Scholars 2006

2006 Future - Cancer Therapy

Yacoby Iftach

Tel Aviv University, Department of Molecular Microbiology and Biotechnology

"Targeted Drug Carrying Viruses"

January 2019


August 2006

Bacteriophages have been used for over a century for Lab tool and (unorthodox) therapy of bacterial infections. Here I present a novel application of filamentous bacteriophages (phages) as targeted drug carriers for the eradication of cancer or (pathogenic) bacteria. The phages are genetically-modified to display the antibody Fc-binding ZZ domain of protein A as a fusion protein to the minor phage coat protein III, which enables the phage to from a stable complex with target-specific IgG's. In addition, the phages are used to deliver a large payload (about 10,000 drug molecules/phage) of the cytotoxic drug doxorubicin for cancer or chloramphenicol for pathogenic bacteria.

The drug is linked to the phages by a cleavable peptide or ester bond (respectively) subject to controlled release by lysosomal cathepsin or serum esterases (respectively). The large carrying capacity of such a hydrophobic drugs was made possible by our linking the drugs to the phage coat through aminoglycosides that served as solubility-enhancing, branched linkers. In the conjugated state the drug is in fact a pro-drug devoid of cytotoxic activity and is activated following its release from the phage at the target site. Our model targets are the breast cancer Erb2 and the following pathogenic bacteria: the Gram positive, MRSA Staphylococcus aureus COL ; Streptococcus pyogenes and the Gram negative E.coli O78 (781) bacteria.

I demonstrated a complete inhibition of growth in all of them, and a potency improvement by factor of ~10,000 in comparison to free doxorubicin or chloramphenicol. This approach replaces the selectivity of the drug itself with target selectivity born by the targeting moiety, which may allow the use and re-introduction of "non-specific" drugs that have thus far been excluded from use (due to toxicity or low selectivity). The re-introduction of such drugs into the useful arsenal of tools may help to combat cancer and the emerging bacterial antibiotic resistance.