Nanomedicine-based enhancement of chemotherapy

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 5718 CYT-6091 is a tumor-targeting nanomedicine that is assembled on 27 nm particles of pegylated colloidal gold (cAu). Our preclinical data in tumor-burdened mice reveal that CYT-6091 improves the safety of systemically administered TNF by altering the biodistribution of the cytokine. Additionally pegylation shields the nanoparticles from clearance by the reticuloendothelial system, while the size of cAu particles limits the drug’s biodistribution to the tumor due to the unique leakiness of the tumor vasculature. Ample preclinical and clinical data have shown that TNF is most effective as an anticancer therapy when given in combination with a chemotherapeutic agent, such as doxorubicin (Dox). Given that CYT-6091 is currently in a Phase I single agent clinical trial, its use in combination with Dox is a logical next step for an anticipated Phase Ib combinational clinical trial. The first experiment, conducted in B16/F10 tumor burdened C57BL/6 mice, was designed to establish a baseline response of these tumors to a single intravenous injection of TNF, CYT-6091 or a sub-optimal dose of Dox (2.5 mg/kg). In a second study, tumor-burdened animals received multiple injections of TNF or CYT-6091 alone. A separate group of animals received multiple treatments of CYT-6091 in combination with Dox (2.5 mg/kg; administered two hours after CYT-6091 injection). In each study, tumor volume was monitored over time. Single treatments with TNF, CYT-6091 or Dox were ineffective at slowing the growth of B16/F10 tumors. This held true for CYT-6091 although the nanodrug caused significant accumulation of TNF within these tumors. In contrast, repeated treatments with either TNF or CYT-6091 significantly inhibited tumor growth, resulting in a near 70% reduction in the size of the tumors when compared to controls. Consistent with previous observations, repeated injections with TNF proved very toxic resulting in a 75% mortality rate. Although multiple injections with Dox proved ineffective, the combination of CYT-6091 with Dox induced a synergistic response that was significantly more effective than either treatment alone. Compared to untreated controls, tumor growth for Dox alone, CYT-6091 alone and the CYT-6091/Dox combination group was inhibited by 24%, 62% and 94%, respectively. No overt signs of toxicity were noted for any group. CYT-6091 was recently shown to cause the selective disruption of the tumor neovasculature. These studies build upon those data and demonstrate that repeated exposure to CYT-6091 may, not only induce anti-angiogenic responses in tumors, but also selectively breakdown the tumor neovasculature to significantly improve the efficacy of chemotherapy.