Lipid-Based Antimicrobial Delivery-Systems for the Treatment of Bacterial Infections

Abstract

Many nanotechnology-based antimicrobials and antimicrobial-delivery-systems have been developed over the past decades with the aim to provide alternatives to antibiotic treatment of infectious-biofilms across the human body. Antimicrobials can be loaded into nanocarriers to protect them against de-activation, and to reduce their toxicity and potential, harmful side-effects. Moreover, antimicrobial nanocarriers such as micelles, can be equipped with stealth and pH-responsive features that allow self-targeting and accumulation in infectious-biofilms at high concentrations. Micellar and liposomal nanocarriers differ in hydrophilicity of their outer-surface and inner-core. Micelles are self-assembled, spherical core-shell structures composed of single layers of surfactants, with hydrophilic head-groups and hydrophobic tail-groups pointing to the micellar core. Liposomes are composed of lipids, self-assembled into bilayers. The hydrophilic head of the lipids determines the surface properties of liposomes, while the hydrophobic tail, internal to the bilayer, determines the fluidity of liposomal-membranes. Therefore, whereas micelles can only be loaded with hydrophobic antimicrobials, hydrophilic antimicrobials can be encapsulated in the hydrophilic, aqueous core of liposomes and hydrophobic or amphiphilic antimicrobials can be inserted in the phospholipid bilayer. Nanotechnology-derived liposomes can be prepared with diameters <100-200 nm, required to prevent reticulo-endothelial rejection and allow penetration into infectious-biofilms. However, surface-functionalization of liposomes is considerably more difficult than of micelles, which explains while self-targeting, pH-responsive liposomes that find their way through the blood circulation toward infectious-biofilms are still challenging to prepare. Equally, development of liposomes that penetrate over the entire thickness of biofilms to provide deep killing of biofilm inhabitants still provides a challenge. The liposomal phospholipid bilayer easily fuses with bacterial cell membranes to release high antimicrobial-doses directly inside bacteria. Arguably, protection against de-activation of antibiotics in liposomal nanocarriers and their fusogenicity constitute the biggest advantage of liposomal antimicrobial carriers over antimicrobials free in solution. Many Gram-negative and Gram-positive bacterial strains, resistant to specific antibiotics, Wang et al. Lipid-Based Antimicrobial Delivery-Systems have been demonstrated to be susceptible to these antibiotics when encapsulated in liposomal nanocarriers. Recently, also progress has been made concerning large-scale production and long-term storage of liposomes. Therewith, the remaining challenges to develop self-targeting liposomes that penetrate, accumulate and kill deeply in infectious-biofilms remain worthwhile to pursue.

Liposomes as a Nanoplatform to Improve the Delivery of Antibiotics into Staphylococcus aureus Biofilms

“…Bacterial biofilms are composed of bacteria aggregates, involved in an extracellular matrix, containing proteins, polysaccharides and DNA [ 9 ]. This structure provides an excellent mechanism of defense, against immune response and blocks the antibiotic penetration, leading to extended hospitalization periods and high social costs [ 8 , 10 , 11 , 12 ].…”

“…Drug delivery systems play an important role to improve the safety and efficacy of loaded antibiotics, by allowing more appropriated pharmacokinetics and biodistribution profiles, thus improving the success of antimicrobial compounds already in clinical use [ 14 ]. Indeed, several nanotechnological platforms have been developed over the past decades, aiming to deliver the antibiotics at the infection sites and increase their penetration into biofilm structures [ 10 , 11 ].…”

Water-in-Oil-in-Water Nanoemulsions Containing Temulawak (Curcuma xanthorriza Roxb) and Red Dragon Fruit (Hylocereus polyrhizus) Extracts

“…The particle dispersed in an emulsion has a surface charge due to its attraction to a layer of oppositely charged particle; an electric double layer is thus generated [ 24 ]. An absolute value of zeta potential greater than 25 mV generally indicates a stable emulsion [ 21 , 37 , 38 , 39 ]. The zeta potentials of all nanoemulsions tested in this study were in the range –32.0 mV to –38.2 mV ( Table 1 ), which means that the w/o emulsion droplets were negatively charged.…”

Multicellular and unicellular responses of microbial biofilms to stress

“…Global stresses can be applied to biofilms by the addition of a stress-inducing component to the growth medium that can diffuse through the biofilm. For example, many antibiotics can easily diffuse through biofilms, yet highly charged or large antibiotics are prevented from diffusion, unless they are encased in special delivery systems (Diaz-Pascual et al 2019;Singh et al 2010;Tseng et al 2013;Wang et al 2020). Monitoring all individual cells in Vibrio cholerae biofilms during exposure to translational inhibitors revealed that these antibiotics could diffuse throughout the biofilm within minutes.…”