaprylocaprate:glycerol monolinoleate 1:4 (m/m)). Self-emulsifying drug delivery systems (SEDDS) loaded with RM and HIP were characterized regarding size distribution, zeta potential, cytocompatibility and Caco-2 permeability. Droplet sizes between 50 and 300 nm with polydispersity index (PDI) around 0.3 and zeta potentials between − 45 mV (RM_DOC) and 36 mV (RM_ELA) were obtained. RM provided an almost 2-fold higher lipophilicity of semaglutide than HIP resulting in a 4.2-fold higher payload of SEDDS compared to HIP. SEDDS containing RM or HIP showed high cytocompatibilities with a cell survival above 75% for concentrations up to 0.1% on Caco-2 cells and acceptable hemolytic activity. Permeation studies across Caco-2 monolayer revealed an at least 2-fold increase in permeability of semaglutide for the developed formulations.

Stimuli-responsive nanomaterials show promise in eradicating Staphylococcus aureus biofilm from implants. Peptidoglycan hydrolases (PGHs) are cationic antimicrobials that can be bioengineered to improve the targeting of persisters and drug-resistant bacteria. However, these molecules can be degraded before reaching the target and/or present limited efficacy against biofilm. Therefore, there is an urgent need to improve their potency. Herein, PGH–polyphosphate nanoparticles (PGH–PP NPs) are formed by ionotropic gelation between cationic PGHs and anionic polyphosphate, with the aim of protecting PHGs and delivering them at the target site triggered by alkaline phosphatase (AP) from S. aureus biofilm. Optimized conditions for obtaining M23–PP NPs and GH15–PP NPs are presented. Size, zeta potential, and transmission electron microscopy imaging confirm the nanoscale size. The system demonstrates outstanding performance, as evidenced by a dramatic reduction in PGHs’ minimum inhibitory concentration and minimum bactericidal concentration, together with protection against proteolytic effects, storage stability, and cytotoxicity towards the Caco-2 and HeLa cell lines. Time-kill experiments show the great potential of these negatively charged delivery systems in overcoming the staphylococcal biofilm barrier. Efficacy under conditions inhibiting AP proves the enzyme-triggered delivery of PGHs. The enzyme-responsive PGH–PP NPs significantly enhance the effectiveness of PGHs against bacteria residing in biofilm, offering a promising strategy for eradicating S. aureus biofilm.