The Pathways to Create Containers for Bacteriophage Delivery: Comparison
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Antimicrobial resistance is a global public health threat. One of the possible ways to solve this problem is phage therapy, but the instability of bacteriophages hinders the development of this approach. A bacteriophage delivery system that stabilizes the phage is one of the possible solutions to this problem. 

  • microcapsules
  • bacteriophage
  • E. coli
  • CaCO3
  • encapsulation
  • polyarginine
  • dextran sulfate

1. Introduction

Antimicrobial resistance occurs when bacteria of a certain type acquire the ability to protect themselves from antibiotics, which normally effectively disrupt their vital activity. It significantly complicates the treatment of infectious diseases that they cause. The Centers for Disease Control and Prevention reported that in the United States, the number of reported deaths due to antibiotic-resistant infections reaches 35,000 per year [1]. It is necessary to develop not only new antibiotics but also new methods of treating bacterial infections to slow down the emergence of resistant bacterial strains [2].
One of the possible ways to solve this problem is bacteriophages. Bacteriophages are viruses that can selectively infect the bacterial cells of one strain or antigenically homologous strains of the same species or genus. This infection is followed by lysis (after intracellular replication, except for temperate or chronic phages) of the bacterial host cell [3] and does not threaten eukaryotic cells. Phages are used as natural antimicrobial agents to fight bacterial infections in humans, animals and crops [4][5][6][7][8]. Bacteriophages are used in phage therapy. This is a direction in medicine that allows the treatment of bacterial infections by ingestion or local application of a specific polyvalent phage [9]. Phage therapy is rapidly developing around the world and has great prospects; however, the development of this strategy is hindered by the instability of the bacteriophage [10], especially in the acidic environment of the digestive system. Thus, it is necessary to develop effective delivery systems capable of protecting the bacteriophage from the external environment.

In work by Smith W. et al. [11], to increase the survival of the bacteriophage in the acidic environment of the stomach, its pH was changed by using a suspension of calcium carbonate. The calcium carbonate allows to neutralize the acidic environment and create favourable conditions for bacteriophages. However, the acidic environment of the stomach is necessary for the normal functioning of the gastrointestinal tract. In this way, it is necessary to preserve the survival of the bacteriophage without significantly changing the acidity of the digestive system. One of the ways to solve this problem is to encapsulate bacteriophages.

2. The Pathways to Create Containers for Bacteriophage Delivery

Both organic and inorganic particles can be used as containers for bacteriophages. Among inorganic particles, porous calcium phosphate particles are most often used as a carrier of bacteriophages [11][12]. J.C. Hornez et al. loaded 1 µm calcium phosphate beads and suggested using microspheres as a matrix for a local drug delivery system to prevent and cure infections associated with bone implants [12]. Musin E. et al. propose to include bacteriophages in CaCO3 spherulites [14]. Encapsulation of bacteriophages in CaCO3 allows to neutralize the acidic local environment around phages and create favourable conditions for them without having a critical effect on the pH of the stomach and digestive system.
Alginate is one of the most commonly used organic materials for bacteriophage encapsulation [13]. Alginate microcapsules possess mucoadhesive properties that allow them to entrap molecules higher than 10,000 Da [14]. However, this type of encapsulation is not suitable for all bacteriophages; therefore, it is necessary to study new methods for encapsulating phages [15]. Chitosan particles are the second most often used organic microparticles for bacteriophage delivery [14][16][17]. In addition to chitosan, other polymer compounds are used to create microcapsules: poly(ethylene oxide)/cellulose diacetate fibers [18], poly(acryl starch) and poly(lactide-co-glycolide) [19]. For example, Jamaledin R et al. used microparticles (MPs) made of poly(lactic-co-glycolic acid) (PLGA) to encapsulate fd bacteriophages, and it was revealed that the encapsulated bacteriophages were stable and retained their immunogenic properties. In addition, the combination of alginate with carrageenan, chitosan and whey protein was used for bacteriophage encapsulation, and these phages remained viable even when subjected to pH 2.5 for 2 h [20]. Thus, the use of polyelectrolytes is a promising direction for the encapsulation of bacteriophages [21].
Polyelectrolyte nano- and microcapsules (PMCs) are objects of a new rapidly developing field—polymer nanotechnology. They are made by alternately layering oppositely charged polyelectrolytes on dispersed nano- or microsized particles, with their subsequent destruction and removal [22][23][24]. Polyelectrolyte capsules are used as sensor systems for the determination of low-molecular-weight substances in multicomponent media [25][26][27][28][29], as delivery systems for biologically active components to cells and tissues [30][31][32][33] and as materials in the creation of prolonged-release medicines [34][35][36]. In this context, many works have been devoted to biocompatibility, biodistribution, biodegradation and clearance from the body [30][37]. In particular, S. De Koker et al. demonstrated that most of the polyelectrolyte microcapsules are internalized by the cells and start to degrade [38]. However, works devoted to the encapsulation of bacteriophages in polyelectrolyte microcapsules could not be found.
A specific destruction system of the PMC shell requires the successful delivery of bacteriophages. At the moment, there are several ways to decapsulate substances from polyelectrolyte microcapsules: using light (by destroying photosensitive polymers) [39], using a constant magnetic field (due to the presence of a magnetic core particle in the PMC shell) [40], with the help of proteolytic enzymes (in this case, the PMC shell consists of biodegradable polyelectrolytes) [41], by changing the pH of the medium [42], with the help of bacterial spores (due to the germination of bacterial spores on a nutrient medium) [43] and other methods.
It is necessary to study the effect of polyelectrolytes on phage activity to encapsulate bacteriophages in PMCs while maintaining their activity. At the moment, this problem remains under-researched and is discussed in only a few publications, which did not study the effect of polyanions on the activity of bacteriophages. Few studies have demonstrated a decrease in phage activity in the presence of polyamino acids. In particular, most of the works are devoted to the antiviral and antibacterial properties of polylysine [44][45]. For example, S. Shima et al. [46] showed that the cationic polyelectrolyte poly-L-lysine caused a 2.5-fold reduction in the activity of the bacteriophage at a polymer concentration of 10 μg/mL; at a concentration of 1 mg/mL, complete inactivation of the T4 bacteriophage was observed. In addition, polyelectrolytes based on amino acids, such as poly-y-methyl-γ, L-glutamate and poly-N-(p-aminoethyl) glutamine, were synthesized, and they also reduced the activity of bacteriophages T4 and T5 [47].

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