Photodynamic Therapy Pre-Targeting to Enhance Selectivity of Drug Delivery
Laser scanning confocal fluorescence images of control (left) and PDT-treated (right) tumors in vivo, with blood vessels stained green and ICAM-1 stained red.
The dose and the frequency of administration of systemically administered chemotherapies are routinely limited by serious toxicities, which include immune suppression, reduced platelet counts, and anemia. Molecular therapies such as gene and RNAi therapy are also limited by difficulties in achieving therapeutic concentrations at the tumor site. Thus, there is great interest in improving the selectivity and delivery of all forms of systemically administered anti-cancer therapies.
In collaboration with the Benoit lab, the Foster lab is investigating approaches to enhance delivery and selectivity of drugs by pre-treating the tumor with photodynamic therapy (PDT), which leads to the local expression of cell-surface targets toward which appropriately packaged therapeutic agents can be directed. Specifically, we are studying PDT induction of the cell surface protein intercellular adhesion molecule 1 (ICAM-1). Antibodies against ICAM-1 will be conjugated to micelles - drug-delivery vehicles capable of efficiently packaging hydrophobic molecules. Our work is guided by the hypothesis that targeting these micelles to ICAM-1 in PDT-pre-treated tumors will result in significantly increased accumulation.
Using fluorescence-based molecular imaging and flow cytometry, we are determining the magnitude of targeted micelle accumulation, its spatial extent relative to tumor blood vessels, and the specific cell types - tumor and tumor-resident host cells - expressing ICAM-1 in response to PDT. Knowledge of the cell populations targeted using this strategy may suggest novel therapeutic approaches. These studies represent the first use of PDT or, to the best of our knowledge, any FDA-approved therapy, as a means of creating local targets to enhance the delivery and selectivity of a second, systemic therapy.