(Verbatim from the application): We will devise novel cell surface receptor-targeting carbohydrate ligands and a method to attach them to drug carrier surfaces. These will provide a robust, versatile and efficient system for targeting drugs associated with drug carriers to tumors, in vivo. We will use these ligands to test the hypothesis that drugs, encapsulated in liposomes with appropriate drug retention and circulatory residence time characteristics, exhibit substantially increased potency when targeted to tumors compared to other modes of delivery. We will evaluate our hypothesis by completing the following specific aims: 1. Construct targeting ligands and attach them to liposomes, 2. Quantify binding and potency of targeted doxorubicin-containing liposomes to tumor target cells in vitro, 3. Quantify localization and internalization of targeted liposomes to tumor cells in mice, 4. Evaluate anti-tumor efficacy of targeted liposomal drugs in murine tumor models. We specifically propose that the conjugation/association of low molecular weight hyaluronan oligomers to lipids and their incorporation into a liposome bilayer can be used to increase the therapeutic index of a liposome encapsulated drug via selective delivery to CD44 overexpressing cancer cells. Hyaluronan is a glycoaminoglycan that can bind to CD44/RHAMM receptors found in various tumors and especially in lung tumors. Low molecular weight hyaluronan fragments have a low affinity for the CD44 receptor. However, our preliminary results show that when they are attached to a lipid, incorporated into a liposome bilayer (HAL) they confer a high avidity to the liposome for CD44 expressing cells and the HAL are internalized into the cell. This system (hyaluronan ligand, liposome, B16F10 tumor) is ideal for the quantitative evaluation of the effects of other modifications (drug type, ligane type, method to attach the ligand to the liposome surface and lipid compositin) on the in vivo potency of liposome encapsulated drugs. Liposomes targeted to the CD44 receptor and optimized for extended circulation could be a widely applicable tumor targeting drug carrier that provides superior therapy when compared to other drug delivery modalities.
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