In vivo characteristics of targeted drug-carrying filamentous bacteriophage nanomedicines

Abstract

BackgroundTargeted drug-carrying phage nanomedicines are a new class of nanomedicines that combines biological and chemical components into a modular nanometric drug delivery system. The core of the system is a filamentous phage particle that is produced in the bacterial host Escherichia coli. Target specificity is provided by a targeting moiety, usually an antibody that is displayed on the tip of the phage particle. A large drug payload is chemically conjugated to the protein coat of the phage via a chemically or genetically engineered linker that provides for controlled release of the drug after the particle homed to the target cell. Recently we have shown that targeted drug-carrying phage nanomedicines can be used to eradicate pathogenic bacteria and cultured tumor cells with great potentiation over the activity of the free untargeted drug. We have also shown that poorly water soluble drugs can be efficiently conjugated to the phage coat by applying hydrophilic aminoglycosides as branched solubility-enhancing linkers.ResultsWith an intention to move to animal experimentation of efficacy, we tested anti-bacterial drug-carrying phage nanomedicines for toxicity and immunogenicity and blood pharmacokinetics upon injection into mice. Here we show that anti-bacterial drug-carrying phage nanomedicines that carry the antibiotic chloramphenicol conjugated via an aminoglycoside linker are non-toxic to mice and are greatly reduced in immunogenicity in comparison to native phage particles or particles to which the drug is conjugated directly and are cleared from the blood more slowly in comparison to native phage particles.ConclusionOur results suggest that aminoglycosides may serve as branched solubility enhancing linkers for drug conjugation that also provide for a better safety profile of the targeted nanomedicine.

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“…Phage delivery of the lethal agents reduced target bacterial numbers by several orders of magnitude in vitro and in a bacteremic mouse model of infection [111]. Antibacterial agents such as chloramphenicol can be targeted to pathogenic bacteria using phage which display a bacteria-specific binding peptide along with covalently bound chloramphenicol carried on the surface of the phage as a pro-drug [112][113][114]. Given that, for example, M13 phage has the capacity to cross the gastrointestinal mucosal barrier with [115] or without [116] a displayed peptide facilitating uptake, this provides the possibility of oral delivery of a drug payload targeted to a pathogen or specific cell type in the body (e.g.…”

Bacteriophage-based tools: recent advances and novel applications

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1st French-Israeli International Conference on B Cells and therapeutic antibodies

“…Itai Benhar (The George S. Wise Faculty of Life Sciences - Tel Aviv University) then presented the production of a new method to produce IgG and IgG-cargo fusion molecule in bacteria, named “Inclonals” technology 23 . It is based on expert biochemical procedures starting with the different proteins (heavy and light chains of IgG, toxins) produced in bacterial cultures and present in insoluble inclusion bodies.…”