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Landscape Phage Fusion Protein Self-assembled with Pharmaceutical Nanocarriers for Targeted and Cytoplasmic Delivery of Chemotherapeutics to Breast Cancer Cells

T. Wang, V.A. Petrenko, V.P. Torchilin
Northeastern University, US

Keywords: targeted delivery, liposome, micelle, phage fusion protein, breast cancer


The objective of the project is to integrate phage display technology with pharmaceutical nanocarriers (liposomes and micelles) for improved cancer treatment by targeted and cytoplasmic delivery of chemotherapeutics to breast cancer MCF-7 cells. We developed an innovative approach using a landscape phage fusion protein (a tumor specific peptide fused to phage pVIII coat protein) for its self-assembly with liposomes for delivery of doxorubicin (phage-Doxil). The approach exploits the unique propensity of phage coat proteins to incorporate spontaneously into lipid bilayers to form liposomal particles mimicking the structure of phage proteins in bacterial membranes. Furthermore, the amiphiphilic nature of phage fusion protein was explored to construct a micelle formulation (phage-micelle) self-assembled with the phage fusion proteins and PEG-PE conjugates for targeted delivery of hydrophobic paclitaxel. Both phage-Doxil and phage-micelles showed specifical targeting to MCF-7 cells and higher cytotoxicity towards target cells than non-targeted formulations, but this effect was absent with non-target cells. We found that the internalization of phage-liposomes follows an endocytosis pathway, and that the phage protein possesses a pH-dependent fusogenic property providing the endosomal-escape of such liposomes. Accordingly, the substantial increase in the efficiency of target cancer cell killing by phage-Doxil compared to Doxil is a result of an advantageous combination of cell targeting and endosomal escape of drug-loaded nanocarrier.
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