? Antisense oligonucleotides have generated enormous interest as therapeutic molecules since their initial demonstration in 1978, but their full utilization as effective human therapies has been hampered by inadequate drug delivery to the correct cellular compartment of the correct tissue. We have designed a water-based, ultra-small nanocapsule formulation for targeted intracellular delivery of biologics to solid tumors. This delivery system takes advantage of caveolar endocytosis for highly efficient transit of nanocapsules and their cargo to the target cell's nucleus. The extremely small size of these particles (< 50 nm, """"""""s50"""""""") enables high tissue penetration and transdermal delivery via topical application offering creative options for drug delivery to pressurized solid tumors. ? ? Possession of a tumor-targeted delivery for biologics enables us to consider manipulation of extremely sensitive and potentially very effective targets for tumor eradication. The enzyme Casein Kinase 2 (CK2) is such a target as it: i) is consistently unregulated in all cancers studied to date; ii) correlates with poor clinical outcome; iii) is essential for cellular proliferation activity; and, iv) regulates apoptosis suppression as well as other validated chemotherapeutic targets, such as Topoisomerase 2 and histone deacetylase. In this proposal, building on promising initial animal studies, we will test feasibility of the s50 nanocapsule antisense CK2 therapeutic for clinical development in the treatment of recurrent squamous cell carcinoma of the head and neck (SSCHN), a grim disease with an approximate 30% five-year survival rate. In these studies, we will optimize the choice of backbone chemistry for the CK2 antisense molecule, then conduct in vitro studies and in vivo animal studies with the s50 nanoencapsulated molecule. Our focus in these studies will be on more aggressive SCCHN tumors; in particular, those tumors not expected to be treatable by experimental therapies currently in development. ? ? ?
