Viral and non-viral vectors have been intensively modified to include targeting elements to improve efficacy of tumor delivery. It is also desirable that cell-based carriers deliver a cargo in targeted fashion by either a natural or an engineered ability to home to tumor sites. However, targeting strategies for the cell carriers are not well developed. Attempts to apply targeting elements to the cell carriers was performed exclusively on T cells by introducing single chain fragment variable domains (scFvs) of antibodies as targeting moieties to the cell membrane. Possibility of transferring this approach to other cell types can broaden the range of cells for cancer applications. Among cell types tested as cellular vehicles, mesenchymal progenitor cells (MPCs) are a good candidate due to favorable combination of intrinsic properties. The ability of these cells to home to the sites of tissue injury or growing tumors makes them suitable for the cell-based delivery in cancer settings. This application seeks to apply a targeting approach to cell carriers to test our hypothesis that native tumor homing efficiency of MPC-based cell vectors can be modulated via expressing targeting moiety. Thus, together with fulfillments of the additional vector properties, such as loading with anti-cancer therapeutics, MPC may successfully serve as cell vehicles for gene delivery in cancer settings. This targeting strategy could be generally applicable not only to MPC but to other useful cell types currently are in testing as cell vehicles. In the long run,all targeting efforts would facilitate the delivery of more effective, less toxic cancer therapy.
Our Specific Aims (SA): SA 1: To design genetically targeted MPC via cell surface expression of tumor-specific single chain antibodies. SA 2: To evaluate targeting gains of MPC expressing targeting moieties in vivo using model system. SA 3: To evaluate therapeutic gains of targeted MPC loaded with anti- cancer therapeutics in a xenograft murine model.
| Roth, J C; Curiel, D T; Pereboeva, L (2008) Cell vehicle targeting strategies. Gene Ther 15:716-29 |
