Targeted delivery of siRNA using Q-starch modified by cetuximab for head and neck cancer therapy.

The scientific progress in cancer therapy, which is based on understanding molecular process inside cancerous cells, had brought to the development of biological medications that target a specific protein or a specific process inside cancer cells. One of those drugs is the synthetic antibody, cetuximab (Erbitux), who belongs to the receptors blockers family epidermal growth factor receptor (EGFR). This antibody is highly specific to cells expressing EGFR that are typical to certain types of cancers among which is head and neck cancer. The antibody-receptor binding delays the receptor’s activation and subsequent signal-transduction events leading to cell proliferation. One of the main issues related to this treatment is that along the treatment course, the cancer cells develop tolerance to the antibody and retune uncontrolled proliferation. Another approach, currently investigated, to treat cancer and genetic diseases is delivery of small interfering RNA (siRNA) by downregulating proteins that are involved with the cancer cascade. The main goal of this research is to exploit the specific features of the antibody to cancer cells overexpressing EGFR in order to deliver siRNA in a specific route to these cells. This delivery system is based on quaternized starch (Q-starch) as a carrier for siRNA which is biocompatible and bio-degradable therefore an attractive biopolymer for therapeutic purposes. In one hand, Q-starch assists siRNA to overcome biological barriers in its delivery pathway, and on the other hand, serves as a linker to the cetuximab to make this system highly specific to cancer cells without harming healthy organs.

So far, modified starch was successfully obtained by substitution with quaternary reagent, providing Q-starch the cationic property. The attachment of cetuximab antibody to Q-starch via PEGylation was also successful. The new carrier was able to interact with siRNA to form suitable complexes at N/P 1.5 (molar ratio between positive amine groups in Q-starch to negative phosphate groups in siRNA), at PBS medium. These complexes are characterized by size (D~200 nm), positive surface charge without damaging the cetuximab function. These properties are important for successful siRNA delivery and gene silencing, which will be examined in the next part of this study.