Abstract:
The goal of the research described in this thesis is to develop a liposome based drug delivery system which targets Her-2 overexpressing breast tumors with high specificity. Overexpression of the Her-2 receptor occurs in many cancers but is most prevalent in breast tumors, with 20--30 percent of all cases displaying overexpression of the receptor. In addition, Her-2 overexpressing breast tumors are often aggressive and have a high probability of metastasizing. In the research reported here, a drug delivery system has been created that selectively targets Her-2 overexpressing mammary cells by combining three liposomal technologies. First, a Her-2 targeting antibody was conjugated to the outer surface of the liposomes, resulting in highly specific binding and internalization of liposomes into mammary epithelial cells that overexpress Her-2. Second, the liposomes were designed to be thermosensitive, only releasing their encapsulated cargo in response to mild hyperthermia at 42�C. Finally, the liposomes were attached to a pore-forming protein, listeriolysin O (LLO), which compromises the target cell endosome, allowing for drug delivery directly to the cellular cytoplasm. The liposomes delivered a 22-fold higher concentration of fluorescent marker to cells overexpressing Her-2 than to normal cells, demonstrating the delivery system's potential for targeting Her-2 overexpressing tumors. When a cytotoxin, gelonin, was encapsulated within the liposomes, the delivery system selectively targeted and killed Her-2 overexpressing cells in vitro. To further increase specificity for Her-2 overexpressing cells, the concept of a two-component delivery system was explored. This system would require internalization of two different types of liposomes within a cell endosome for effective drug delivery. Experiments using fluorescent markers show that this method greatly increased targeting specificity for Her-2 overexpressing cells.
