Abstract 3695: CYT-20000: Targeted and temporal delivery of a VDA and chemotherapy by a single gold nanodrug
Authors: Giulio F. Paciotti, Lawrence Tamarkin, Jielu Zhao, Shugeng Cao, Shugeng Cao, David G.I. Kingston
Journal: Cancer Research (2010)

Abstract Clinically, surgical isolation and local perfusion of intractable tumor bearing limbs with a vascular disrupting agent (VDA) and a chemotherapy is highly effective. CYT-20000 is a gold nanoparticle-based drug that delivers TNF (a VDA) and an inactive paclitaxel prodrug to any solid tumor, without the need for surgery. The nanotherapy is manufactured by covalently linking TNF and a thiolated paclitaxel prodrug onto the surface of 27-nm PEGylated colloidal gold (cAu) particles. Each component of the nanodrug serves a specific function. PEG-THIOL shields the nanotherapy from clearance by the reticuloendothelial system, while the size of cAu particles limits the drug's biodistribution to the tumor. CYT-20000 utilizes the EPR effect to gain initial entry into the solid tumor environment. Subsequently, the cAu-bound TNF, by binding to its receptor anchors the nanotherapy along with its cAu-bound paclitaxel prodrug within the tumor. Finally, the paclitaxel prodrug undergoes hydrolysis, via breakdown of a carbonate linker, to generate paclitaxel within the tumor. The design of CYT-20000 comes from the successful, ongoing clinical experience with the perfusion of in-transit, drug resistant tumors on patients’ arms or legs (isolated limb perfusion (ILP)). Performing this surgical procedure just once results in 70-85% response rates. Key to achieving these remarkable response rates is not only limiting the biodistribution of the APIs to the tumor bearing limb, but also the order of their perfusion. Maximum efficacy is seen only when TNF is perfused 0.5-1 h prior to the chemotherapy. Clinical data suggest that TNF breaks down the tumor neovasculature leading to enhanced uptake of the chemotherapy. Reversing the order by perfusing the chemotherapy first is ineffective. Systemically administered CYT-20000 achieves both of these critical actions, breaking down the tumor vasculature and then slowly releasing the chemotherapy within the tumor. First, preclinical data show that PEGylated cAu-TNF induces progressive vascular disruption as 30-180 minutes following its administration vascular leak is seen at the boundary of the tumor neovasculature. Second, PEGylated cAu bound with the paclitaxel prodrug alone (i.e., no TNF) shows significantly less uptake in the tumor. Third, the thiolated paclitaxel prodrug bound to the cAu particles does not undergo hydrolytic conversion in the circulation as little to no paclitaxel is detected in the blood. In contrast, PD data reveal a 6-12 hour latency period between the arrival of CYT-20000 in the tumor and the detection of paclitaxel. The combination of TNF-mediated vascular targeting coupled with the improved delivery of the paclitaxel prodrug and its slow conversion to paclitaxel in the tumor mimics the ILP and is consistent with CYT-20000's ability to induce paclitaxel mediated anti-tumor responses at significantly lower doses of chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3695.