Coupling Surface Interactions with Colloidal Transport to Understand Antibiotic Delivery with Self-Assembled Lipid Nanocarriers

Low discovery rates for new antibiotics, commercial disincentives to invest and inappropriate use of existing drugs has created a perfect storm of antimicrobial resistance (AMR). This ‘silent pandemic’ of AMR looms as an immense, global threat to human health. In tandem, many potential novel drug candidates are not progressed due to elevated hydrophobicity which may result in poor intracellular internalization and undesirable serum protein binding. With a reducing arsenal of effective antibiotics, enabling technology platforms which improve the outcome of treatments, such as repurposing existing bioactive agents is a prospective option. Self-assembled lipid nanoparticles, such as cubosomes, have emerged as promising nanocarriers (NCs) capable of amplifying the therapeutic outcome.<br/><br/>Here, the performance of several antibiotic classes encapsulated within the lipid-based cubosomes are examined. The findings demonstrate that encapsulation affords significant improvements in drug concentration:inhibition outcomes and assists in other therapeutic challenges associated with internalization, enzyme degradation and protein binding. Here we demonstrate the utilisation of surface sensitive techniques[1], particularly total internal reflection fluorescence microscopy to reveal dynamics in interactions and uptake of cubosomes. The rationale in optimized drug selection and nanocarrier choice is contextualized by surface interactions and multiscale transport modelling which agrees with experimental inhibition results[2]. We emphasize that currently sidelined compounds became active and revealed a significant increase in inhibition against the pathogenic gram-negative strain, <i>Pseudomonas aeruginosa</i>. The results demonstrate that lipid nanocarrier encapsulation may alleviate a range of challenges faced by antibiotic therapies and increase the range of antibiotics available to treat bacterial infections.<br/><br/>[1] Dyett, B. P.; Yu, H.; Sarkar, S.; Strachan, J. B.; Drummond, C. J.; Conn, C. E. 2021 Uptake Dynamics of Cubosome Nanocarriers at Bacterial Surfaces and the Routes for Cargo Internalization. ACS Appl. Mater. Interfaces , 13 (45), 53530–53540.<br/>[2] Dyett, B.P., Sarkar, S., Yu, H., Strachan, J., Drummond, C.J. and Conn, C.E. 2024. Overcoming Therapeutic Challenges of Antibiotic Delivery with Cubosome Lipid Nanocarriers. <i>ACS Applied Materials & Interfaces</i>, <i>16</i>(19), pp.24191-24205.