Cancer Therapy via Intranasal Administration of Cancer Cell Targeted Ff Phages Conjugated to Chemotherapy Agents

Ff bacteriophages (phages) are non-lytic Escherichia coli viruses widely used in various phage display applications for their capacity to present foreign peptides and proteins fused to their coat proteins (usually P3, P8) . Ff phages have been previously demonstrated to:

1. Accumulate rapidly (within minutes) in the brain, lungs and stomach of mice following intranasal delivery.
2. Interact with Tie2, a tyrosine kinase receptor predominantly expressed on the surface of endothelial cells , and inhibit endothelial cell activity, angiogenesis and tumor growth.
3. Act as immunomodulators and skew tumor associated macrophages (TAM’s) polarization towards the anti-angiogenic and anti-tumorigenic M1 phenotype, leading to infiltration of cytotoxic neutrophils into the tumor microenvironment and tumor rejection.

Collectively, these observations prompted us to evaluate the feasibility of treating brain and lung malignancies via intranasal administration of Ff phages. Treatment of mice bearing aggressive brain and lung tumors (glioblastoma and lung carcinoma respectively) with purified, wild-type like Ff phages delivered through the intranasal route, attenuated tumor progression and prolonged survival rate in both models without any apparent toxic effect. The main objective of the current project is to improve the anti-tumorigenic activity of phages by conjugating chemotherapy agents such as Paclitaxel to their coat proteins and deliver them selectively into lung tumors via the intranasal route. Furthermore, as brain metastases are found in 40-50% of the lung cancer patients, we also wish to evaluate the efficacy of the conjugate in inhibiting brain metastases following intranasal administration. By coupling chemotherapy agents such as Paclitaxel to Ff phages we hope to achieve an additive or synergistic effect on tumor progression while overcoming some of the drawbacks that limit Paclitaxel use in cancer therapy.