Cancer Targeting through Drug Conjugates

University Of Illinois At Urbana-Champaign, Urbana IL

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Abstract

Abstract Improving the accumulation of drugs in cancer and minimizing their exposure to other parts of the body have been pursued to achieve targeted cancer therapy. The key challenge lies in the identification of `unique' receptors in cancer area and development of corresponding targeting ligands. Several types of targeting ligands including folate, small peptides, and aptamers have been developed. However, their corresponding receptors are rarely cancer specific and the binding affinity between protein receptors and these ligands is relatively low. Monoclonal antibody (mAb) has been developed as by far the most promising targeting technology. Advances in this area have made it possible to create a mAb specific to almost any extracellular/cell surface protein, and several cancer-exclusive proteins have been identified. Despite being the most successful targeting ligands in clinic currently, mAbs suffer from multiple drawbacks such as high production cost, severe immunogenicity, receptor saturation, and poor solid tumor penetration. In addition, each mAb developed only works well for certain types of cancer because the targeted protein receptors vary from cancer to cancer. Completely different from conventional targeting strategies, we propose a general cancer targeting strategy making use of cell surface sugars as receptors. By selectively labeling cancer cell surface with azido groups through intravenously injected Ac3ManAzO-P which can be activated by histone deacetylase and cathepsin L, cancer cells could be well targeted by dibenzocyclooctyne (DBCO)-drug conjugates via efficient copper-free click chemistry. We have designed a library of sugar derivatives that could label cell surface with azido groups only in the presence of specific triggers. One of these sugar compounds, E-S, Enzymatically-responsive Sugar, is activated only in the co-presence of histone deacetylase and cathepsin L, thus possessing excellent selective labeling capability. By optimizing the structure and property of E-S, we may achieve selective labeling of cancer cells in vivo and develop this targeting strategy into a potentially clinically applicable technology for cancer treatment.