| The therapeutic effect of many small molecule chemotherapeutic agents is limited by their severe off-target toxicities. Drug delivery systems, such as liposomes, can be employed to increase drug selectivity, leading to improved therapeutic activity and/or reduced off-target toxicity. The benefits of combination chemotherapy can also be exploited using nanomedicines -- targeted or untargeted liposomal anti-cancer agents can be administered in combination with free or liposomal formulations of other drugs. This thesis examines two different approaches to the utilization of liposomes in combination cancer chemotherapy for the treatment of solid tumors.;A novel formulation of irinotecan (Irinophore C(TM)) was investigated for its therapeutic activity in the treatment of colorectal cancer. In vitro experiments revealed the potential for anti-cancer synergy following simultaneous exposure to irinotecan and 5-fluorouracil, with sustained simultaneous exposure hypothesized to enhance synergy. In a subcutaneous xenograft model and an orthotopic model of colorectal cancer, treatment with Irinophore C(TM) was significantly more effective than treatment with free irinotecan, but did not benefit from combination with free 5-fluorouracil. The data presented in this thesis suggest that further examination of Irinophore C(TM) is warranted, possibly as a replacement for free irinotecan in colorectal cancer combination chemotherapy regimens.;Proof-of-concept studies explored a combined vasculature-targeted and tumor-targeted (dual-targeted) approach to the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Initial in vitro experiments with tumor-targeted and vasculature-targeted liposomes characterized their cellular association and cytotoxicity properties. NGR peptides and anti-HER2 Fab' fragments were selected as targeting ligands, based on pharmacokinetic/biodistribution studies. Although the order of administration of the vasculature-targeted and tumor-targeted formulations did not affect the therapeutic outcome, pre-treatment with vasculature-targeted liposomal drug produced a short window of increased tumor accumulation of a second dose of liposomes, which could be exploited for therapeutic benefit by altering the dosing schedule. Proof-of-concept therapeutic studies in an orthotopic breast cancer model revealed that liposomal drugs targeted to two different cell populations could be simultaneously administered at half the dose of tumor-targeted monotherapy, without compromising therapeutic effect. A dual-targeted treatment approach is applicable to a wide variety of solid tumors, and warrants further optimization and investigation. |
