Formulation, stabilisation and encapsulation of bacteriophage for phage therapy

Malik, Danish and Sokolov, Ilya and Vinner, Gurinder and Mancuso, Franseco and Cinquerrui, Salvatore and Vladisavljevic, Goran and Clockie, Martha and Garton, Natalie and Stapley, Andrew and Kirpichnikova, Anna (2017) Formulation, stabilisation and encapsulation of bacteriophage for phage therapy. Advances in Colloid and Interface Science. ISSN 0001-8686 (Accepted for Publication)

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Abstract

Against a backdrop of global antibiotic resistance and increasing awareness of the importance of the
human microbiota, there has been resurgent interest in the potential use of bacteriophages for
therapeutic purposes, known as phage therapy. A number of phage therapy phase I and II clinical
trials have concluded, and shown phages don’t present significant adverse safety concerns. These
clinical trials used simple phage suspensions without any formulation and phage stability was of
secondary concern. Phages have a limited stability in solution, and undergo a significant drop in
phage titre during processing and storage which is unacceptable if phages are to become regulated
pharmaceuticals, where stable dosage and well defined pharmacokinetics and pharmacodynamics
are de rigueur. Animal studies have shown that the efficacy of phage therapy outcomes depend on
the phage concentration (i.e. the dose) delivered at the site of infection, and their ability to target and
kill bacteria, arresting bacterial growth and clearing the infection. In addition, in vitro and animal
studies have shown the importance of using phage cocktails rather than single phage preparations to
achieve better therapy outcomes. The in vivo reduction of phage concentration due to interactions
with host antibodies or other clearance mechanisms may necessitate repeated dosing of phages, or
sustained release approaches. Modelling of phage-bacterium population dynamics reinforces these
points. Surprisingly little attention has been devoted to the effect of formulation on phage therapy
outcomes, given the need for phage cocktails, where each phage within a cocktail may require
significantly different formulation to retain a high enough infective dose.
This review firstly looks at the clinical needs and challenges (informed through a review of key animal
studies evaluating phage therapy) associated with treatment of acute and chronic infections and the
drivers for phage encapsulation. An important driver for formulation and encapsulation is shelf life and
storage of phage to ensure reproducible dosages. Other drivers include formulation of phage for
encapsulation in micro- and nanoparticles for effective delivery, encapsulation in stimuli responsive
systems for triggered controlled or sustained release at the targeted site of infection. Encapsulation of
phage (e.g. in liposomes) may also be used to increase the circulation time of phage for treating
systemic infections, for prophylactic treatment or to treat intracellular infections. We then proceed to
document approaches used in the published literature on the formulation and stabilisation of phage for
storage and encapsulation of bacteriophage in micro- and nanostructured materials using freeze
drying (lyophilization), spray drying, in emulsions e.g. ointments, polymeric microparticles,
nanoparticles and liposomes. As phage therapy moves forward towards Phase III clinical trials, the
review concludes by looking at promising new approaches for micro- and nanoencapsulation of
phages and how these may address gaps in the field.

Item Type:	Article
Additional Information and Comments:	NOTICE: this is the author’s version of a work that was accepted for publication in Advances in Colloid and Interface Science. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Available at http://www.sciencedirect.com/science/article/pii/S000186861630392X
Keywords:	antibiotic resistance; bacteriophage; encapsulation; phage therapy; pharmacodynamics
Faculty / Department:	Faculty of Human and Digital Sciences > Mathematics and Computer Science
Depositing User:	Anna Kirpichnikova
Date Deposited:	07 Jun 2017 14:01
Last Modified:	31 Aug 2017 11:26
URI:	https://hira.hope.ac.uk/id/eprint/2025

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