Tao Wang Receives the 2011 John and Evelyn Neumeyer's Research
Tao Wang, a doctoral candidate in Professor Vladimir Torchilin's laboratory in the Center for Pharmaceutical Biotechnology and Nanomedicine received the 2011 John and Evelyn's Neumeyer's Research Award. Ms. Wang's doctoral dissertation is entitled "Landscape Phage Fusion Protein Self-Assembled with Pharmaceutical Nanocarriers for Targeted and Cytoplasmic Delivery of Chemotherapeutics to Breast Cancer Cells".
Conventional chemotherapy is often accompanied by severe side effects in cancer treatment owing to its inability to kill specifically tumor cells. The use of targeted pharmaceutical nanocarriers has improved pharmacokinetic and pharmacodynamic properties of chemotherapy. Ongoing challenges for targeted delivery include the search for alternative ligands ("substitute antibodies") and development of methods of their conjugation with nanomedicines. The phage display technique is emerging as a powerful tool to identify tumor recognition molecules. The objective of the project is to integrate phage display technology with nanocarrier-based drug delivery systems (liposomes and micelles) for advanced targeted drug delivery. The traditional phage display approach for targeted delivery assumes the necessity of a chemical synthesis of identified tumor-selective peptides and their conjugation with pharmaceuticals or pharmaceutical nanocarriers. Here, we developed an innovative approach using a landscape phage fusion protein (a tumor specific peptide fused to phage pVIII coat protein) to avoid drawbacks associated with chemical modifications. The novelty of the approach is its exploration of intrinsic properties of the landscape phage fusion protein. First, we utilized 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 also allows the construction of a mixed micelle self-assembled with the phage fusion protein and micellar-forming material, such as PEG-PE, for targeted delivery of hydrophobic drug. Last but not least, pH-sensitive carboxylic groups, appended to acidic amino acid residues within N-terminus of a MCF-7 specific landscape phage protein, add another layer of value to the phage protein-mediated delivery system, that facilitate endosome escape and cytoplasmic delivery of liposomal drugs. Therefore, the innovative landscape phage approach combined with drug-loaded nanocarriers for ligand-mediated tumor targeting and pH-sensitive controlled release is expected to enhance the efficacy of chemotherapeutics.
Our in vitro results are a proof of concept, showing that the phage pVIII coat protein displaying breast cancer cell MCF-7-targeting peptides can serve as an anchor for the integration of these peptides into doxorubicin-loaded liposomes or paclitaxel-loaded micelles to make them cancer cell-targeting and cytoplasmic delivery, and hence enhanced selective cytotoxicity towards target cancer cells rather than normal cells. The ongoing efforts in this direction will focus on the evaluation of the in vivo anti-tumor activity using an immune-compromised nude mouse MCF-7 tumor xenografted model.
We believe that the integration of nanotechnology with a combinatorial phage technique represents a paradigm shift in the development of efficient targeted nanomedicines. Our new approach may open the way for the use of inexpensive and easy-to-prepare fused phage proteins as "substitute antibodies" for site-specific targeted delivery of drugs and drug-loaded pharmaceutical nanocarriers to tumors.