The failure of cancer chemotherapy to produce major improvements in survival rates for most types of cancer reflects the close biochemical similarity between cancer and non- cancer cells. Unfortunately, most drugs that can kill cancer cells are also highly toxic to normal cells, which limits the dose (and thus the effectiveness) of these drugs. The key measure of a drugs ability to target cancer cells specifically is the therapeutic index. Several strategies are used to improve the therapeutic index: (1) Use synergistic drug combinations with non-overlapping toxicity profiles, (2) Target processes that are particularly vital to the cancer cells, such as proliferation, suppression of apoptosis, and metastasis, and (3) Deliver the drugs preferentially to cancer cells. Even with these strategies, the impact of chemotherapy remains limited. We propose a novel and patent-protected strategy (Directed Synergy) for administration of synergistic drugs that has the potential to substantially increase the therapeutic index. By separately targeting two (or more) synergistic drugs to relatively cancer-specific cell surface receptors, the combined (synergistic) action is effectively limited to the cancer cells; other cells, which express one or other of these surface receptors will be exposed to, at most, one of the drugs. The greater the synergy, the greater the discrepancy between tumor cell kill and normal cell kill. We propose a set of in vitro experiments to develop and validate the Directed Synergy concept. Irinotecan and oxaliplatin will be formulated in liposomal nanoparticles, coated with ligands for surface markers known to be expressed by the experimental cell lines (TC71, Ewing's sarcoma and HRT-18, colon cancer). The TC71 surface markers will be transferrin, CD99 and EGFR, and the HRT-18 surface markers will be transferrin and EGFR. Cytotoxicity will be compared for cells binding both nanoparticles versus those binding just one type of nanoparticle versus those with both types of receptor blocked. The aim of phase I is to optimize drug combinations, delivery system, targeting ligands and cancer cell lines in preparation of the animal studies (in phase II) which will provide direct measures of improvement in therapeutic index achievable using the Directed Synergy approach. This proposal is for proof-of-principal experiments to validate Directed Synergy, a novel and patent-protected strategy for delivering targeted cancer drugs to maximize the therapeutic index. Two or more synergistic drugs are formulated for targeted delivery to separate markers found on the cancer cells. Only the cancer cells (receiving the combined, synergistic, effect of both drugs) are exposed to a lethal dose; non-cancer cells, which may have one or other of the cell-surface markers will be spared, being exposed to, at most, one drug
