Bacteriophages are a massively diverse group of bacterial viruses and are often cited as the most abundant organisms on the planet. Although the abundance of natural phages means that they...
Targeted drug delivery strategies are a vital part of the pipeline in converting a promising drug into a successful therapeutic strategy. Evolving drug delivery strategies are necessary to keep up with the ever-changing therapeutic landscape and to overcome challenges with previously successful therapeutics, for example, in dealing with the antimicrobial resistance (AMR) epidemic.
The five main therapeutic classes are small molecules, proteins and peptides, antibodies, nucleic acids, and live cells; all of which have huge therapeutic benefits in various applications. However, their delivery poses some challenges, particularly regarding stability, intracellular delivery requirements, and viability. The evolution of novel drug delivery strategies aims to address such challenges. A drug delivery system describes the packaging and method of delivery of a drug into the body, which allows it to travel safely through the body to the target area. Delivery routes include swallowing, inhalation, injection, or absorption through the skin. Drug delivery vehicles include micelles, coated microparticles, hydrogels, and implants. A targeted drug delivery system that has gained attention recently is nanocarriers. These include liposomes, polymers, nanoparticles, stem cells, and viruses, such as bacteriophages.
Bacteriophages, commonly known as phages, are abundant viruses that selectively target and kill specific species of bacteria. Most phages contain a protein capsid surrounding nucleic acid (DNA or RNA) and a tail. They infect bacteria and replicate within them, selectively killing the bacterial host. They do this by attaching to a susceptible host, introducing their genome into the host cytoplasm, and replicating by lytic or lysogenic replication. Phages are incredibly diverse in their morphology, genomic organisation, and host species. Though they do not naturally infect eukaryotic cells, they play vital roles in human immunity and microbiome maintenance.
Bacteriophages have been used therapeutically to some extent for over 100 years, and their unique properties make them highly attractive drug delivery systems. Firstly, phages have a huge surface-bearing capacity and genetic tractability, which means they can easily be loaded with drugs, either by chemical conjugation onto the phage surface or inserting genes into the phage genome by recombinant DNA technology. Phage surface proteins or peptides can conjugate with and self-assemble into nanoparticles, enabling specific targeting and high drug-loading capacities.
Lytic phages are naturally successful bactericidal agents, meaning bacteria cannot retain or regain viability after infection. This is advantageous over traditional anti-bacterial therapies such as antibiotics, some of which are bacteriostatic, meaning that some bacteria can regain viability, encouraging resistance. Phages’ high host specificity further narrows the potential for resistance and minimises disruption to the gut microbiome.
Phages are also very practical as delivery vehicles. Firstly, phages have “auto-dosing” properties; this refers to the ability of phages to increase in number in a target area, meaning very low and even single doses can be used, reducing treatment costs. Due to their composition, phages are inherently non-toxic to the body and the environment. They are easily and quickly discovered, often from bacteria-abundant waste or sewage. They have flexible genetic engineering properties and are very versatile in terms of application, and can be combined with other phages, antibiotics, or chemical drugs where necessary.
However, there are some disadvantages to phage-based drug delivery. Firstly, although phages are easily discovered and manipulated, phage characterisation and isolation can be technically demanding. Bacteriophages are relatively unstable in vivo, meaning delivery strategies must be optimised to shield phages from harsh environmental factors such as acidic pH and enzymatic activity. Furthermore, their instability poses problems for production and storage. Though resistance potential is much lower than with antibiotics, the emergence of phage-insensitive mutants is almost inevitable.
Bacteriophages have proven vital in the fight against AMR via several strategies. First, bacteriophages can be used in place of antibiotics, due to their much lower propensity for promoting resistance. Alternatively, phages have been used in combination with antibiotics or for the delivery of antibiotics. This is particularly useful for combating biofilms, and studies have shown that phage pre-treatment reduces the concentration of antibiotics required to successfully treat infections. Finally, a study highlighted the ability of phages to re-sensitise bacteria to antibiotics, by reintroducing sensitivity genes to resistant bacteria.
Recently, evidence has emerged describing bacteriophages as potentially useful cancer therapeutics, due to their host specificity and ability to transfer cargo into host cells. Engineered phages have displayed high efficiency and safety as vehicles for the delivery of genes and drugs into eukaryotic cancer cells. Phages naturally have a lower efficiency for crossing mammalian cell barriers, and a recent study showed how this could be overcome by introducing a phage/polymer complex, which achieved greater cancer cell killing than phage alone. Another recent study showed selective, efficient phage particle-mediated gene delivery to chondrosarcoma cells, which resulted in cancer cell death. Repeated phage administration in a mouse model resulted in tumour suppression, while another study showed a phage-based system as an effective immunotherapy against solid tumours, highlighting the potential of phage as a cancer therapeutic.
The inherent antimicrobial properties of bacteriophages mean they have been used therapeutically for many years, but in recent years they have seen a rise in popularity as drug delivery systems, promoting their use for treating a more broad range of conditions. There are clear advantages to using phages as drug delivery systems for antibiotics and cancer therapeutics. While many studies have shown their success in these areas, further research is required to optimise phage-mediated drug delivery and overcome associated challenges. The rising trend in bacteriophages as delivery systems, coupled with the current AMR epidemic, leads to the prediction that phage-based drug delivery will continue to be optimised for treating many more conditions in the near future.