(156h) Single-Walled Carbon Nanotubes Targeted to the Tumor Vasculature for the Treatment of Breast Cancer

While nanoparticles have a large potential to be used to improve the treatment of cancer, a major barrier of further development is the navigation of the nanoparticle from its point of introduction into the body to its final destination.  A new cancer treatment system is being developed with the goal of delivering single-walled carbon nanotubes (SWNTs) to the tumor rapidly and efficiently.  This system uses SWNTs that are functionalized with the protein annexin V or the F3 peptide.  Annexin V binds selectively to anionic phospholipids such as phosphatidylserine (PS).  PS exposure on the outer cell membrane is almost completely exclusive to cancer cells and endothelial cells that line the tumor vasculature.  F3, a fragment of the high mobility group protein, is a 31-amino acid peptide that has been shown to home to the nuclei of tumor vasculature cells and tumor cells and bind to the cell surface nucleolin receptor and become internalized.  In a treatment of cancer by this system, SWNTs bound to the tumor vasculature are exposed to near-infrared light (NIR) at a wavelength that heats the SWNTS but not the surrounding normal tissue, resulting in the tumor being destroyed.    

In this study, we have covalently coupled the human protein annexin V or the F3 peptide to a phospholipid-polyethylene glycol-maleimide linker that is strongly adsorbed to the SWNTs by the phospholipid in the linker.  We avoided covalently coupling the protein to the SWNT sidewall to avoid loss of the NIR absorption by the SWNTs.  Using non-confluent human endothelial cells in vitro, there was a significant loss of cell viability in cells that had been treated with the SWNT-annexin V or SWNT-F3 conjugate, washed, and then exposed to NIR light.  We have found that non-confluent endothelial cells mimic these cells in the tumor vasculature in their expression of PS on the cell surface.  Results of using this treatment in immune competent mice implanted with 4T1 murine mammary cancer cells will be reported.  This treatment was also combined with simultaneous administration of the immunostimulant cycylophosphamide, which is known to deplete regulatory T cells.  Regulatory T cells are believed to block antitumor immune responses mediated by tumor-specific T cells.