A Bio-mimetic Approach to Design a Targeted Drug Delivery System

Abstract

Bacterial resistance is rapidly emerging worldwide, endangering the efficacy of existing antibiotics. As a result, extensive research is being done on the development of new antimicrobials; however, these new drugs could be toxic. An effective targeted drug delivery technique, which could increase the local drug concentrations at the site of infection, is an ideal tool to reduce drug toxicity and enhance drug efficacy. Here, we aim to develop a novel hetero-multivalent targeted liposome system to deliver antibiotics by mimicking the process of bacterial adherence to epithelia. Here, we particularly focus on Pseudomonas aeruginosa, because P. aeruginosa is among the top three pathogens that are in a critical need of new antibiotics.

Inspired by the nature of bacterial adhesion to the host cells, we have discovered previously unknown molecules from host cells that mediate the bacterial adhesion. P. aeruginosa interaction with host cells is primarily mediated by the adhesion of bacterial lectins (carbohydrate binding proteins) to glycans (carbohydrates) on host cell surfaces. We have investigated the role of multiple glycolipids and the fluidity of cell membrane in two different multivalent binding systems, including pentavalent cholera toxin subunit B (CTB) and tetravalent P. aeruginosa lectin PA-IL (LecA). Based on the experimental observations, we have proposed a hetero-multivalent binding mechanism based on Reduction in Dimensionality (RD), which might be playing a major role in the bacterial adhesion. Kinetic Monte Carlo (kMC) simulations were then used to further validate these experimental observations and the hetero-multivalent binding.

We then used these new ligands as targeting ligands on the surface of liposomal carriers to mimic the host cell membrane environment. Because the liposomal drug carriers are made of host cell molecules, the whole assembly poses minimal toxicity and immunogenicity. A two times higher targeting efficiency was achieved. Furthermore, the antimicrobial activity of a common antibiotic, ciprofloxacin, was evaluated using this targeted drug delivery system and showed higher drug efficacy in vitro and in vivo compared to non-targeted liposomes and free drug. We envisage that this research will lead to development of similar drug delivery systems for treatment against other pathogens too.