TNF Bound to PEGylated Gold Nanoparticles: a Platform for a Family of Cancer Nanomedicines

L. Tamarkin, G.F. Paciotti
CytImmune Sciences Inc., US

Keywords: gold, nanoparticles, cancer

Summary:

The use of nano-sized drug delivery systems to target potent, but toxic anticancer therapeutics to solid tumors is best accomplished by avoiding the drug’s uptake by the immune system and by limiting its biodistribution. Binding recombinant human tumor necrosis factor alpha (TNF) to the surface of 27 nm PEGylated colloidal gold particles (CYT-6091) meets these objectives. Each component serves a specific function. The gold nanoparticles limit biodistribution, while PEGylation prevents immune detection. TNF serves to actively localize nanoparticles to tumor, causing vascular disruption of the tumor blood supply. This action is why systemically administered TNF is clinically ineffective, since it causes vascular leak of healthy blood vessels. However, using the surgical procedure, isolated limb perfusion (ILP), infusion of native TNF followed by chemotherapy is dramatically effective in reducing tumors on arms and legs. CYT-6091 seeks to mimic the ILP clinical experience. In a Phase I clinical trial, systemically administered CYT-6091 was safe at potentially therapeutic levels of TNF. Core biopsies of tumor and healthy tissue revealed that CYT-6091 trafficked to tumors, not healthy organs. Mimicking the ILP protocol, CYT-6091 will be combined with standard of care chemotherapy in a Phase II clinical trial. However, the ideal nanomedicine delivers both TNF and chemotherapy to tumors. This design has been accomplished by binding an analog of paclitaxel to TNF-bound PEGylated gold nanoparticles (CYT-20000). While TNF on CYT-20000 enables rapid tumor targeting, paclitaxel is slowly released at the tumor site. These data demonstrate that two hydrophilic molecules, a biologic (TNF) and an immune avoiding molecule (PEG), and a hydrophobic, small molecule therapeutic (paclitaxel) may be bound simultaneously to same gold nanoparticle, highlighting a tunable and scalable manufacturing process that is the basis for a family of nanomedicines.