Basics for Improved Use of Phages for Therapy

Abstract

Blood-borne therapeutic phages and phage capsids increasingly reach therapeutic targets as they acquire more persistence, i.e., become more resistant to non-targeted removal from blood. Pathogenic bacteria are targets during classical phage therapy. Metastatic tumors are potential future targets, during use of drug delivery vehicles (DDVs) that are phage derived. Phage therapy has, to date, only sometimes been successful. One cause of failure is low phage persistence. A three-step strategy for increasing persistence is to increase (1) the speed of lytic phage isolation, (2) the diversity of phages isolated, and (3) the effectiveness and speed of screening phages for high persistence. The importance of high persistence-screening is illustrated by our finding here of persistence dramatically higher for coliphage T3 than for its relative, coliphage T7, in murine blood. Coliphage T4 is more persistent, long-term than T3. Pseudomonas chlororaphis phage 201phi2-1 has relatively low persistence. These data are obtained with phages co-inoculated and separately assayed. In addition, highly persistent phage T3 undergoes dispersal to several murine organs and displays tumor tropism in epithelial tissue (xenografted human oral squamous cell carcinoma). Dispersal is an asset for phage therapy, but a liability for phage-based DDVs. We propose increased focus on phage persistence—and dispersal—screening.

Biophysical Breakthroughs Projected for the Phage Therapy of Bacterial Disease

“…To test the accuracy of this latter assumption in a controlled way, we [33] recently assembled (1) a collection of four phages and (2) bacterial hosts to selectively plate each of the phages. These phages and bacteria were used to perform the first test of the blood lifetime (to be called persistence) of four different phages in one mouse.…”

Recent Progress in Phage‐Based Nanoplatforms for Tumor Therapy

“…The vectors need to possess three basic conditions: tumor homing, nonleakage of the drug, and persistence in the blood circulation. Based on the discovery of potential gating property of phage T4 vector, [ 121 ] Serwer and co‐workers loaded ethidium and bleomycin on phage T4 by high‐temperature gating and purified them. [ 122 ] The phage was safe and simple to prepare and purify.…”

A Perspective on Studies of Phage DNA Packaging Dynamics

“…As noted for DNA packaging above, strategy should be focused on identifying and solving the key problem that inhibits progress. We have made the points that (1) this problem is phage lifetime (also called phage persistence) in blood that is low and (2) persistence is highly variable among different phages, even phages that are related [ 25 ]. In other words, the lower the persistence is, the lower the chance that a phage will have a therapeutic effect.…”

“…Phage T4 has been shown to be gated for ethidium [ 47 ]; a phage T3 capsid has been shown to be gated for GelStar [ 48 ]. Both these phages exhibit high murine persistence [ 25 ], which is potentially as critical for a DDV as it is for phage therapy of infectious disease. Each newly isolated phage has the potential for having improved characteristics, including an increased EPR effect, for use as a gated DDV.…”

“…sistence [25], which is potentially as critical for a DDV as it is for phage the tious disease. Each newly isolated phage has the potential for having impro istics, including an increased EPR effect, for use as a gated DDV.…”